阅读说明：本技术 经取代的己糖醇类用于治疗恶性肿瘤的用途 (Use of substituted hexitols for the treatment of malignant tumors ) 是由 J·巴沙 S·杜恩 D·布朗 于 2013-01-22 设计创作，主要内容包括：本发明涉及经取代的己糖醇类用于治疗恶性肿瘤的用途。使用二脱水半乳糖醇提供一种新颖的治疗方式以治疗多形性胶质母细胞瘤和成神经管细胞瘤。二脱水半乳糖醇作为烷化剂而作用于DNA上引起N<Sup>7</Sup>甲基化。二脱水半乳糖醇是对抑制癌症干细胞的生长有效并有抵抗耐替莫唑胺的肿瘤的活性；药物作用与于MGMT修复机转无关。(The present invention relates to the use of substituted hexitols for the treatment of malignancies. The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of glioblastoma multiforme and medulloblastoma. Dianhydrogalactitol acts on DNA as an alkylating agent to cause N 7 And (4) methylation. Dianhydrogalactitol is effective in inhibiting the growth of cancer stem cells and has activity against temozolomide-resistant tumors; the drug effect was independent of MGMT repair machinery.)

1. A Chinese medicinal composition is prepared by mixing effective amount of Chinese medicinal materialsUse of substituted hexitol derivatives of the group consisting of galactitol, diacetyldianhydrogalactitol and dibromodulcitol for the preparation of a medicament for the treatment of diseases with O⁶-methylguanine-DNA-methyltransferase driven resistant malignancies.

2. The use of claim 1, wherein the malignant tumor is glioblastoma multiforme.

3. The use of claim 1, wherein the malignancy is characterized by an MGMT gene having a methylated promoter.

4. The use of claim 1, wherein the malignant tumor is a glioblastoma multiforme resistant to temozolomide.

5. Use according to claim 1, wherein the substituted hexitol derivative is dianhydrogalactitol.

6. The use of claim 5 wherein the therapeutically effective amount of dianhydrogalactitol is about 1mg/m²To about 40mg/m²。

7. The use of claim 5 wherein the therapeutically effective amount of dianhydrogalactitol is an amount of dianhydrogalactitol that results in a concentration of dianhydrogalactitol in the cerebrospinal fluid that is equal to or greater than 5 μ M.

8. The use of claim 1, wherein the substituted hexitol derivative is administered by a route selected from the group consisting of intravenous and oral.

Technical Field

The present application relates to the use of Dianhydrogalactitol (DAG) and analogs and derivatives thereof for the treatment of glioblastoma multiforme and medulloblastoma, and pharmaceutical compositions suitable for such use.

Background

Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor (primary brain tumor) occurring in humans. Glioblastoma multiforme involves glial cells (glial cells); it accounts for 52% of all cases of functional tissue brain tumors and 20% of all cases of intracranial tumors. It is estimated that the frequency of the disease in the european and north american regions is 2 to 3 cases per 100,000 people.

Although there are various treatment modalities, including surgical resection of the tumor as much as possible with craniotomy followed by subsequent or concurrent chemoradiation therapy, anti-angiogenic therapy with bevacizumab (bivacizumab), gamma knife radiation surgery (gamma knife radiation therapy) and symptom management with corticosteroids (systemic management) glioblastoma multiforme have a very poor prognosis. The median survival time for glioblastoma multiforme patients was only 14 months.

Common symptoms of glioblastoma multiforme include seizures, nausea, vomiting, headache and hemiparesis (hemiparesis). However, the single symptom most commonly occurring in glioblastoma multiforme is a progressive impairment of memory, personality or nervous system function due to involvement of the temporal and frontal lobes of the brain. The symptoms caused by glioblastoma multiforme are highly dependent on the tumor site and less dependent on its actual pathology. The tumor may begin to develop symptoms quickly, but occasionally may be asymptomatic until it reaches an extremely large size.

The etiology of glioblastoma multiforme is largely unknown. Somehow, glioblastoma multiforme is more common in males. Most glioblastoma tumors appear sporadic without any significant genetic predisposition (geneticpredisposition). There is no correlation found between glioblastoma multiforme and many known carcinogenic risk factors, including diet, smoking, and exposure to electromagnetic fields. There are several suggestions for viral etiologies that may be SV40 (simian virus 40) or cytomegalovirus (cytomegalovirus). Exposure to free radiation may also have some correlation with glioblastoma multiforme. Furthermore, a link between exposure to polyvinyl chloride and glioblastoma multiforme has been proposed; lead exposure in the workplace has also been suggested as a possible cause. The correlation between brain tumor incidence and malaria suggests that the malaria mosquito, the etiological agent carrying malaria, may transmit the virus or other causative factors of glioblastoma multiforme.

Glioblastoma multiforme is also relatively common in caucasian or asian races over the age of 50 years, and in patients already with low-malignancy astrocytomas (astrocytoma) that can progress to higher malignancy. In addition, one of the following genetic diseases is associated with a higher incidence of glioblastoma multiforme: neurofibromas (neurofibromatosis), tuberous sclerosis (tuberous sclerosis), von hippel-Lindau disease, Li-flumini syndrome (Li-francenui syndrome) or taconite syndrome (Turcot syndrome).

Glioblastoma multiforme is generally characterized by the presence of small areas of necrotic tissue surrounded by undifferentiated cells. These features and the presence of vascular proliferation distinguish these third-stage astrocytoma-derived malignancies that do not have these main features.

There are 4 subtypes of glioblastoma tumors (subtypes). A significant percentage (97%) of tumors in the so-called "classical" subtype carry additional copy numbers of the Epidermal Growth Factor Receptor (EGFR) gene, and most of these tumors have higher than normal EGFR expression, whereas the TP53 gene, a tumor suppressor gene with substantial anti-cancer activity, which is frequently mutated in glioblastomas, is rarely mutated in this subtype. In contrast, the TP53 gene and PDGFRA gene of the proneural subtype, which encode growth factor receptors derived from alpha-type platelets, often have high rates of variation; and lDH1 gene, the gene encoding isocitrate dehydrogenase 1. The mesenchymal (mesenchyme) subtype is characterized by a high mutation rate or variation rate in the NF1 gene (the gene encodes the Neurofibromin type one (Neurofibromin type 1) and by a minor variation in the EGFR gene, and EGFR expression is less than for the other subtypes.

Glioblastoma multiforme is often formed in the white brain (cerebral white matter) and grows rapidly and can become very large before symptoms develop. Less than 10% of glioblastoma multiforme forms more slowly after the regression of low malignancy astrocytomas or degenerative astrocytomas (anaplastic astrocytomas); such tumors are so-called secondary glioblastoma multiforme (secondary GBM) and are relatively common in younger patients. The tumor may extend to the meninges and the ventricular wall resulting in abnormally high protein content (greater than 100 milligrams (mg)/fair (dL)) in cerebrospinal fluid (CSF) and sporadic cerebrospinal fluid cytopenia (pleocytosis) of 10 to 100 cells, mostly lymphocytes. Malignant cells present in the cerebrospinal fluid rarely spread to the spinal cord or cause meningeal gliomas (menial gliomas); however, the metastasis of glioblastoma multiforme beyond the central nervous system is extremely rare. About 50% of glioblastoma multiforme occupy more than one lobe or bilateral in the cerebral hemisphere. This type of tumor usually results from the brain and may rarely show traditional penetration through the corpus callosum, resulting in bilateral (butterfly) gliomas. The tumor may take on various forms depending on the amount of bleeding or the presence of necrosis or the age of the tumor. Computerized tomography of glioblastoma multiforme usually shows heterogeneous masses with various annular enhancements of low density (hypodense) central and peripheral edema. The mass effect and peripheral edema from tumors may constrict the ventricles and cause hydrocephalus (hydrocephalus).

Cancer cells with stem cell-like properties are found in glioblastomas. This may be one reason for its resistance to conventional therapy and its high recurrence rate.

Glioblastoma multiforme is often characterized by Magnetic Resonance Imaging (MRI), but these characteristics do not occur only in glioblastoma multiforme, but may be caused by other conditions. In particular, glioblastoma multiforme often presents ring-enhanced lesions (ring-enhanced lesions) when viewed with magnetic resonance imaging. However, other lesions, such as abscesses, metastases of malignancies occurring outside the central nervous system, tumor-like multiple sclerosis (tumor multiple sclerosis), or other disorders may also have a similar appearance. The diagnosis of suspected glioblastoma multiforme by computerized tomography or magnetic resonance imaging requires a stereotactic biopsy (stereotactic) or craniotomy for tumor resection and pathological confirmation. Because the progression from tumor to tumor depends on the most malignant portion of the tumor, biopsy or major tumor resection may result in a decrease in the progression of the tumor (undersgrading). Tumor blood flow images using perfusion magnetophoresis and measurements of tumor metabolite concentrations in the magnetic resonance spectrum (MR spectroscopy) may increase the value of standard magnetophoresis, but the pathology remains the gold standard for glioblastoma multiforme diagnosis.

The treatment of glioblastoma multiforme is extremely difficult due to several factors: (1) the tumor cells are very resistant to conventional therapy; (2) the brain is very susceptible to damage from habitual therapy; (3) the brain has very limited self-repair capacity; and (4) the inability of many therapeutic agents to cross the blood-brain barrier to act on tumors. Symptomatic therapy, including the use of corticosteroids and antispasmodics, is directed to alleviating symptoms and improving the nervous system function of patients. However, this symptomatic therapy does not help to slow the progression of the tumour, and if diphenylhydantoin (phytyin) is administered in conjunction with radiation therapy, substantial side effects may result including erythema multiforme and Steven-Johnson syndrome.

Palliative therapy (palliative therapy) is often administered to improve quality of life and to achieve longer survival times. Palliative therapy may include surgery, radiation therapy, or chemotherapy. The maximum feasible ablation with maximum absence of tumor margin is usually performed with an applied radiation beam and chemotherapy. The total resection of the tumor and preferably the prognosis are correlated.

Surgery is the first stage of glioblastoma treatment. Glioblastoma multiforme contains on average 10¹¹Individual cell, and it can be reduced to 10 on average after surgery⁹Individual cells (99% reduction). Surgery is the sectioning used to take a pathological diagnosis, to remove symptoms that some large masses press against the brain, to remove disease before its secondary resistant radiation therapy and chemotherapy, and to prolong survival. The greater the extent of tumor removal, the better the results. Removal of 98% or more of the tumors has been shown to be associated with significantly longer and healthier survival times than when less than 98% of the tumors were removed. If the procedure is guided by a fluorescent dye, known as 5-aminolevulinic acid, the chances of near complete primary removal of the tumor can be greatly increased. In diagnosis, glioblastoma multiforme cells widely penetrate the brain, and thus, although all visible tumors are "completely resected", most patients with glioblastoma multiforme suffer from recurrent tumors later in the brain, either near the original location or at a slight distance from "satellite lesions". Other means, including irradiation, are used post-operatively in an attempt to suppress and slow recurrent disease.

After surgery, radiation therapy is the most predominant treatment for patients with glioblastoma. A key clinical trial performed early in the 1970 s showed that, in 303 patients with glioblastoma multiforme, radiation or non-radiation therapy was performed randomly, with those who received radiation having a median survival time that was twice as high as those who did not receive radiation. Subsequent clinical studies have attempted to establish the basis for post-operative radiation therapy. On average, postoperative careThe injection treatment can reduce the tumor size to 10⁷And (4) cells. Whole brain radiation therapy does not improve its outcome when compared to more precise and targeted three-dimensional conformal radiation therapy. Total radiation doses of 60 to 65 golay (Gy) have been shown to be optimal for treatment.

The use of radiation therapy other than chemotherapy in glioblastoma multiforme has to date only resulted in a low improvement in survival when compared to the use of radiation therapy alone. In the treatment of other malignancies, additional chemotherapy has resulted in substantial improvement in survival upon irradiation, but this has not yet been demonstrated in the case of glioblastoma multiforme. One drug that shows a consequence related to radiation is Temozolomide (TMZ). TMZ plus radiation is now the standard therapy for most glioblastoma multiforme cases. TMZ appears to act to sensitize the tumor cells to radiation.

However, TMZ is often due to O⁶-methylguanine-DNA methyltransferase (O)⁶The catalytic activity of the MGMT enzyme, which leads to the repair of O in guanine in DNA molecules, leads to the failure of the drug resistance produced⁶To the affected part.

In addition, Cancer Stem Cells (CSCs) are a subpopulation of tumors that resist treatment and cause recurrence.

Additional treatment methods involve the use of the monoclonal antibody bevacizumab. However, unlike in some other malignancies where the use of bevacizumab leads to a potentiation of chemotherapy (chemotherapy), in glioblastoma multiforme, the additional addition of chemotherapy to bevacizumab does not improve the outcome of bevacizumab alone. Bevacizumab reduces brain edema and the resulting symptoms, and this may result from the benefit of the drug being that it acts against edema rather than any effect against the tumor itself. Some patients with brain edema do not actually have any active tumor residues, but rather develop edema, which is a late effect of previous radiation therapy (late effect). Such edema is difficult to distinguish from tumor-induced edema, which may be present simultaneously. Both types of edema respond to bevacizumab.

Another proposed method is gene transfer. Although gene transfer therapy has the potential to kill cancer cells while sparing healthy cells, this approach is plagued by a number of difficulties in other diseases, including the possibility of inducing other types of malignant cells and interfering with the function of the immune system.

There are other proposed treatment modalities for glioblastoma multiforme, including the use of protein therapies, including the soluble CD95-Fc fusion protein APG 101; immunotherapy with tumor vaccines; changing the electric field; and metabolic therapy. The value of these treatment modalities remains to be determined.

In glioblastoma multiforme, the median survival time of patients after self-diagnosis is 3 months without any treatment, but generally 1 to 2 years after treatment. The older (older than 60 years) the higher the risk of prognosis. Death often results from brain edema or increased intracranial pressure.

Good initial carnosks' physical functional status assessment scores (Karnofsky Performance Score, KPS) and methylation of the promoter of the O-6-methylguanine-DNA methyltransferase (MGMT) gene are associated with longer survival rates. A DNA assay can be performed in glioblastomas to determine whether the promoter of the MGMT gene is methylated. Even in patients under the age of 50 years and with KPS equal to or higher than 90%, 5-year survival rates are only 14%.

Medulloblastoma is a highly malignant primary brain tumor originating from the cerebellum or posterior fossa. It is one of the most common malignant brain tumors and is more frequently found in people less than 20 years of age than in adults. Medulloblastoma may spread through the central nervous system and often metastasize to different locations in the brain and spinal cord.

It is currently believed that medulloblastoma is caused by cerebellar stem cells, which are prevented from dividing and differentiating into their normal cell types. This explains the different histopathological variations in biopsies. Perivascular pseudo-floral cluster (perivasular pseudo-rosette) and holmer-Wright (Homer-Wright) rosette pseudo-floral cluster architecture are the most distinctive features of medulloblastoma and are found in up to half of the cases. The rosette of HomoRattes is a pseudo-cluster of tumor cells that surrounds a fibrous region. Also, a typical rosette can be seen as tumor cells surrounding a central lumen (lumen). Molecular genetics revealed a deletion in the genetic signal of the distal (digital) portion of the 17 th pair of genomes, the distal p53 gene probably accounting for the tumorigenic transformation of these undifferentiated cerebellar cells. Medulloblastoma is also found in the gollin syndrome (Gorlin syndrome) and taconite syndrome. It has been proposed that the cause of JC virus, a multiple cerebral leukosis (multifocalleukoencephalopathopy), may be related to medulloblastoma.

The symptoms of medulloblastoma are mainly due to increased intracranial pressure due to the fourth ventricle block and are mainly of the nervous system, with other symptoms such as vomiting also occurring.

Treatment began with the removal of the largest portion of the tumor. Additional radiation and chemotherapy to the entire neural axis (neuraxis) may increase disease-free survival. This combination makes possible a 5-year survival rate in more than 80% of cases. The presence of a primary feature that promotes connective tissue proliferation, such as the formation of connective tissue, provides a preferred prognosis. The prognosis is poor if the child is less than 3 years old, has an inadequate degree of resection, or has any cerebrospinal fluid, spinal cord, supratentorial (supratentorial), or systemic spread. In the treatment continued after 2 to 4 years, post-radiotherapy or chemotherapy intellectual disability is a common outcome. Increased intracranial pressure can be controlled by corticosteroids or ventricular peritoneal shunt (ventriculoperitaneal shunt).

Currently, chemotherapy for medulloblastoma involves a combination of lomustine (lomustine), cisplatin (cissplatin), carboplatin (carboplatin), vincristine (vincristine), or cyclophosphamide (cyclophosphamide). An additional chemotherapeutic agent, vismodegib (2-chloro-N- (4-chloro-3-pyridin-2-ylphenyl) -4 methylsulfobenzamide), has also been proposed for use in medulloblastoma.

The outcome of medulloblastoma varies depending on the cytogenetic subpopulation. Poor prognosis is associated with either 6q acquisition or MYC or MYCN amplification. The intermediate prognosis was associated with the acquisition of 17q or i (17q) without the acquisition of 6q or amplification of MYC or MYCN. A relatively good prognosis is associated with 6q and 17q balance or 6q deletion.

Patients diagnosed with medulloblastoma have a 50-fold chance of death compared to a match in the general population. Although the 5-year survival rate in children is about 72%, the 20-year survival rate in children is only 51%. Long-term sequelae of standard treatment include hypothalamic-pituitary and thyroid dysfunction and intellectual impairment; the hormonal and intellectual damage caused by these therapies can cause significant damage to survivors.

Accordingly, there is a need to provide improved therapies for glioblastoma multiforme and medulloblastoma that provide improved survival and reduce side effects and functional impairment in surviving patients.

There is a particular need for a treatment that can cross the blood-brain barrier (BBB), which can inhibit the growth and division of Cancer Stem Cells (CSCs) and can avoid O-dependent events⁶-methylguanine-DNA methyltransferase (MGMT) is inactivated. There is also a particular need for therapeutic modalities that bring about increased response rates and improved quality of life to those suffering from such malignancies.

Disclosure of Invention

The use of substituted hexitol derivatives for the treatment of glioblastoma multiforme and medulloblastoma provides an improved therapy for malignancies of these brains, which results in increased survival rates and essentially no side effects. Generally, substituted hexitols useful in methods or compositions according to the present invention include galactitols, substituted galactitols, dulcitols (dulcitols), and substituted dulcitols. Typically, the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, a dianhydrogalactitol derivative, diacetyldianhydrogalactitol, a diacetyldianhydrogalactitol derivative, dibromodulcitol (dibromodulcitol), and a dibromodulcitol derivative. A particularly preferred substituted hexitol derivative is dianhydrogalactitol. Said substituted hexitol derivativesOrganisms can target these malignancies as a means of treatment for use with other therapies. Dianhydrogalactitol is particularly suitable for the treatment of these malignancies because it can cross the blood-brain barrier, because it can inhibit the growth of cancer stem cells, and because it can be resistant to O⁶-methylguanine-DNA methyltransferase (MGMT) caused drug inactivation. The substituted hexitols bring about an increased reaction rate and improved quality of life for those suffering from glioblastoma multiforme or medulloblastoma.

Dianhydrogalactitol is a cause of N in DNA⁷Methylated novel alkylating agents. Specifically, dianhydrogalactitol makes N of guanine residue in DNA⁷And (4) position methylation.

Accordingly, one aspect of the present invention is a method of enhancing efficacy and/or reducing side effects of administration of a substituted hexitol derivative for treatment of glioblastoma multiforme or medulloblastoma, comprising the steps of:

(1) identifying at least one factor or parameter associated with efficacy and/or occurrence of side effects for the administration of a substituted hexitol derivative for the treatment of glioblastoma multiforme or medulloblastoma; and

(2) modifying the factors or parameters to improve efficacy and/or reduce side effects for the administration of substituted hexitol derivatives for the treatment of glioblastoma multiforme or medulloblastoma.

Typically, the factor or parameter is selected from the group consisting of:

(1) dose modification;

(2) the route of administration;

(3) a dosing schedule;

(4) a use indication;

(5) selection of disease stage;

(6) other indications;

(7) selecting a patient;

(8) patient/disease phenotype;

(9) genotype of patient/disease;

(10) pre/post treatment preparation;

(11) managing toxicity;

(12) pharmacokinetic/pharmacodynamic monitoring;

(13) a pharmaceutical composition;

(14) chemosensitization (chemosensitization);

(15) chemical strengthening effect;

(16) patient management after treatment;

(17) replacement drug/therapy support;

(18) improving a raw material medicine product;

(19) a diluent system;

(20) a solvent system;

(21) an excipient;

(22) a dosage form;

(23) dose kits and packaging;

(24) a drug delivery system;

(25) a drug conjugated form;

(26) an analog of the compound;

(27) a prodrug;

(28) a multiple drug system;

(29) biological treatment synergy;

(30) modulation of biotherapeutic resistance;

(31) synergy of radiotherapy;

(32) a novel action machine is rotated;

(33) selective targeted cell population therapeutics.

As detailed above, typically the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, a dianhydrogalactitol derivative, diacetyldianhydrogalactitol, a diacetyldianhydrogalactitol derivative, dibromodulcitol, and a dibromodulcitol derivative. Preferably, the substituted hexitol derivative is dianhydrogalactitol.

Another aspect of the invention is a composition for sub-optimal drug delivery therapy using substituted hexitol derivatives for treatment of glioblastoma multiforme or medulloblastoma, enhanced efficacy and/or reduced side effects, comprising an alternative selected from the group consisting of:

(i) a therapeutically effective amount of a modified substituted hexitol derivative or a derivative, analog, or prodrug of a modified substituted hexitol derivative, wherein the modified substituted hexitol derivative or a derivative, analog, or prodrug of a modified substituted hexitol derivative has increased therapeutic efficacy or reduced side effects on the treatment of glioblastoma multiforme or medulloblastoma as compared to an unmodified substituted hexitol derivative;

(ii) a composition comprising:

(a) a therapeutically effective amount of a substituted hexitol derivative, modified substituted hexitol derivative, or derivative, analog, or prodrug of a modified substituted hexitol derivative; and

(b) at least one additional therapeutic agent, a therapeutic agent affected by chemosensitization, a therapeutic agent affected by chemopotentiation, a diluent, an excipient, a solvent system, or a drug delivery system, wherein the composition has increased therapeutic efficacy or reduced side effects for the treatment of glioblastoma multiforme or medulloblastoma as compared to the unmodified substituted hexitol derivative;

(iii) a therapeutically effective amount of a substituted hexitol derivative, a modified substituted hexitol derivative, or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative incorporated into a dosage form, wherein the substituted hexitol derivative, the modified substituted hexitol derivative, or the derivative, analog, or prodrug of the substituted hexitol derivative or the modified substituted hexitol derivative incorporated into the dosage form has increased therapeutic efficacy or reduced side effects on treating glioblastoma multiforme or medulloblastoma compared to an unmodified substituted hexitol derivative;

(iv) a therapeutically effective amount of a substituted hexitol derivative, a modified substituted hexitol derivative, or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative incorporated into a dosage kit or package, wherein the substituted hexitol derivative, the modified substituted hexitol derivative, or the derivative, analog, or prodrug of the substituted hexitol derivative or the modified substituted hexitol derivative is incorporated into the dosage kit or package with enhanced efficacy or reduced side effects for treatment of glioblastoma multiforme or medulloblastoma as compared to the unmodified substituted hexitol derivative; and

(v) a therapeutically effective amount of a substituted hexitol derivative, a modified substituted hexitol derivative, or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is affected by modification of a drug substance product, wherein the substituted hexitol derivative, the modified substituted hexitol derivative, or the derivative, analog, or prodrug of the substituted hexitol derivative or the modified substituted hexitol derivative that is affected by modification of the drug substance product has increased therapeutic efficacy or reduced side effects on treating glioblastoma multiforme or medulloblastoma as compared to an unmodified substituted hexitol derivative.

As detailed above, typically the unmodified substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, a dianhydrogalactitol derivative, diacetyldianhydrogalactitol, a diacetyldianhydrogalactitol derivative, dibromodulcitol and a dibromodulcitol derivative. Preferably, the unmodified substituted hexitol derivative is dianhydrogalactitol.

Another aspect of the invention is a method of treating a malignancy selected from the group consisting of glioblastoma multiforme and medulloblastoma, comprising the step of administering to a patient suffering from said malignancy a therapeutically effective amount of a substituted hexitol derivative. As detailed above, the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, a dianhydrogalactitol derivative, diacetyldianhydrogalactitol, a diacetyldianhydrogalactitol derivative, dibromodulcitol, and a dibromodulcitol derivative. Preferably, the substituted hexitol derivative is dianhydrogalactitol.

Typically, when the substituted hexitol is dianhydrogalactitol, the therapeutically effective amount of dianhydrogalactitol is about 1mg per square meter (m)²) To about 40mg/m²The dosage of (a). Preferably, the therapeutically effective amount of dianhydrogalactitol is about 5mg/m²To about 25mg/m²The dosage of (a). Other doses are as follows.

Typically, substituted hexitol derivatives, such as dianhydrogalactitol, are administered by a route selected from the group consisting of intravenous and oral routes. Other possible routes of administration are as follows.

The method may further comprise the step of administering a therapeutically effective dose of free radiation. If the malignancy being treated is glioblastoma multiforme, the method may further comprise the step of administering a therapeutically effective amount of temozolomide, bevacizumab, or a corticosteroid. If the malignancy being treated is medulloblastoma, the method may further comprise administering a therapeutically effective amount of at least one chemotherapeutic agent selected from the group consisting of lomustine, cisplatin, carboplatin, vincristine, and cyclophosphamide.

The method may further comprise administering a therapeutically effective amount of a tyrosine kinase inhibitor, as described below.

The method may further comprise administering a therapeutically effective amount of an Epithelial Growth Factor Receptor (EGFR) inhibitor, as described below. The EGFR inhibitor may affect the binding site, whether wild-type or mutated, including the third variant thereof, as described below.

Drawings

The following invention will become more readily apparent with reference to this specification, appended claims and accompanying drawings in which:

FIG. 1 is a diagram showing cell lines of three glioblastoma multiforme strains used, their degree of resistance to Temozolomide (TMZ) and their status of being methylated by the promoter of the O-6-methylguanine-DNA methyltransferase (MGMT) gene.

FIG. 2A is a graph showing the inhibition of growth of glioblastoma multiforme cell line SF188 by increasing concentrations of TMZ and dianhydrogalactitol (shown as "VAL" in the figure) (two experiments) in FIG. 2A, (◆) represents the results for TMZ and (■) represents the results for dianhydrogalactitol.

FIG. 2B is a graph showing the inhibition of growth of glioblastoma multiforme cell line U251 with increasing concentrations of TMZ and dianhydrogalactitol (two experiments). in FIG. 2B, (◆) represents the results for TMZ, and (■) represents the results for dianhydrogalactitol.

FIG. 2C is a graph showing the inhibition of the growth of the glioblastoma multiforme cell line T98G with increasing concentrations of TMZ and dianhydrogalactitol (two experiments) in FIG. 2C, (◆) represents the results for TMZ and (■) represents the results for dianhydrogalactitol.

FIG. 3 is a graph showing a schematic of TMZ resistance and MGMT status for the three cell lines used in FIGS. 2A, 2B and 2C.

FIG. 4 is a photograph showing that after 7 days of treatment with 5. mu.M dianhydrogalactitol, the formation of a population of glioblastoma multiforme cell line SF188 cells was inhibited by more than 95%.

FIG. 5 is a graph showing that dianhydrogalactitol is more effective than TMZ in inhibiting the growth of SF188 cells, particularly for secondary sphere formation (secondary sphere formation).

Fig. 6A and 6B show that dianhydrogalactitol completely inhibits secondary neurosphere formation and essentially inhibits primary neurosphere formation of BT74 cancer stem cells; a micrograph is shown above, and a graph showing the degree of inhibition thereof is shown below the micrograph.

FIG. 7 is a graph showing that dianhydrogalactitol is more efficient than TMZ in inhibiting primary neurosphere formation in SF188 and DAOY cell lines. DAOY is a medulloblastoma cell line.

FIG. 8 is a photograph showing that the formation of DAOY cell colony of medulloblastoma cell strain was completely inhibited after 7 days of treatment with 5uM dianhydrogalactitol.

Fig. 9 is a graph showing that BT74 cells did not exhibit significant sensitivity to TMZ and a comparative micrograph.

FIG. 10 is a graph showing the effect of dianhydrogalactitol on primary adult glioblastoma multiforme cells freshly isolated from BCCH, showing a substantial degree of inhibition; whereas TMZ has essentially no effect on these cells.

FIG. 11 is a graph showing the effect of combined treatment with TMZ and dianhydrogalactitol on SF188 cells and showing inhibition of neurosphere formation; wherein the combination of TMZ plus dianhydrogalactitol provides the greatest degree of inhibition.

FIG. 12 is a panel showing the effect of combined treatment with TMZ and dianhydrogalactitol on SF188 cells and showing the inhibition of cell colony formation; wherein the combination of TMZ plus dianhydrogalactitol provides the greatest degree of inhibition.

Detailed Description

Dianhydrogalactitol compounds have been shown to have substantial potency in inhibiting the growth of glioblastoma multiforme (GBM) cells and medulloblastoma cells. In the case of glioblastoma multiforme, dianhydrogalactitol has been shown to be more effective in inhibiting glioblastoma multiforme cell growth than Temozolomide (TMZ) selection, which is now used in chemotherapy to treat glioblastoma multiforme. As described in detail below, dianhydrogalactitol can effectively cross the blood-brain barrier and effectively inhibit the growth of cancer stem cells. The action of dianhydrogalactitol is independent of MGMT repair turnover.

The structure of Dianhydrogalactitol (DAG) is shown in formula (I), below.

As described in detail below, other substituted hexitols may be used in the methods and compositions according to the present invention. In general, substituted hexitols useful in the methods and compositions according to the present invention include galactitols, substituted galactitols, dulcitols, and substituted dulcitols, including dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, and derivatives and analogs thereof. Typically, the substituted hexitol derivative is selected from the group consisting of dianhydrogalactitol, a dianhydrogalactitol derivative, diacetyldianhydrogalactitol, a diacetyldianhydrogalactitol derivative, dibromodulcitol, and a dibromodulcitol derivative. Preferably, the substituted hexitol derivative is dianhydrogalactitol.

These galactitols, substituted galactitols, dulcitols, substituted dulcitols are prodrugs that are alkylating or alkylating agents, as discussed further below.

Also within the scope of the present invention are dianhydrogalactitol, e.g., having one or both of the two hydroxyl groups replaced by a lower alkyl group; one or more hydrogens attached to two epoxy rings are replaced with lower alkyl; or having a methyl group present in dianhydrogalactitol and attached with a C group₂-C₆Lower alkyl, or the same carbon of hydroxy substituted by e.g. halo, by replacing the hydrogen of methyl with e.g. halo. As used herein, without further limitation, the term "halo" refers to one of fluoro, chloro, bromo, or iodo. As used herein, the term "lower alkyl", without further limitation, refers to C₁-C₆And includes methyl. Unless otherwise defined, the term "lower alkyl" may be further defined, such as "C₂-C₆Lower alkyl "which excludes methyl. The term "lower alkyl" otherwise refers to straight or branched chain alkyl groups. These groups may be further substituted as necessary, as described below.

The structure of diacetyldianhydrogalactitol is shown in formula (II), below.

Also within the scope of the present invention are derivatives of diacetyldianhydrogalactitol, e.g. having one or both of the two methyl moieties of the acetyl moiety (moity) being substituted by C₂-C₆Lower alkyl substituted; one or both hydrogens attached to said two epoxy rings are replaced with lower alkyl; or having a methyl group attached to the same carbon bearing an acetyl group substituted by a lower alkyl group or by e.g. halo, by replacing a hydrogen with e.g. halo.

The structure of dibromodulcitol is shown in formula (III) below. Dibromodulcitol can be produced by reacting dulcitol with hydrobromic acid at elevated temperatures followed by crystallization of dibromodulcitol. Some of the properties of dibromodulcitol are described in "dibromoglucitol" Cancer treat. Rev.6:191-204(1979) by N.E. Mischler et al, which is incorporated herein by reference. In particular, dibromodulcitol acts as an α, ω -dibrominated hexitol, and dibromodulcitol shares many of the same biochemical and biological properties with its similar drugs, such as dibromomannitol and mannitol melrane. Activation of dianhydrogalactitol, which is a diepoxide, by dibromodulcitol occurs in vivo and dianhydrogalactitol may represent the major active form of the drug; this indicates that dibromogalactitol has many prodrug properties. The absorption of dibromodulcitol by the oral route is rapid and quite complete. Dibromodulcitol is known to be active against melanoma (melanoma), lymphoid tumors of the breast (Hodgkins) or non-Hodgkins), rectal cancer and acute lymphatic leukemia (acute lymphoblastic leukemia), and has been shown to have a low incidence of central nervous system leukemia, non-small cell lung cancer, cervical cancer, bladder cancer and metastatic vascular endothelial cell tumors.

Also included within the scope of the present invention are derivatives of dibromodulcitol, for example where one or more of the hydrogens with hydroxyl groups are replaced by lower alkyl groups, or where the bromo group is replaced by other halo groups, such as chloro, fluoro or iodo groups.

In general, for optional substituents on saturated carbon which are part of the structure of dianhydrogalactitol, dianhydrogalactitol derivatives, diacetyldianhydrogalactitol derivatives, dibromodulcitol and dibromodulcitol derivatives, the following substituent C can be used₆-C₁₀Aryl, heteroaryl containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, C₁-C₁₀Alkyl radical, C₁-C₁₀Alkoxy, cycloalkyl, fluoro, amino (NR)¹R²) Nitro, -SR, -S (O) R, -S (O)₂)R、-S(O₂)NR¹R²and-CONR¹R²Which may in turn be optionally substituted. Further illustrations of substituents that may be required are provided below.

The optional substituents as described above within the scope of the present invention do not substantially affect the activity of the derivative or the stability of the derivative, especially the stability of the derivative in aqueous solution. Some common definitions of groups used as optional substituents are provided below; however, as long as the chemical and pharmacological requirements for an optional substituent are met, any omission of a group from these definitions is not to be construed as an inability of such group to serve as an optional substituent.

The term "alkyl" as used herein refers to an optionally substituted unbranched, branched, or cyclic saturated hydrocarbon residue having 1 to 12 carbon atoms, or a combination thereof; when unsubstituted, the alkyl residue contains only carbon and hydrogen. Typically, unbranched or branched saturated hydrocarbyl residues are those having from 1 to 6 carbon atoms, referred to herein as "lower alkyl". When the alkyl group is cyclic and includes one ring, it is understood that the hydrocarbyl residue includes at least three carbon atoms, which is the minimum number to form one ring. As used hereinThe term "alkenyl" refers to an unbranched, branched, or cyclic hydrocarbon residue having one or more carbon-carbon double bonds. The term "alkynyl" as used herein refers to an unbranched, branched, or cyclic hydrocarbyl residue having one or more carbon-carbon references. With respect to the use of "alkenyl" or "alkynyl", the presence of multiple double bonds does not result in an aromatic ring. The terms "hydroxyalkyl", "hydroxyalkenyl" and "hydroxyalkynyl" as used herein refer to an alkyl, alkenyl or alkynyl group, respectively, which includes one or more hydroxyl groups as substituents; as described in detail below, further substituents may optionally be included. The term "aryl" as used herein refers to a monocyclic or fused bicyclic moiety having well-known aromatic properties; examples include phenyl and naphthyl, which may be optionally substituted. The term "hydroxyaryl" as used herein refers to aryl groups which contain one or more hydroxy groups as substituents; as described in further detail below, further substituents may be optionally included. The term "heteroaryl" as used herein refers to a monocyclic or fused bicyclic ring system having aromatic character and comprising one or more heteroatoms selected from oxygen, sulfur and nitrogen. The inclusion of heteroatoms allows aromaticity in the five-membered ring as well as in the six-membered ring. Typical heteroaryl systems include monocyclic C₅-C₆Heteroaryl groups, such as pyridyl, pyrimidinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, triazinyl, tetrazolyl, tetrazinyl and imidazolyl, and C formed from these monocyclic heteroaryl groups and a phenyl ring or any monocyclic heteroaryl group₈-C₁₀The fused bicyclic portion of the bicyclic group, such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, quinazolinyl, quinoxalinyl, cinnolinyl, and other ring systems known in the art. Any characteristic monocyclic or fused bicyclic ring system having aromaticity with respect to delocalized electron distribution throughout the cyclic system is included within the definition. This definition also includes bicyclic groups where at least the ring directly attached to the remainder of the molecule is aromatic in character, including delocalized electron distributions that are aromatic in character. Tong (Chinese character of 'tong')Often the ring system contains 5 to 12 membered ring atoms and up to 4 heteroatoms, where those heteroatoms are selected from the group consisting of nitrogen, oxygen and sulfur. Often, the monocyclic heteroaryl group contains 5 to 6 membered ring atoms and up to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; often, the bicyclic heteroaryl contains 8 to 10 membered ring atoms and up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The number and position of heteroatoms in heteroaryl ring structures is in accordance with well-known limitations of aromaticity and stability, where stability requires the heteroaryl group to be stable enough to be exposed to water at physiological temperatures without rapid degradation. The term "hydroxyheteroaryl" as used herein refers to heteroaryl groups comprising one or more hydroxyl groups as substituents; as described in further detail below, further substituents may be optionally included. The terms "haloaryl" and "haloheteroaryl" as used herein mean that the aryl and heteroaryl groups are each substituted with at least one halo group, wherein "halo" means a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine, typically the halogen is selected from the group consisting of chlorine, bromine and iodine; as described in more detail below, optionally containing more substituents. The terms "haloalkyl", "haloalkenyl" and "haloalkynyl" as used herein mean that the alkyl, alkenyl and alkynyl groups are each substituted with at least one halo group, wherein "halo" means a halogen selected from the group consisting of fluorine, chlorine, bromine and iodine, typically said halogen is selected from the group consisting of chlorine, bromine and iodine; as described in more detail below, optionally containing more substituents.

The term "optionally substituted" as used herein means that the particular group or groups identified as optionally substituted may not have a hydrogen-free substituent, or that or those groups may have one or more hydrogen-free substituents consistent with the chemical and pharmacological activity of the product molecule. Unless otherwise indicated, the total number of substituents that may be present may be the same as the total number of hydrogen atoms present in the unsubstituted form of the group being described; and less than the maximum number of those substituents. In the case where the position to which the optional substituent is attached is through a double bond, such as a carbonyl oxygen (C ═ O), the group occupies two available valence electrons of the carbon atom at the position to which the optional substituent is attached, so the total number of substituents that may be included is reduced depending on the number of available valences. The term "substituted" as used herein, whether used in reference to a "optionally substituted" moiety or otherwise, when used to modify a particular group, moiety or radical, means that one or more hydrogen atoms thereof are each independently replaced by the same or different substituents.

Substituents that may be used to replace a saturated carbon atom in these particular groups, moieties or radicals include, but are not limited to, -Z^a、＝O’、－OZ^b、－SZ^b、＝S^-、－NZ^cZ^c、＝NZ^b、＝N－OZ^bTrihalomethyl, -CF₃、－CN、－OCN、－SCN、－NO、－NO₂、＝N₂、－N₃、－S(O)₂Z^b、－S(O)₂NZ^b、－S(O₂)O^-、－S(O₂)OZ^b、－OS(O₂)OZ^b、－OS(O₂)O^-、－OS(O₂)OZ^b、－P(O)(O^-)₂、－P(O)(OZ^b)(O^-)、－P(O)(OZ^b)(OZ^b)、－C(O)Z^b,－C(S)Z^b、－C(NZ^b)Z^b、－C(O)O^-、－C(O)OZ^b、－C(S)OZ^b、,－C(O)NZ^cZ^c、－C(NZ^b)NZ^cZ^c、－OC(O)Z^b、－OC(S)Z^b、－OC(O)O^-、－OC(O)OZ^b、－OC(S)OZ^b、－NZ^bC(O)Z^b、－NZ^bC(S)Z^b、－NZ^bC(O)O^-、－NZ^bC(O)OZ^b、－NZ^bC(S)OZ^b、－NZ^bC(O)NZ^cZ^c、－NZ^bC(NZ^b)Z^b、－NZ^bC(NZ^b)NZ^cZ^cWherein Z is^aIs selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, arylAralkyl, heteroaryl and heteroaralkyl groups; each Z^bIs independently hydrogen or Z^a(ii) a And each Z^cIs independently Z^bOr the two Z^cMay be bonded together with the nitrogen atom to form a 4-, 5-, 6-or 7-membered cycloheteroalkyl ring structure, which may optionally include 1 to 4 identical or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. As an example, -NZ^cZ^cIs meant to comprise-NH₂-NH-alkyl, -N-pyrrolidyl, and-N-morpholinyl, but are not limited to those specific alternatives, and include other alternatives known in the art. Similarly, as another example, substituted alkyl is meant to include-alkylene-O-alkyl, -alkylene-heteroaryl, -alkylene-cycloheteroaryl, -alkylene-C (O) OZ^b-alkylene-C (O) NZ^bZ^band-CH₂－CH₂－C(O)-CH₃But are not limited to those specific alternatives and include other alternatives known in the art. The one or more substituent groups, together with the atoms to which they are bonded, may form a ring including, but not limited to, cycloalkyl and cycloheteroalkyl.

Similarly, substituents useful for substituting an unsaturated carbon atom in a particular group, moiety or radical include, but are not limited to, -Z^aHalogen, -O^-、－OZ^b、－SZ^b、－S^-,－NZ^cZ^cTrihalomethyl, -CF₃,－CN、－OCN、－SCN、－NO、－NO₂、－N₃、－S(O)₂Z^b、－S(O₂)O^-、－S(O₂)OZ^b、－OS(O₂)OZ^b、－OS(O₂)O^-、－P(O)(O^-)₂、－P(O)(OZ^b)(O^-)、－P(O)(OZ^b)(OZ^b)、－C(O)Z^b、－C(S)Z^b、－C(NZ^b)Z^b、－C(O)O^-、－C(O)OZ^b、－C(S)OZ^b、－C(O)NZ^cZ^c、－C(NZ^b)NZ^cZ^c、－OC(O)Z^b,－OC(S)Z^b、－OC(O)O^-,－OC(O)OZ^b、－OC(S)OZ^b、－NZ^bC(O)OZ^b、－NZ^bC(S)OZ^b、－NZ^bC(O)NZ^cZ^c、－NZ^bC(NZ^b)Z^band-NZ^bC(NZ^b)NZ^cZ^cWherein Z is^a、Z^bAnd Z^cIs as defined above.

Similarly, substituent groups useful for substituting the nitrogen atom in heteroalkyl and cycloheteroalkyl groups include, but are not limited to-Z^aHalogen, -O^-、－OZ^b、－SZ^b、－S^-、－NZ^cZ^cTrihalomethyl, -CF₃、－CN、－OCN、－SCN、－NO、－NO₂、－S(O)₂Z^b－S(O₂)O^-、－S(O₂)OZ^b、－OS(O₂)OZ^b、－OS(O₂)O^-、－P(O)(O^-)₂、－P(O)(OZ^b)(O^-)、－P(O)(OZ^b)(OZ^b)、－C(O)Z^b、－C(S)Z^b、－C(NZ^b)Z^b、－C(O)OZ^b、－C(S)OZ^b、－C(O)NZ^cZ^c、－C(NZ^b)NZ^cZ^c、－OC(O)Z^b、－OC(S)Z^b、－OC(O)OZ^b、－OC(S)OZ^b、－NZ^bC(O)Z^b、－NZ^bC(S)Z^b、－NZ^bC(O)OZ^b、－NZ^bC(S)OZ^b、－NZ^bC(O)NZ^cZ^c、－NZ^bC(NZ^b)Z^band-NZ^bC(NZ^b)NZ^cZ^cWherein Z is^a、Z^bAnd Z^cIs as defined above.

The compounds described herein may contain one or more chiral centers and/or double bonds and thus may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers, such as E and Z), enantiomers, or diastereomers. The present invention includes each of the isolated stereoisomeric forms (e.g., the enantiomerically pure isomers, the E and Z isomers, and other optional stereoisomers) as well as mixtures of stereoisomers of varying degrees of enantiomeric purity or percentages of E and Z, including racemic mixtures, mixtures of non-enantiomeric isomers, and mixtures of E and Z isomers. Thus, drawing the chemical structures herein includes all possible enantiomers and stereoisomers of the illustrated compounds, including stereoisomerically purified forms (e.g., geometric, mirror or non-mirror purified) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures may be resolved into their constituent enantiomers or stereoisomers using separation techniques or mirror synthesis techniques known to those skilled in the art. The invention includes each isolated stereoisomeric form as well as stereoisomeric mixtures of varying degrees of mirror purity, including racemic mixtures. It also includes various non-enantiomeric isomers. Other structures may appear to depict specific isomers, but this is merely for convenience and is not intended to limit the invention to the depicted olefin isomers illustrated. When the chemical name does not specify an isomeric form of the compound, it represents any of the possible isomeric forms of the compound or a mixture of those isomeric forms.

The compounds may also exist in several tautomeric forms, and one tautomer drawn herein is for convenience only and should also be understood to include the other tautomers in the forms shown. The chemical structures depicted herein thus encompass all possible tautomers of the illustrated compounds. The term "tautomer" as used herein refers to an isomer that can be converted into another form with extreme ease, so that the isomers can exist simultaneously in an equilibrium state; depending on stability considerations, the equilibrium state may be strongly biased towards one of the tautomers. For example, a ketone and an enol are two tautomeric forms of a compound.

The term "solvate" as used herein refers to a compound (a combination of solvent molecules and molecules or ions of a solute) formed by solvation, or which comprises an aggregate of solute ions or molecules (i.e., a compound of the invention) and one or more solvent molecules. When water is the solvent, the corresponding solvate is the "hydrate". Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, hexahydrate, and other aqueous species (species). It will be appreciated by those of ordinary skill in the art that pharmaceutically acceptable salts and/or prodrugs of the compounds of the present invention may also be present in solvated form. Solvates are typically formed through hydration as part of the preparation of the compounds of the invention or by the natural absorption of moisture by the anhydrous compounds of the invention.

The term "ester" as used herein refers to any ester of a compound of the present invention wherein any-COOH functionality in the molecule is replaced with a-COOR functionality, wherein the R portion of the ester is any carbon-containing group that forms a stable ester moiety, including, but not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl, and substituted derivatives thereof. The hydrolysis esters of the compounds of the present invention are compounds whose carboxyl groups are present in the form of hydrolysis ester groups. That is, these esters are pharmaceutically acceptable and may be hydrolyzed to their corresponding carboxylic acids in vivo.

In addition to the substituents mentioned above, alkyl, alkenyl and alkynyl groups may alternatively or additionally be substituted by C₁-C₈Acyl radical, C₂-C₈Heteroacyl radical, C₆-C₁₀Aryl radical, C₃-C₈Cycloalkyl radical, C₃-C₈Heterocyclyl or C₅-C₁₀Heteroaryl substituted, each of which may be optionally substituted. And, in addition, when two groups having the ability to form a 5-to 8-membered ring are present at the same or adjacent atoms, the two groups may be optionally bonded together with the atom or atoms to which the substituent group is attached to form the ring.

"heteroalkyl," "heteroalkenyl," and "heteroalkynyl" and the like are groups defined similarly to the corresponding hydrocarbyl (alkyl, alkenyl, and alkynyl) but the term "hetero" refers to a group containing from 1 to 3 oxygen, sulfur, or nitrogen heteroatoms, or combinations thereof, in the backbone residue thereof; thus at least one carbon atom in the corresponding alkyl, alkenyl and alkynyl group is replaced with a particular heteroatom to form a heteroalkyl, heteroalkenyl and heteroalkynyl group, respectively. For reasons of chemical stability, it is also understood that such groups, unless otherwise specified, do not include more than two consecutive heteroatoms, except for pendant oxy groups attached to nitrogen or sulfur, as in nitro or sulfonyl groups.

When used herein, "alkyl" includes cycloalkyl and cycloalkylalkyl, the term "cycloalkyl" may be used herein to describe a cyclic carbon nonaromatic group attached by a cyclic carbon atom, and "cycloalkylalkyl" may be used herein to describe a cyclic carbon nonaromatic group attached to the molecule through an alkyl linkage (linker).

Similarly, "heterocyclyl" may describe a non-aromatic cyclic group containing at least one heteroatom (typically selected from nitrogen, oxygen and sulfur) as a ring member and which is attached to the molecule through a ring atom, which may be carbon (carbon-linked) or nitrogen (nitrogen-linked); and "heterocyclylalkyl" may be used herein to describe a group that is linked to another molecule through a linker group. The heterocyclic group may be fully saturated or partially saturated, but is not aromatic. Suitable cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl groups are the same in size and substituents as those described above for the alkyl groups. Said heterocyclyl group typically contains 1,2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur as ring members; and the nitrogen or sulfur may be substituted with groups commonly found at those atoms in heterocyclic systems. As used herein, these terms also include rings containing one or two double bonds, as long as the attached ring is non-aromatic. The substituted cycloalkyl and heterocyclyl groups also include cycloalkyl or heterocyclyl rings fused to an aromatic or heteroaryl ring, which provides the point at which the group is attached to the cycloalkyl or heterocyclyl group, rather than to the aromatic/heteroaryl ring.

As used herein, "acyl" contains groups comprising an alkyl, acyl, alkynyl, aryl, or arylalkyl radical attached to one of the available valence positions of the carbonyl carbon atoms, while heteroacyl refers to the corresponding group in which at least one carbon other than the carbonyl carbon is replaced with a heteroatom selected from nitrogen, oxygen, and sulfur.

Acyl and heteroacyl groups are bonded to any group or molecule that is attached through the open valency of the carbonyl carbon atom. Typically, they are C₁-C₈Acyl groups including formyl, acetyl, pivaloyl and benzoyl, and C-₂-C₈Heteroacyl groups including methoxyacetyl, ethoxycarbonyl and 4-picolinoyl (4-pyridinoyl).

Similarly, "arylalkyl" and "heteroarylalkyl" refer to a system of aromatic and heteroaromatic rings bonded to their point of attachment through a linking group, such as an alkylene group, including substituted or unsubstituted, saturated or unsaturated, cyclic or acyclic linking groups. Typically the linker group is C₁-C₈An alkyl group. These linking groups may also include a carbonyl group, thus enabling them to provide substituents as acyl or heteroyl moieties. The aromatic or heteroaromatic rings in arylalkyl or heteroarylalkyl may be substituted with the same substituents as described above for aryl. Preferably, the arylcycloalkyl group comprises a phenyl ring optionally substituted with substituents as defined above for the cycloalkyl group and unsubstituted or substituted with one or two C₁-C₄Alkyl or heteroalkyl substituted C₁-C₄An alkylene group, wherein the alkyl or heteroalkyl group may optionally be cyclized to form a ring, such as cyclopropane, dioxolane (dioxolane), or oxocyclopentane. Similarly, heteroarylalkyl preferably includes C₅-C₆Monocyclic heteroaryl which may optionally be substituted as described above for substituents usually on aromatic groups and unsubstituted or substituted by one or two C₁-C₄Alkyl or heteroalkyl substituted C₁-C₄Alkylene, or it includes an optionally substituted benzene ring or C₅-C₆Monocyclic heteroaryl and unsubstituted or substituted by one or two C₁-C₄Alkyl or heteroalkyl substituted C₁-C-₄A heteroalkylene, wherein the alkyl or heteroalkyl group is optionally cyclized to form a ring, such as a cyclopropane, a dioxolane, or a oxocyclopentane.

Where an arylalkyl or heteroarylalkyl group is described as optionally substituted, the substituent may be located on the alkyl or heteroalkyl portion of the group or on the aryl or heteroaryl portion of the group. The substituents optionally present on the alkyl or heteroalkyl moiety are generally the same as those described above for alkyl; the substituents optionally present on the aryl or heteroaryl moiety are generally the same as those described above for aryl.

As used herein, "arylalkyl" is, if unsubstituted, a hydrocarbyl group and is described in terms of the total number of carbon atoms in the ring and in the alkylene or similar bond chain groups. Benzyl is C₇Arylalkyl and phenethyl is C₈-arylalkyl.

"Heteroarylalkyl" as described above refers to a moiety comprising an aryl group attached through a linkage group, which, unlike "arylalkyl", is a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, different from at least one ring atom in the aryl moiety or one atom in the linkage group. The heteroarylalkyl group is the total number of atoms bonded according to the ring and linking group herein, and it includes aryl groups linked through the heteroalkyl linking group; heteroaryl groups linked through a hydrocarbyl linkage, such as an alkylene linkage; and heteroaryl groups linked through a heteroalkyl linkage. Thus, for example, C₇Heteroarylalkyl would include pyridylmethyl, phenoxy and N-pyrrolylmethoxy.

As used herein, "alkylene" refers to divalent hydrocarbon groups; because it is divalent, two other groups may be linked together. Generally, it refers to- (CH) - (CH)₂)_nWhere n is 1 to 8 and preferably 1 to 4, although specified herein, the alkylene groups may be substituted with other groups and may be of other lengths, and the open valencies need not be at opposite ends of a chain.

In general, any alkyl, alkenyl, alkynyl, acyl, or aryl or arylalkyl group contained within a substituent may itself be substituted with other substituents as desired. If these substituents are not otherwise described, the nature of these substituents is the same as those detailed for the original substituent itself.

As used herein, "amino" refers to —)NH₂However, if an amino group is described as "substituted" or "optionally substituted", the term includes NR 'R "where each R' and R" is independently hydrogen, or is alkyl, alkenyl, alkynyl, acyl, aryl or arylalkyl, and each of those alkyl, alkenyl, alkynyl, acyl, aryl or arylalkyl groups may be optionally substituted with substituents described herein as appropriate for the corresponding group; the R 'and R "groups and the nitrogen atom to which they are attached may optionally form a 3-to 8-membered ring, which may be saturated, unsaturated or aromatic, and which contains from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur as ring members, and which may optionally be substituted with the suitable alkyl substituents described, or if NR' R" is aryl, which may optionally be substituted with substituents as described for heteroaryl in general.

As used herein, the term "carbocycle", "carbocyclyl" or "cyclocarbyl" refers to a cyclic ring that contains only carbon atoms in the ring, whereas the term "heterocycle" or "heterocyclic" refers to a ring that contains heteroatoms. The carbocyclic group may be fully saturated or partially saturated, but not aromatic. For example, carbocyclyl contains cycloalkyl. The cyclocarbyl and heterocyclyl structures contain compounds having a monocyclic, bicyclic or polycyclic ring system; and the system can mix aromatic, heterocyclic and carbocyclic rings. Mixed ring systems are described in terms of rings attached to other remaining portions of the described compounds.

As used herein, the term "heteroatom" refers to any atom other than carbon or hydrogen, such as nitrogen, oxygen, or sulfur. When it is a backbone or basic backbone of a chain or ring, the heteroatom must be at least divalent and is typically selected from nitrogen, oxygen, phosphorus and sulfur.

As used herein, the term "alkanoyl" refers to an alkyl group covalently linked to a carbonyl (C ═ O). The term "lower alkanoyl" means an alkanoyl group wherein the alkyl moiety is C₁-C₆. The alkyl portion of the alkanoyl group can be optionally substituted as described above. The term "alkanoyl" may be used alternatively. Similarly, the terms "alkenoyl" and "alkynoyl" refer to alkenyl or alkynyl groups, respectively, bonded to a carbonyl group.

As used herein, the term "Alkoxy "means that the alkyl group is covalently bonded to an oxygen atom; the alkyl group may be considered as replacing a hydrogen atom in the hydroxyl group. The term "lower alkoxy" refers to an alkoxy group wherein the alkyl moiety of the alkoxy group is C₁-C₆Alkoxy group of (2). The alkyl portion of the alkoxy group may be optionally substituted as previously described. As used herein, the term "haloalkoxy" refers to an alkoxy group in which the alkoxyalkyl moiety is substituted with one or more halo groups.

As used herein, the term "sulfo" refers to sulfonic acid (-SO)₃H) And (4) a substituent.

As used herein, the term "sulfamoyl" refers to a compound having the formula-S (O)₂)NH₂A substituent of the structure (la), wherein NH of said group₂Part of the nitrogen may optionally be substituted as described above.

As used herein, the term "carboxy" refers to-C (O)₂) A group of H structure.

As used herein, the term "carbamoyl" refers to-C (O)₂)NH₂A group of the structure (I), wherein NH in said group₂Part of the nitrogen may optionally be substituted as described above.

As used herein, the terms "monoalkylaminoalkyl" and "dialkylaminoalkyl" refer to-Alk₁-NH-Alk₂and-Alk₁-N(Alk₂)(Alk₃) Group of the structure (I) wherein Alk₁、Alk₂And Alk₃Refers to alkyl groups as previously described.

As used herein, the term "alkylsulfonyl" refers to-S (O)₂-a group of Alk structure, wherein Alk means an alkyl group as previously described. The terms "alkenylsulfonyl" and "alkynylsulfonyl" similarly mean a sulfonyl group covalently bonded to an alkenyl and alkynyl group, respectively. The term "arylsulfonyl" refers to-S (O)₂-Ar structure, wherein Ar denotes an aryl group as previously described. The term "aryloxyalkylsulfonyl" refers to the group-S (O)₂-Alk-O-Ar, wherein Alk is an alkyl group as previously described and Ar is an aryl group as previously described. The term "arylalkylsulfonyl" refers to-S(O)₂-a group of the structure AlkAr, wherein Alk is an alkyl group as defined above and Ar is an aryl group as defined above.

As used herein, the term "alkoxycarbonyl" refers to an ester substituent comprising an alkyl group, where the carbonyl carbon is the point of attachment to the molecule. Examples are ethoxycarbonyl, which is CH₆CH₂OC (O) -. Similarly, the terms "alkenyloxycarbonyl," "alkynyloxycarbonyl," and "cycloalkylcarbonyl" refer to similar ester substituents including alkenyl, alkynyl, or cycloalkyl groups, respectively. Similarly, the term "aryloxycarbonyl" refers to ester substituents, including aryl groups, where the carbonyl carbon is the point of attachment to the molecule. Similarly, the term "aryloxyalkylcarbonyl" refers to an ester substituent comprising an alkyl group, wherein the alkyl group is itself substituted with an aryloxy group.

Other combinations of substituents are known in the art and are described, for example, in U.S. patent No. 8,344,162 to Jung et al, which is incorporated herein by reference. For example, the term "thiocarbonyl" and combinations of substituents including "thiocarbonyl" include carbonyl groups in which doubly bonded sulfur replaces the normally doubly bonded oxygen in the group. The term "alkylene" and similar terms refer to an alkyl, alkenyl, alkynyl, or cycloalkyl group, as specified, having two hydrogen atoms removed from a single carbon atom such that the group is double bonded to the remainder of the group.

Aspects relating to the improved therapeutic use of substituted hexitol derivatives are described below, typically the substituted hexitol derivatives are selected from the group consisting of dianhydrogalactitol, a dianhydrogalactitol derivative, diacetyldianhydrogalactitol, a diacetyldianhydrogalactitol derivative, dibromodulcitol, and a dibromodulcitol derivative, unless otherwise specified. Preferably, the substituted hexitol derivative is dianhydrogalactitol unless otherwise specified. In some cases, derivatives of dianhydrogalactitol (such as compound analogs or prodrugs) are preferred, as set out below.

One aspect of the invention is controlled by timing of administration of the compound, dose-modifying agentsThe use of metabolic rates, use of normal tissue protective agents and other alterations of the compounds to improve the therapeutic use of substituted hexitol derivatives such as dianhydrogalactitol for the treatment of glioblastoma multiforme and medulloblastoma. General examples include: variations in infusion schedules (e.g., single (bolus) intravenous versus continuous infusion); the use of lymphokines (e.g., G-CSF, GM-CSF, EPO) to increase the white blood cell count to improve the immune response or to avoid anemia due to myelosuppressive agents; or the use of rescue agents such as folinic acid (leucovorin) for 5-FU treatment or thiosulfate for cisplatin treatment. Specific inventive examples directed to substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: continuous intravenous infusion for hours to days; the once-for-two-week administration is more than 5mg/m²The dosage per day; from 1mg/m according to tolerance of the patient²Gradually increasing the dose per day; at less than 1mg/m²Is administered for more than 14 days; use of caffeine to regulate metabolism; using isopickled acid tincture (isoniazid) to regulate metabolism; from 5mg/m in a single pass²Single and multiple doses are adjusted daily; the oral dosage is less than 30 or more than 130mg/m²(ii) a The oral dosage can reach 40mg/m²3 days and then a minimum/recovery period of 18 to 21 days; lower doses administered over a prolonged period of time (e.g., 21 days); higher degree of dosage; administering a dose with a minimum/recovery period longer than 21 days; administering a dose to achieve a concentration of substituted hexitol derivatives, such as dianhydrogalactitol, in the cerebrospinal fluid to an extent equal to or greater than 5 uM; administering a dose to the extent that a cytotoxic concentration is achieved in cerebrospinal fluid; or using said substituted hexitol derivatives, such as dianhydrogalactitol, as the sole cytotoxic agent.

Another aspect of the invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by altering the route of administration of the compounds. General examples include: changing the route from oral to intravenous administration and vice versa; or by specific routes such as subcutaneous, intramuscular, intraarterial, intraperitoneal, intralesional, intralymphatic, intratumoral, intrathecal, intravesicular, intracranial. Specific inventive examples directed to substituted hexitol derivatives, such as dianhydrogalactitol, for glioblastoma multiforme and medulloblastoma include: daily administration; weekly dosing; weekly dosing for three weeks; once every two weeks; once every two weeks for three weeks with a 1 to 2 week rest period; intermittent escalating dosing; or daily for one week for multiple weeks.

Yet another aspect of the invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by altering the stage of diagnosis/prognosis of the disease to which the compound is administered. General examples include: chemotherapy is used for unresectable local disease, prophylactic agents are used to avoid metastatic spread of tumors or to inhibit disease progression to more malignant stages. Specific inventive examples directed to substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: the use of substituted hexitol derivatives, such as dianhydrogalactitol, in combination with angiogenesis inhibitors, such as cistin (Avastin), which is a Vascular Endothelial Growth Factor (VEGF) inhibitor, to prevent or limit the spread of malignant cells, especially in the central nervous system; the use of substituted hexitol derivatives, such as dianhydrogalactitol, for newly diagnosed diseases; the use of substituted hexitol derivatives, such as dianhydrogalactitol, in recurrent diseases; the use of substituted hexitol derivatives, such as dianhydrogalactitol, for resistant or refractory diseases; or using substituted hexitol derivatives, such as dianhydrogalactitol, for example, in childhood glioblastoma.

Yet another aspect of the invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by altering the type of patient best suited or benefited from the use of the compounds. General examples include: pediatric doses for elderly patients, changing doses for obese patients; the use of concomitant disease conditions such as diabetes, cirrhosis of the liver or other conditions that may uniquely exploit the characteristics of the compounds. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: patients with disease conditions that are a large number of metabolic enzymes selected from the group consisting of histone deacetylases (histones deacetylase) and ornithine decarboxylases (ornithline decarboxylases); a patient with low or high sensitivity selected from the group consisting of thrombocytopenia and neutropenia; patients intolerant to gastrointestinal toxicity; patients with over-or under-expression of a gene characterized by being selected from the group consisting of c-Jun, GPCR, signaling protein, VEGF, prostate specific gene, and protein kinase; prostate specific genes and protein kinases; patients with EGFR characterized by excessive gene copy number for glioblastoma multiforme; a patient having at least one gene characterized by a mutation selected from the group consisting of TP53, PDGFRA, IDH1, and NF1 for glioblastoma multiforme; patients with methylation or lack of methylation characterized by the promoter of the MGMT gene; a patient with a deletion of one or more genes characterized by the distal portion of chromosome 17 (which is distal to the p53 gene for medulloblastoma); patients having a specific cytogenetic subpopulation characterized by being selected from the group consisting of (i) procurement of 6q or amplification of MYC or MYCN, (ii) an increase in 17q or i (17q) without procurement of 6q or amplification of MYC or MYCN, and (iii)6q and 17q balance or 6q deletion; patients with a mutation characterized by the presence of IDH 1; patients with a characteristic appearance of the wild-type IDH1 gene; patients with a co-deletion characterized by the presence of 1p/19 q; patients with high performance characterized by MGMT; patients with low grade presentation characterized by MGMT; or patients with mutations characterized by EGRF, including, but not limited to, third variants of EGRF.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by more precisely identifying the patient's tolerance, and metabolic and handling capabilities for the use of said compounds in association with the patient's specific phenotype. General examples include: the use of diagnostic tools and kits to better describe a patient's ability to process/metabolize a chemotherapeutic agent or the patient's susceptibility to toxicity due to a potentially specific cellular, metabolic or organ system phenotype. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: the use of a diagnostic tool, diagnostic technique, diagnostic kit or diagnostic test to confirm a particular phenotype of a patient; measuring the use of a marker selected from the group consisting of a protein selected from the group consisting of histone deacetylase, ornithine decarboxylase, VEGF, jun gene products, and protein kinase; a surrogate test; or low dose pretest for enzyme status.

Another aspect of the invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by more precisely identifying the patient's tolerance, and metabolic and handling capabilities for the use of said compounds in association with the patient's specific genotype. General examples include: biopsy samples of tumor or normal tissue (glial cells or other central nervous system cells) can be taken and analyzed to specifically tailor the use of drugs that are tailored to or monitor specific anti-gene targets; study of unique tumor gene expression patterns; or Single Nucleotide Polymorphisms (SNPs) to enhance efficacy or avoid normal tissue toxicity to which a particular drug is sensitive. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: diagnostic tools, techniques, kits and tests to confirm a patient's specific genotype; gene/protein expression wafers and assays; single nucleotide polymorphism assessment; a single nucleotide polymorphism of histone deacetylase, ornithine decarboxylase, GPCR, protein kinase, telomerase or jun; identification and measurement of metabolic enzymes and metabolites; determination of TP53 gene mutation; determination of PDGFRA gene mutations; determination of IDH1 gene mutation; determination of NF1 gene mutation; determination of the copy number of the EGFR gene; determination of the methylation status of the MGMT gene promoter; determination of cytogenetic subpopulation classification (for medulloblastoma); use of IDH1 mutations as disease features; use of wild-type IDH1 as a disease trait; use of 1p/19q co-deletion as a disease feature; use of the absence of 1p/19q co-deletion as a disease feature; the use of a methylated promoter region of the non-MGMT gene as a disease feature; use of a promoter region of the MGMT gene as a disease trait by methylation; use of high expression by MGMT as a disease trait; or use of low-grade expression by MGMT as a characteristic of disease.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by specially preparing the patient before or after the administration of chemotherapeutic agents. General examples include: induction or inhibition of metabolic enzymes, specific protection of sensitive normal tissues or organ systems. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: the use of colchicine or analogues; the use of diuretics such as probenecid (probenecid); use of uricase; non-oral use of nicotinamide; sustained release forms of nicotinamide; use of an inhibitor of Poly (adenosine diphosphate Ribose) Polymerase (Poly (ADP-Ribose) Polymerase); the use of caffeine; rescue of folinic acid; controlling infection; antihypertensive agents.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by the use of additional drugs or surgery to avoid or reduce potential side effects or toxicity. General examples include: the use of antiemetics, the use of anti-nausea agents, the use of hematologic support agents to limit or avoid neutropenia, anemia, thrombocytopenia, the use of vitamins, the use of antidepressants, the use of treatments for sexual dysfunction and other supportive techniques. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: the use of colchicine or analogues; the use of diuretics such as probenecid; use of uricase; non-oral use of nicotinamide; sustained release forms of nicotinamide; the use of an inhibitor of poly (adenosine diphosphate) ribose polymerase; the use of caffeine; rescue of folinic acid; the use of a sustained release form of allopurinol (allopurinol); non-oral use of allopurinol; bone marrow transplant stimulants, blood, platelet infusion, Neupogen, G-CSF; GM-CSF; pain management; an anti-inflammatory agent; a liquid; a corticosteroid; insulin control drugs; an antipyretic; treatment for nausea; treating diarrhea; n-acetyl cysteine; or antihistamines.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by monitoring the amount of drug after dosing to maximize the amount of drug in the patient's plasma, to monitor the production of toxic metabolites, and to monitor that auxiliary drugs may be beneficial or detrimental in terms of drug interactions. General examples include: monitoring of drug plasma protein combinations and monitoring of other pharmacokinetic or pharmacodynamic variables. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: multiple determinations of drug plasma concentrations; multiplex determination of metabolites in blood or urine.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by employing specific pharmaceutical compositions that in combination may provide more than additive or synergistic improvements in potency or side effect control. For polymorphic colloidsSpecific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of blastoma and medulloblastoma include: the use of a topoisomerases (topoisomerases) inhibitor in combination; the use of pseudo (froudulent) nucleosides in combination; pseudo nucleotide is used in combination; the thymidylate synthetase inhibitor is used in combination; the use of a signaling inhibitor in combination; co-using cisplatin or platinum analogs; using alkylating agents such as nitrosoureas (BCNU, gliadin implants (Gliadelwafers), CCNU, nimustine (ACNU), bendamustine (Trenda)); the use of DNA damaging alkylating agents at different sites than DAG (TMZ, BCNU, CCNU and other alkylating agents all damage DNA guanine O⁶Otherwise DAG is crosslinked to N⁷) (ii) a A monofunctional alkylating agent is used in combination; a bifunctional alkylating agent is used in combination; the anti-tubulin agent is used in combination; the antimetabolite is used in combination; used in combination with berberine (berberine); apigenin (apigenin) is used in combination; amonafide (amonafide) is used in combination; colchicine and analogues are used in combination; genistein (genistein) is used in combination; the etoposide is used in combination; using arabinoside (cytarabine) in combination; combretastatin (campothecins) was used in combination; vinca alkaloids (vinca alkaloids) are used together; the topoisomerase inhibitor is used in combination; 5-fluoropyrimidinedione (5-fluorouracil) is used in combination; matching curcumin (curcumin); the NF-kB inhibitor is used in combination; rosmarinic acid (rosmarinic acid) was used in combination; mitoguazone (), is used in combination; tetrandrine (tetrandrine) is used in combination; TMZ is used in combination; in combination with biological therapies, such as antibiotics such as cancerocin (a VEGF inhibitor), rituxin (Rituxan), Herceptin (Herceptin), Erbitux (Erbitux); the epithelial growth factor receptor inhibitor is used in combination; tyrosine kinase inhibitor is used in combination; the use of a poly (adenosine diphosphate) ribose polymerase inhibitor (PARP); or used in combination with cancer vaccine.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by using substituted hexitol derivatives, such as dianhydrogalactitol, as chemosensitizers, wherein no measurable activity is observed when used alone, but an improvement of more potency than additive or synergistic is observed when combined with other drugs. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: as a chemosensitizer in combination with a topoisomerase; as a chemosensitizer in combination with a pseudonucleoside; as a chemosensitizer in combination with a pseudonucleotide; as a chemosensitizer in combination with a thymidylate synthase inhibitor; as a chemosensitizer in combination with a signaling inhibitor; as a chemosensitizer in combination with cisplatin or a platinum analog; as chemosensitizers in combination with alkylating agents such as BCNU, BCNU implants, Gliadel, CCNU, bendamustine (Treanda), or temozolomide (Temodar); as a chemosensitizer in combination with an anti-tubulin agent; as a chemosensitizer in combination with an antimetabolite; as a chemosensitizer in combination with berberine; as a chemosensitizer in combination with apigenin; as a chemosensitizer in combination with amonafide; as chemosensitizers in combination with colchicine and analogs; as a chemosensitizer in combination with genistein; as a chemosensitizer in combination with etoposide; as a chemosensitizer in combination with arabinoside; as chemosensitizers in combination with camptothecins; as chemosensitizers in combination with vinca alkaloids; as a chemosensitizer in combination with a topoisomerase inhibitor; as a chemosensitizer in combination with 5-fluoropyrimidinedione; as a chemosensitizer in combination with curcumin; as a chemosensitizer in combination with an NF- κ B inhibitor; as a chemosensitizer in combination with rosmarinic acid; as a chemosensitizer in combination with mitoguazone; as a chemosensitizer in combination with tetrandrine; as a chemosensitizer in combination with a tyrosine kinase inhibitor; as a chemosensitizer in combination with an EGFR inhibitor; or as a chemosensitizer in combination with an inhibitor of poly (adenosine diphosphate) ribose polymerase.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by using substituted hexitol derivatives, such as dianhydrogalactitol, as a chemical enhancer, wherein less therapeutic activity is observed when used alone, but more improvement in potency than additive or synergistic is observed when combined with other unique drugs having therapeutic effects. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: as a chemical enhancer in combination with a topoisomerase; as a chemical enhancer in combination with a pseudo nucleoside; as a chemical enhancer in combination with a thymidine synthase inhibitor; as a chemical enhancer in combination with a signaling inhibitor; as a chemical booster in combination with cisplatin or platinum analogs; as a chemical booster in combination with alkylating agents such as BCNU, BCNU implants, Gliadel or bendamustine (Treanda); as a chemical booster in combination with an anti-tubulin agent; as a chemical enhancer in combination with an antimetabolite; as a chemical booster in combination with berberine; as a chemical enhancer in combination with apigenin; as a chemical enhancer in combination with amonafide; as a chemical enhancer in combination with colchicine and analogues; as a chemical enhancer in combination with genistein; as a chemical booster in combination with etoposide; as a chemical enhancer in combination with arabinoside; as a chemical booster in combination with camptothecin; as a chemical booster in combination with vinca alkaloids; as a chemical booster in combination with a topoisomerase inhibitor; as a chemical enhancer in combination with 5-fluoropyrimidinedione; as a chemical enhancer in combination with curcumin; as a chemical booster in combination with NF- κ B inhibitors; as a chemical enhancer in combination with rosmarinic acid; as a chemical enhancer in combination with mitoguazone; as a chemical enhancer in combination with tetrandrine; as a chemical booster in combination with a tyrosine kinase inhibitor; as a chemical booster in combination with an EGFR inhibitor; or as a chemical booster in combination with a poly (adenosine diphosphate) ribose polymerase inhibitor (PARP).

Yet another aspect of the invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by allowing the greatest benefit of treating patients with the compounds through medicine, therapy and diagnosis. General examples include: pain management, nutritional support, antiemetic agents, anti-nausea treatments, anti-anemia treatments, anti-inflammatory agents. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for glioblastoma multiforme and medulloblastoma include: concomitant use with pain management-related treatments; supporting nutrition; stopping vomiting; treatment for nausea; anti-anemia treatment; an anti-inflammatory agent; an antipyretic; an immunostimulant.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by using alternative therapies or methods to enhance benefit or reduce side effects. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: hypnosis; acupuncture and moxibustion; meditation; preparing herbs comprising NF- κ B inhibitor (such as parthenolide, curcumin or rosmarinic acid) synthetically or by extraction; natural anti-inflammatory agents (including rhein (rhein), parthenolide); immune stimulants (such as those found in Echinacea purpurea (Echinacea;. antibacterial agents (such as berberine);. flavonoids, isoflavones and flavones (such as apigenin, trihydroxyisoflavone (genistein), genistein, 6' -O-malonyl genistein, 6' -O-acetyl genistein, daidzein, daidzin (daidzin), 6' -O-malonyl daidzein, 6' -O-acetyl trihydroxyisoflavone, glycitein (glycitein), glycitin (glycitin), 6' -O-malonyl glycitein, and 6-O-acetyl glycitein);. Utilid muscle dynamics (appliekineticinogy) are used.

Yet another aspect of the invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by altering the drug substance bulk. General examples include: salt formation, homogeneous crystalline structure, purification of isomers. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: salt formation, homogeneous crystalline structure, purification of isomers, increased purity, reduced residual solvent, or reduced heavy metals.

Yet another aspect of the invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by varying the diluents used to solubilize and deliver/present the administered compounds. General examples include: Cremophor-EL, a cyclodextrin of a water-insoluble compound. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: using an emulsifier, dimethyl sulfoxide, N-methylformamide (NMF), Dimethylformamide (DMF), Dimethylacetamide (DMA), ethanol, benzyl alcohol; water for injection containing glucose; cremophor, cyclodextrin, PEG.

Yet another aspect of the invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by varying the use or need of a solvent for the administration or further dilution of the compound to be solubilized. General examples include: ethanol, Dimethylacetamide (DMA). Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: using emulsifier, dimethyl sulfoxide, N-methyl formamide, dimethyl acetamide, ethanol, benzyl alcohol; water for injection containing glucose; cremophor, cyclodextrin, PEG.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by modifying the materials/excipients, buffers or preservatives that are required to stabilize and present the compounds for proper administration. General examples include: mannitol, albumin, EDTA, sodium bisulfite and benzyl alcohol. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for use in the treatment of glioblastoma multiforme and medulloblastoma include: mannitol, albumin, EDTA, sodium bisulfite, benzyl alcohol, carbonate buffer, and phosphate buffer were used.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by modifying the potential dosage forms of the compounds depending on the route of administration, duration of effect, desired plasma concentrations, normal tissues exposed to side effects, and metabolic enzymes. General examples include: lozenges, sachets, topical gels, emulsions, patches, suppositories. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma include: lozenges, sachets, topical gels, emulsions, patches, suppositories, lyophilized dosage forms fillers (lyophilized dosagefils) are used.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol agents, for the treatment of glioblastoma multiforme and medulloblastoma by altering the dosage form, container/closure system, mixing and accuracy and presentation of the formulation. General examples include: brown bottles to avoid light, specially coated stoppers. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma include: brown bottles are used to avoid light, specially coated stoppers to increase shelf life stability.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by using a delivery system to enhance the potential value of the pharmaceutical product, such as convenience, duration of effect, reduction in toxicity. General examples include: nanocrystals, bioerodible polymers, liposomes, sustained release injectable gels, microspheres. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma include: nanocrystallites, bioerodible polymers, liposomes, sustained release injectable gels, microspheres are used.

Yet another aspect of the present invention is the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by altering the parent compound with covalent, ionic or hydrogen bonding moieties to alter the potency, toxicity, pharmacokinetics, metabolism or route of administration. General examples include: polymer systems such as polyethylene glycol, polylactic acid, polyglycolic acid, amino acids, peptides or polyvalent linker groups. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, in glioblastoma multiforme and medulloblastoma include: polymer systems such as polyethylene glycol, polylactic acid, polyglycolide, amino acids, peptides or polyvalent linkage groups are used.

Yet another aspect of the invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by altering the molecules such that improved drug performance is achieved using variants of the active molecules (by revealing the preferred active molecule due to partial cleavage of said molecule after introduction into the body). General examples include: enzyme-sensitive lipids, dimers, Schiff bases (Schiff bases). Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma include: enzyme-sensitive lipids, dimers, schiff bases, pyridoxal (pyridoxal) complexes, caffeine complexes are used.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by the use of additional compounds, biological agents, which when administered in an appropriate manner will have a unique and effective effect. General examples include: multiple drug resistance inhibitors, specific inhibitors of selective enzymes, signaling inhibitors, repair inhibitors. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma include: use of multiple drug resistance inhibitors, specific inhibitors of selective enzymes, signaling inhibitors, repair inhibition; topoisomerase inhibitors having non-overlapping side effects.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by using substituted hexitol derivatives, such as dianhydrogalactitol, as sensitizer/enhancer in combination with biological response modifiers. General examples include: use as a sensitizer/booster in combination with biological response modifiers, cytokines, lymphokines, therapeutic antibodies, antisense therapy, gene therapy. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma include: use as a sensitizer/enhancer in combination with a biological response modifier; a cytokine; a lymphokine; a therapeutic antibody; antisense therapies such as cistron, haaiping, rituximab and erbitux; gene therapy; a ribozyme; RNA interference; or a vaccine.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by employing a substituted hexitol derivative, such as dianhydrogalactitol, that is selected for use to overcome the full resistance to development or efficient use for biological therapy. General examples include: resistance of tumors to biological response modifiers, cytokines, lymphokines, therapeutic antibodies, antisense therapy, gene therapy effects. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma include: use of anti-tumor to biological response modifiers; a cytokine; a lymphokine; a therapeutic antibody; antisense therapy; such as Aisinting, rituximab, Heaiping, erbitux therapy; gene therapy; a ribozyme; RNA interference; or resistance to the effects of a vaccine.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by using the following in combination with free radiation, phototherapy, thermotherapy or radiofrequency generation therapy. General examples include: hypoxic cell sensitizers (hypoxiccell sensitizers), radiosensitizers/protectants, photosensitizers, and radiation repair inhibitors. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma include: free radiation is used in a matching way; an oxygen-deficient cell sensitizer is used in combination; a radiation sensitizer/protective agent is used in combination; the photosensitizer is used in a matching way; the radiation repair inhibitor is used in combination; depletion of the co-used thiol; matching and using a blood vessel targeting agent; matching radioactive seeds; matching and using radioactive nuclide; matching with a radioactive marker antibody; the therapy is administered in combination with brachytherapy (brachythermy). This is effective because radiotherapy is almost always used for the early treatment of glioblastoma multiforme, and the ability of this radiotherapy to improve efficacy or exert its synergistic effect is significant by combining radiotherapy with substituted hexitol derivatives such as dianhydrogalactitol.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by determining the biological targets of various effector molecules, compounds to optimize their utility by better understanding and more precisely to better utilize the utility of the molecule. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma include: use of an inhibitor of poly (adenosine diphosphate) ribose polymerase; agents that affect vascularity; a vasodilator; an agent of an oncogenic target; a signal transmission inhibitor; EGFR inhibition; protein kinase C inhibition; down regulation of phospholipid lipolytic enzyme C; regulating jun downwards; a histone gene; VEGF; ornithine decarboxylase; jun D; v-jun; a GPCR; protein kinase a; a telomerase; a prostate specific gene; a protein kinase; a histone deacetylase; and tyrosine kinase inhibitors.

Yet another aspect of the present invention is to improve the therapeutic use of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma by more precisely identifying and exposing those selected cell populations with a compound in which the effect of the compound can be maximized, particularly on tumor cells of glioblastoma multiforme and medulloblastoma. Specific inventive examples of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma include: use against radiation sensitive cells; use in radiation resistant cells; or against energy-depleted cells.

Accordingly, one aspect of the present invention is directed to a method of improving efficacy and/or reducing side effects of the administration of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme and medulloblastoma, comprising the steps of:

(1) identifying at least one factor or parameter associated with efficacy and/or occurrence of side effects for the administration of a substituted hexitol derivative, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme or medulloblastoma; and

(2) the factors or parameters are modified to improve efficacy and/or reduce side effects for the administration of substituted hexitol derivatives, such as dianhydrogalactitol, for the treatment of glioblastoma multiforme or medulloblastoma. Typically, the factor or parameter is selected from the group consisting of:

(1) dose modification;

(2) the route of administration;

(3) a dosing schedule;

(4) a use indication;

(5) selection of disease stage;

(6) other indications;

(7) selecting a patient;

(8) patient/disease phenotype;

(9) genotype of patient/disease;

(10) pre/post treatment preparation;

(11) managing toxicity;

(12) pharmacokinetic/pharmacodynamic monitoring;

(13) a pharmaceutical composition;

(14) chemical sensitization;

(15) chemical strengthening effect;

(16) patient management after treatment;

(17) replacement drug/therapy support;

(18) improving a raw material medicine product;

(19) a diluent system;

(20) a solvent system;

(21) an excipient;

(22) a dosage form;

(23) dose kits and packaging;

(24) a drug delivery system;

(25) a drug complex form;

(26) an analog of the compound;

(27) a prodrug;

(28) a multiple drug system;

(29) biological treatment synergy;

(30) biotherapeutic antagonism modulation;

(31) synergy of radiotherapy;

(32) a novel action machine is rotated; and

(33) selective targeted cell population therapeutics.

As detailed above, substituted hexitol derivatives according to the invention that are useful in methods or compositions in general include galactitols, substituted galactitols, dulcitols, and substituted dulcitols, including dianhydrogalactitols, diacetyldianhydrogalactitols, dibromodulcitols, and derivatives and analogs thereof. Typically, the substituted hexitol is selected from the group consisting of dianhydrogalactitol, a dianhydrogalactitol derivative, diacetyldianhydrogalactitol, a diacetyldianhydrogalactitol derivative, dibromodulcitol, and a dibromodulcitol derivative. Preferably, the substituted hexitol is dianhydrogalactitol.

When the improvement results from a dose modification, the dose modification can be, but is not limited to, at least one dose modification selected from the group consisting of:

(a) continuous intravenous infusion lasting hours to days;

(b) once every two weeks;

(c) greater than 5mg/m²The dosage per day;

(d) from 1mg/m according to tolerance of the patient²Gradually increasing the dose per day;

(e) use of caffeine to regulate metabolism;

(f) regulating metabolism with isosalting acid tincture;

(g) selection of the dose to be administered and intermittent stimulation;

(h) from 5mg/m in a single pass²Single and multiple doses adjusted daily;

(i) the oral dosage is less than 30mg/m²；

(j) The oral dosage is over 130mg/m²；

(k) The oral dosage can reach 40mg/m²A minimum/recovery period of 3 days and then 18 to 21 days;

(l) Lower doses administered over a prolonged period of time (e.g., 21 days);

(m) administering a higher degree of dosage;

(n) administration of a minimum/recovery period longer than 21 days;

(o) administering a dose to an extent to achieve a concentration of substituted hexitol derivatives, such as dianhydrogalactitol, in cerebrospinal fluid (CSF) of equal to or greater than 5 uM;

(p) administering a dose to an extent to achieve a cytotoxic concentration in cerebrospinal fluid; and

(q) or using a substituted hexitol derivative, such as dianhydrogalactitol, as the sole cytotoxic agent.

When the improvement results from a route of administration, the route of administration can be, but is not limited to, at least one route of administration selected from the group consisting of:

(a) topical administration;

(b) oral administration;

(c) sustained release oral administration;

(d) intrathecal administration;

(e) intraarterial administration

(f) Continuous transfusion;

(g) intermittent infusion;

(h) intravenous administration, such as intravenous administration for 30 minutes;

(i) administration through longer infusion;

(j) administration via intravenous bolus (IV push); and

(k) substituted hexitol derivatives, such as dianhydrogalactitol, are administered to achieve maximum concentration in the cerebrospinal fluid.

When the improvement results from a dosing schedule, the dosing schedule can be, but is not limited to, at least one dosing schedule selected from the group consisting of:

(a) daily administration;

(b) weekly administration

(c) Weekly dosing for three weeks;

(d) once every two weeks;

(e) once every two weeks for three weeks with a 1 to 2 week rest period;

(f) intermittent booster dosing; and

(g) daily dosing was continued for one week for several weeks.

When improvement results from disease stage selection, the disease stage can be, but is not limited to, at least one disease stage selected from the group consisting of:

(a) for appropriate disease stages against glioblastoma multiforme;

(b) for an appropriate disease stage for medulloblastoma;

(c) for newly diagnosed diseases;

(d) diseases for relapse;

(e) for resistant or refractory diseases; and

(f) for childhood glioblastoma.

When the improvement results from patient selection, the patient selection can be, but is not limited to, patient selection by at least one criterion selected from the group consisting of:

(a) selecting patients having a disease condition characterized by a plurality of metabolic enzymes selected from the group consisting of histone deacetylases and ornithine decarboxylases;

(b) selecting a patient having low or high sensitivity to a disorder selected from the group consisting of thrombocytopenia and neutropenia;

(c) selecting a patient who is intolerant to gastrointestinal toxicity;

(d) selecting a patient with over-or under-expression of a gene characterized by being selected from the group consisting of c-Jun, GPCR, signaling protein, VEGF, prostate specific gene, and protein kinase;

(e) selecting patients with EGFR genes characterized by excessive copy number for glioblastoma multiforme;

(f) selecting a patient having a mutation characterized by the occurrence of at least one gene selected from the group consisting of TP53, PDGFRA, IDH1, and NF1 for glioblastoma multiforme;

(g) selecting a patient having methylation or lack of methylation characterized by the promoter of the MGMT gene;

(h) selecting a medulloblastoma patient having a distal portion characterized by chromosome 17 (which is distal to the p53 gene) having one or more gene deletions;

(i) selecting patients having a specific cytogenetic subpopulation characterized by being selected from the group consisting of (i) acquisition of 6q or expansion of MYC or MYCN, (ii) acquisition of 17q or i (17q) without 6q acquisition or expansion of MYC or MYCN, and (iii)6q and 17q balance or 6q loss for medulloblastoma;

(j) selecting patients having a mutation characterized by the presence of IDH 1;

(k) selecting patients having a characteristic presence of a wild-type IDH1 gene;

(l) Selecting patients having a profile characterized by the presence of 1p/19q co-deletions;

(m) selecting patients having a characteristic lack of 1p/19q co-deletion;

(n) selecting patients with high performance characterized by MGMT;

(o) selecting patients with low performance characterized by MGMT; and

(p) selecting patients having mutations characterized by EGFR, including, but not limited to, the third variant of EGFR.

The cellular proto-oncogene c-Jun encodes a protein which, in combination with c-Fos, forms the AP-1 early response transcription factor. This proto-oncogene plays a key role in transcription and interacts with a large number of proteins that affect transcription and gene expression. It also involves cell proliferation and apoptosis of portions forming some tissues, including endometrial cells and glandular epithelial cells (glandular epithelial cells). G Protein Coupled Receptors (GPCRs) are important signaling receptors. The superfamily of G protein-coupled receptors (superfamilies) includes a large number of receptors. These receptors are membrane-major proteins characterized by an amino acid sequence comprising seven hydrophobic domains, predicted to be transmembrane spanning regions of the protein. They are found in a wide range of organisms and are involved in signal transmission to the interior of cells due to their interaction with heterotrimeric G proteins. They respond to a wide range of agents, including lipid analogs, amino acid derivatives, small molecules such as epinephrine and dopamine, and a wide variety of sensory stimuli. Many known GPCR properties are summarized in "The G-P" by S.Watson and S.ArkinstalProtein Linked receptors computers books "(Academic Press, London,1994), which is incorporated herein by reference. GPCR receptors include, but are not limited to, acetylcholine receptor, beta-adrenoceptor, beta₃-adrenoceptor, serotonin (5-hydroxytryptamine) receptor, dopamine receptor, adenosine receptor, angiotensin II receptor, bradykinin (bradykinin) receptor, calcitonin gene related receptor, cannabinoid receptor, cholecystokinin receptor, chemokine receptor, cytokine receptor, gastrin receptor, endothelin receptor, gamma-aminobutyric acid (GABA) receptor, galanin receptor, glucagon receptor, glutamate receptor, luteinizing hormone receptor, chorionic gonadotropin (CHOGONADOPROPHIN) receptor, follicle stimulating hormone receptor, thyroid stimulating hormone receptor, gonadal hormone releasing hormone receptor, leukotriene (Leukotriene) receptor, neuropeptide Y receptor, opioid (opium) receptor, parathyroid hormone receptor, platelet activating factor receptor, prostanoid (prostaglandin) receptor, prostaglandin receptor, and the like, Somatostatin receptors, thyrotropin-releasing receptors, vasopressin and oxytocin receptors.

Epithelial Growth Factor Receptor (EGFR) Mutations may be correlated with sensitivity of therapeutic agents such as Gefitinib (Gefitinib), as described in "EGFR Mutations in Lung Cancer: correction with clinical Response to Gefitinib" Science 304:1497-1500(2004), by J.G.Paez et al, which is incorporated herein by reference. A specific mutation in EGFR that is associated with an anti-Tyrosine Kinase inhibitor is known as the third Variant of EGRF, and is described in "Resistance to Tyrosine Kinase inhibition by mutation Epidermal Growth Factor Variant to the novel polypeptide type of EGFR Variant III inhibitors" (2004), which is incorporated herein by reference. The third variant of EGFR is characterized by its consistent and tumor-specific in-frame deletion of 801 base pairs from the extracellular domain, which cleaves out the codon and generates a new glycine at the fusion junction. This mutation encodes a constitutively active protein of deoxythymidine hormone, which enhances the tumorigenicity of cells bearing this mutation. The mutated protein sequence is clonally expressed in a significant proportion of glioblastomas, but not in normal tissues.

When the improvement results from an analysis of the patient or disease phenotype, the analysis of the patient or disease phenotype may be, but is not limited to, performing the analysis of the patient or disease phenotype by a method selected from the group consisting of:

(a) using a diagnostic tool, diagnostic technique, diagnostic kit or diagnostic test to confirm a particular phenotype of a patient;

(b) using a method to measure a marker selected from the group consisting of histone deacetylase, ornithine decarboxylase, VEGF, proteins that are gene products of jun, and protein kinases;

(c) the dose of the replacement compound; and

(d) low dose pretest for enzyme status.

When the improvement results from an analysis of the patient's or disease's genotype, the analysis of the patient's or disease's genotype may be, but is not limited to, performing a method of genotyping the patient's or disease by a method selected from the group consisting of:

(a) using a diagnostic tool, diagnostic technique, diagnostic kit or diagnostic test to confirm a particular genotype of a patient;

(b) using a gene chip;

(c) using gene expression analysis;

(d) using Single Nucleotide Polymorphism (SNP) analysis;

(e) measuring the amount of metabolite or metabolic ferment;

(f) determining a mutation in the PDGFRA gene;

(g) determining a mutation of IDH1 gene;

(h) determining a mutation in the NF1 gene;

(i) determining the copy number of the EGFR gene;

(j) determining the methylation state of the MGMT gene promoter;

(k) determining a cytogenetic subpopulation classification (for medulloblastoma);

(l) Determining the presence of the IDH1 mutation;

(m) determining the presence of wild-type IDH 1;

(n) determining the presence of a 1p/19q co-deletion;

(o) determining the absence of a 1p/19q co-deletion;

(p) determining the presence of an unmethylated promoter region of the MGMT gene;

(q) determining the presence of the methylated promoter region of the MGMT gene;

(r) determining the presence of high expression of MGMT; and

(s) methods of determining the presence of low grade expression of MGMT.

The use of gene chips is described in "DNA microarray in biological Discovery and patent Care" by A.J.Lee and S.Ramaswamy in essences of Genomic and personalized Medicine (G.S.Ginsburg & H.F.Willad, eds., Academic Press, Amsterdam,2010), Chapter seventh, pages 73 to 88, which is incorporated herein by reference.

When a Single Nucleotide Polymorphism (SNP) analysis method is used, the SNP analysis may be performed on a gene selected from the group consisting of histone deacetylase, ornithine decarboxylase, VEGF, prostate-specific gene, c-Jun, and protein hormone. SNP analysis is described in "DNA Sequencing for the Detection of human Genome Variation" by S.Levy and Y.H.Rogers in essences of Genomic and Personalized Medicine (G.S.Ginsburg & H.F.Willad, eds., Academic Press, Amsterdam,2010), Chapter III, pages 27 to 37, which is incorporated herein by reference.

Still other genomics techniques, such as copy number variation analysis and DNA methylation analysis, can be used. Copy Number Variation analysis is described in "Copy Number Variation and Human Health" by C.Lee et al, in essences of Genomic and Personalized Medicine (G.S. Ginsburg & H.F.Willard, eds., Academic Press, Amsterdam,2010), Chapter, pages 46 to 59, which is incorporated herein by reference. This approach is particularly significant for glioblastoma multiforme, since an increase in EGFR copy number is associated with a particular subtype of glioblastoma multiforme. DNA methylation Analysis is described in S.Cottrell et al, "DNA methylation Analysis: visualizing New Insight into Human Disease," essences of genomic and Personalized Medicine (G.S.Ginsburg & H.F.Willad, eds., academic Press, Amsterdam,2010), Chapter six, pages 60 to 72, which is incorporated herein by reference. This approach is particularly significant for glioblastoma multiforme, since the diagnosis for glioblastoma multiforme varies with the degree of methylation of the promoter of the MGMT gene.

When the improvement results from pre/post-treatment preparation, the pre/post-treatment preparation may be, but is not limited to, a method of pre/post-treatment preparation selected from the group consisting of:

(a) using colchicine or its analogues;

(b) use of uricosuric agents (uricosuric);

(c) use of uricase;

(d) non-orally administered nicotinamide;

(e) nicotinamide in a sustained release dosage form;

(f) use of an inhibitor of poly (adenosine diphosphate) ribose polymerase;

(g) use of caffeine;

(h) rescue by using folinic acid;

(i) controlling infection; and

(j) antihypertensive agents are used.

Uricosuric agents include, but are not limited to, probenecid, benzalkonium bromide (benzbromarone), and fensulazolone (sulfipyrazone). A particularly preferred uricosuric agent is probenecid. Uricosuric agents, including probenecid, may also have diuretic activity.

Adenosine diphosphate ribopolymerase Inhibitors are described in "Poly (ADP-Ribose) Inhibitors", Curr. Med. chem.10: 321-.

Folinic acid rescue involves administering an aldehydic acid to a patient who has been administered methotrexate (folacin). Folinic acid is in a reduced state of folic acid, and avoids the hydro-folate reductase and restores the hematopoietic function. Folinic acid can be administered intravenously or orally.

In one alternative, wherein the pre/post-treatment is with a uricosuric agent, said uricosuric agent is probenecid or an analog thereof.

When improvement results from toxicity management, the toxicity management may be, but is not limited to, a toxicity management method selected from the group consisting of:

(a) using colchicine or its analogues;

(b) use of uricosuric agents;

(c) use of uricase;

(d) non-orally administered nicotinamide;

(e) nicotinamide in a sustained release dosage form;

(f) use of an inhibitor of poly (adenosine diphosphate) ribose polymerase;

(g) use of caffeine;

(h) rescue by using folinic acid;

(i) allopurinol in a sustained release formulation;

(j) allopurinol is used for non-oral administration;

(k) bone marrow transplantation is used;

(I) the use of a blood cell stimulant;

(m) use of blood or platelet transfusions;

(n) administration is selected from the group consisting of filgrastimAn agent selected from the group consisting of G-CSF and GM-CSF;

(o) applying pain management techniques;

(p) administering an anti-inflammatory agent;

(q) a dosing liquid;

(r) administering a corticosteroid;

(s) administering an insulin management medication;

(t) administering an antipyretic;

(u) administration of an anti-nausea treatment;

(v) administration of antidiarrheal treatments;

(w) administering N-acetyl cysteine; and

(x) Antihistamines are administered.

Filgrastim, an analogue of granulocytic colony-stimulating factor (G-CSF), is produced by recombinant DNA technology, and is used to stimulate the proliferation and differentiation of granulocytes and to treat neutropenia; G-CSF can be used in a similar manner. GM-CSF is a granulocyte macrophage cell line stimulating factor and stimulates stem cells to produce granulocytes (eosinophils, neutrophils and basophils) and monocytes; the administration thereof is effective for preventing or treating infection.

Anti-inflammatory agents are well known in the art and include corticosteroids and non-steroidal anti-inflammatory agents (NSAIDs). Corticosteroids having anti-inflammatory activity include, but are not limited to, hydrocortisone, corticosterone, beccortolone diproprionate, beccortolone, discodermol (dexamethasone), prednisone (prednisone), methylprednisolone acetate, triamcinolone, fluorohydrocortisone acetonate, and fluorohydrocortisone (fluorocortisone). Non-steroidal anti-inflammatory agents include, but are not limited to, acetylsalicylic acid (aspirin), sodium salicylate, choline magnesium trisalicylate (choline magnesium trisalicylate), salsalate (salsalate), diflunisal (diflunisal), sulfasalazine (sulfasalazine), salazine (olsalazine), acetaminophen (acetaminophen), indomethacin (indomethacin), sulindac (sulindac), tolmetin (tolmetin), diclol (diclofenac), clorac (ketorolac), isoibuprofen (uplofen), naproxen (naproxen), flurbiprofen (flurbiprofen), cetoperfen (ketoprofen), nonfonoprofen (fenoprofen), saproprofen (oxyprofen), fenamic acid (fenamic acid), fenacil (fenamic acid), meclofenamic acid (fenamic acid), fenamic acid (fenacet), fenamic acid (fenamic acid), sulfasalazine (doxine), salazine (olsalazine), acetaminophen (losamide (acetofenamic), acetaminophen (ketoprofen), acetofenamic acid (ketoprofen), clofenamic acid (ketoprofen), clorac), clofenamic acid (naloxone), clorac (naloxone), clofenac (naloxone), naloxone (naloxone), naloxone (naloxone), naloxone (, Alclofenac (alclofenac), carprofen (alminoprofen), amfenac (amfenac), ampiroxicam (ampiroxicam), azapropazone (apazone), alaprofen (araprofen), azapropazone (azapropazone), bendazac (bendazac), benoxaprofen (benoxaprofen), benproperine (benzydamine), bucloxacin (brornfenac), bucloxic acid (bucloxicac), bumazone (bumazone), butibubufen (butibubufen), ibuprofen (carprofen), cimetixib (cioxexib), cinnamic acid (cinmetametacin), piroxicam (indoxacillin), clofenac (clofenac), clofenamic acid (clofenazamide), oxyprofen (alclofenac), oxyprofen (alcalix), oxypfen) (alcalix), alcalix (alcalix), alcalix (alcalix), alcalix (alcalix), etoricoxib (etoricoxib), felbinac (elbinac), fenbufen (fenbufen), fenclorac (fenclorac), fenclorac (fenclozine), fendorsum (fendorsal), fentiac (fentiazac), feprazone (feprazone), felbinad (filenadol), flubufen (flobufen), flufenine (flonifenine), flusulamide (floride), forobicin mesylate (fluubicin), flufenamic acid (flufenamic acid), flufenisal (flufenisal), flunixin (flufenacin), flunoprofen (flufenoprofen), fluprofen (flufenamic acid), fluquinacr (flufenamic acid), flufenamic acid (fenpyr), ibuprofen (fenoprofen), ibuprofen (ibuprofen), ibuprofen (ibuprofen), ibuprofen (fenoprofen (ibuprofen (fenfluroxyprofen), ibuprofen (fenoprofen (fenbucloxacin), ibuprofen (fenbucloxacin), ibuprofen (fenbucloxacin), ibuprofen (ibuprofen), ibuprofen (ibuprofen), ibuprofen (fenbucloxacin), ibuprofen (ibuprofen), ibuprofen (fenbucloxacin), ibuprofen mabuprofen, miroprofen (miroprofen), mofebuprofen (mofebutazone), moxezolid (mofezolac), phenobizine (morazone), nepafenac (nepafenac), niflumic acid (niflumic acid), niflumic acid sodium (nitrofenic acid), nifluminbrofen (nifluminbrofen), nitofliprole (nitynaprox), oxyphenoxacin (oxyphenoxaprofen), oxaziro (oxazerol), indac (oxindanac), ospiral (oxypinac), oxyphenbutazone (oxyphentabuzole), pamidrogrel (pamicogrel), pamifloxacosan (paclitasal), parecoxyprofen (oxypheniflozin), salbutamol (pamil), salbutamol (salbutamol), salbutamol (salbutamol) and salbutamol (salbutamol) including salbutamol), salbutamol (salbutamol), Examples of suitable therapeutic agents include, but are not limited to, talniflumate (talniflumate), tazofelone (tazofelone), terbuferone (tebufelone), tenidap (tenidap), tenuacai (tenoxicam), tipoxilin (tepoxalin), tiprofenic acid (tiaprolic acid), tylamexane (tiaramide), temacoxib (tilmacoxib), tenoxidine (tinidine), tiopinac acid (tiopinac), tioxaprofen (tioxaprofen), tolfenamic acid (tolfenamic acid), triflusal (triflusal), indomethacin (tropin), ursolic acid (ursolic acid), valdecoxib (valdecoxib), simoprofen (ximenfen), zaprofen (ltoprofen), ziprofen (lipofectin), zidometacin (mefenocin), and zomepirac, and their salts and solvates, prodrugs, and metabolites, biological metabolites, and metabolites thereof.

Clinical use of corticosteroids is described in b.p. schimmer and k.l. parker as "Adrenocorticotropic Hormone; adrenocortical Steroids and theri synthetic analogs; inhibitors of the Synthesis and Actions of Adenopharmaceutical Hormones "in Goodman&Gilman’s The Pharmacological Basis of Therapeutics(L.L.Brunton,ed.,11^thed.,McGraw-Hill, New York,2006), chapter 59, pages 1587 to 1612, which is incorporated herein by reference.

Anti-nausea treatments include, but are not limited to, ataractin (ondansetron), metoclopramide (metoclopramide), promethazine (promethazine), phenylpyrazine (cyclopizine), scopolamine (hyoscine), dronabinol (dronabinol), theophylline dibenzine (dimehydramine), diphenhydramine (diphenhydramine), carboxyethyl (hydroxyzine), meperidine (medizine), dolasetron (dolasetron), compactin (granisetron), palonosetron (palosetron), ramosetron (ramosetron), domperidone (domperidone), hampalonolide (haloperidol), chlorothiazide (chlorothiazine), fluphenazine (phenazine), phenazine (phenazine), meptazine (meptazinone), meptyline (propylhexythine), and meptyline (propylhexythine).

Antidiarrheal treatments include, but are not limited to, difenoxolone (diphenoxylate), difenoxin (difenoxin), loperamide (loperamide), codeine (codeine), racecadotril (racecadotril), grams solarization (octreoside), and berberine.

N-acetyl cysteine is an antioxidant and has mucolytic properties, which also provides biologically acceptable sulfur.

Adenosine diphosphate ribose polymerase (PARP) inhibitors include, but are not limited to: (1) tetracyclin derivatives as described in Duncan et al, U.S. Pat. No. 8,338,477; (2) 3, 4-dihydro-5-methyl-1 (2H) -isoquinoline, 3-aminobenzamide, 6-aminonicotinamide, and 8-hydroxy-2 methyl-4 (3H) -quinazolinone, as described in U.S. patent No. 8,324,282 to Gerson et al; (3) 6- (5H) -phenanthridinone and 1, 5-isoquinolinediol as described in U.S. Pat. No. 8,324,262 to Yuan et al; (4) (R) -3- [2- (2-hydroxymethylpyrrol-1-yl) ethyl ] -5-methyl-2H-isoquinolin-1-one as described in U.S. Pat. No. 8,309,573 to Fujio et al; (5) 6-alkenyl-substituted 2-quinolinones, 6-phenylalkyl-substituted 2-quinolinones, 6-alkenyl-substituted 2-quinoxalinones, 6-phenylalkyl-substituted 2-quinoxalinones, substituted 6-cyclohexylalkyl-substituted 2-quinolinones (substistuted 6-cyclohexylalkyl substistuted 2-quinolinones), 6-cyclohexylalkyl-substituted 2-quinoxalinones, substituted pyridinones, quinazolinone derivatives, and substituted 2-alkyl quinazolinone derivatives as described in Vialard et al, U.S. Pat. No. 8,299,256; (6) 5-bromoisoquinoline, as described in U.S. Pat. No. 8,299,088 to Mateucci et al; (7) 5-bis- (2-chloroethyl) amino ] -1-methyl-2-benzimidazolebutanoic acid, 4-iodo-3-nitrobenzamide, 8-fluoro-5- (4- ((methylamino) methyl) phenyl) -3, 4-dihydro-2H-azepino [5,4,3-cd ] indol-1 (6H) -one phosphoric acid, and N- [3- (3, 4-dihydro-4-oxo-1-daizinyl) phenyl ] -4-morpholinebutanamide methanesulfonate as described in U.S. Pat. No. 8,227,807 to Gallagher et al; (8) pyridazinone (pyridazinone) derivatives as described in U.S. patent No. 8,268,827 to branch et al; (9) 4- [3- (4-cyclopropanecarbonyl-piperazino-1-carbonyl) -4-fluorobenzyl ] -2H-phthalazin-1-one as described in Menear et al, U.S. patent No. 8,247,416; (10) tetraazaphenaen-3-one compounds (tetraazaphenalen-3-one) as described in U.S. Pat. No. 8,236,802 to Xu et al; (11) 2-substituted-1H-benzimidazole-4-carboxamides, such as Zhu et al, U.S. Pat. No. 8,217,070; (12) substituted 2-alkylquinazolinones as described in Van derAa et al, U.S. patent No. 8,188,103; (13) 1H-benzimidazole-4-carboxamides as described in Penning et al, U.S. Pat. No. 8,183,250; (13) indenoisoquinolinone analogs as described in U.S. patent No. 8,119,654 to Jagtap et al; (14) benzoxazole carboxamides (benzoxazole carboxamides) as described in Chu et al, U.S. Pat. No. 8,088,760; (15) diazabenzo [ de ] anthracen-3-one (diazabenzo [ de ] anthracen-3-one) compounds as described in U.S. Pat. No. 8,058,075 to Xu et al; (16) dihydropyridinophthalazinones as described in Wang et al, U.S. patent No. 8,012,976; (17) substituted azaindoles as described in U.S. patent No. 8,008,491 to Jiang et al; (18) fused tricyclic compounds as described in Chua et al, U.S. patent No. 7,956,064; (19) substituted 6a,7,8, 9-tetrahydropyridine [3,2-e ] pyrrolo [1,2-a ] pyrazin-6 (5H) -ones as described in U.S. patent No. 7,928,105 to Gangloff et al; and (20) thieno [2,3-c ] isoquinolines as described in U.S. patent No. 7,825,129, all of which are incorporated herein by reference. Other PARP inhibitors are known in the art.

Where improvement results from monitoring of pharmacokinetics/pharmacodynamics, the monitoring of pharmacokinetics/pharmacodynamics may be, but is not limited to, a method selected from the group consisting of:

(a) multiplex determination of plasma concentrations; and

(b) multiplex determination of at least one metabolite in blood or urine.

Typically, the determination of the plasma concentration or the determination of the at least one metabolite in the blood or urine is performed by an immunoassay. Methods of manipulating immunoassays are well known in the art and include radioimmunoassay (radioimmunoassay), ELISA (enzyme-linked immunosorbent assay), competitive immunoassay (competitive immunoassay), immunoassay using lateral flow assay plates, and other assays.

When the improvement results from a pharmaceutical composition, the pharmaceutical composition can be, but is not limited to, a pharmaceutical composition selected from the group consisting of:

(a) the topoisomerase inhibitor is used in combination;

(b) the pseudo nucleoside is used in combination;

(c) pseudo nucleotide is used in combination;

(d) the thymidylate synthetase inhibitor is used in combination;

(e) the use of a signaling inhibitor in combination;

(f) co-using cisplatin or platinum analogs;

(g) a monofunctional alkylating agent is used in combination;

(h) a bifunctional alkylating agent is used in combination;

(i) the anti-tubulin agent is used in combination;

(j) the antimetabolite is used in combination;

(k) used in combination with berberine;

(l) The apigenin is used in combination;

(m) amonafide is used in combination;

(n) use of vinca alkaloids in combination;

(o) use of 5-fluoropyrimidinedione in combination;

(p) curcumin is used in combination;

(q) co-using NF- κ B inhibitor;

(r) rosmarinic acid is used in combination;

(s) mitoguazone in combination;

(t) tetrandrine is used in combination;

(u) use with VEGF inhibitors;

(v) the cancer vaccine is matched and used;

(w) co-using an EGFR inhibitor;

(x) Tyrosine kinase inhibitor is used in combination; and

(y) use of a poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor in combination.

Topoisomerase inhibitors include, but are not limited to, irinotecan (irinotecan), carcinosad (topotecan), camptothecin (camptothecin), lamellarin d (lamellarin d), amsacrine (amsacrine), etoposide phosphate, teniposide (teniposide), doxorubicin (doxorubicin), and ICRF-193.

Pseudonucleosides include, but are not limited to, cytarabine (cytisine arabinoside), gemcitabine (gemcitabine), and fludarabine (fludarabine); other pseudo nucleosides are known in the art.

Pseudonucleotides include, but are not limited to, tenofovir disoproxil fumarate (tenofovir disoproxil fumarate) and adefovir dipivoxil (adefovir dipivoxil); other pseudo nucleotides are known in the art.

Thymidine synthetase inhibitors include, but are not limited to, raltitrexed (raltitrexed), eltoprene (pemetrexed), nolatrexed (nolatrexed), ZD9331, GS7094L, fluoropyrimidinedione, and BGC 945.

Signal transduction inhibitors are described in "New Mechanisms of Signal transduction Inhibitor Action: Receptor type kinase Down-Regulation and Signal transduction of" Clin. cancer Res.9:516s (2003) by A.V.Lee et al, which is incorporated herein by reference in its entirety.

Alkylating agents include, but are not limited to, wild (Shionogi)254-S, aldophosphamide (aldophosphamide) analogues, altretamine (altretamine), anaximone (anaxiron), Boehringer Mannheim BBR-2207, bendamustine (bendamustine), Starobustil (bestanil), titanium buditane (buditane), Yongguana (Wakunaga) CA-102, carboplatin, carmustine (BCNU), cisplatin concentrate-139, Qinong-153, chlorambucil (chlorembucil), cyclophosphamide, cyanamide (American Cyanamid) CL-286558, Sanofi) CY-233, Serratite (cyplatate), Dessaga D-19, Myophosphamide (CHMOP)₂Diphenylspiromustine (spiromustine), diclosartan, Erba distamycin (distomycin) derivatives, Zhongyuan pharmaceutical (Chugai) DWA-2114R, ITI E09, emetine (elmustine), Erbamong (Erbamemont) FCE-24517, estramustine () sodium phosphate, fotemustine (fotemustine), ewingiderd (Unimed) G-6-M, Qinong GYKI-17230, von Schifanum (hepsulfam), ifosfamide (ifosfamide), iproplatin (iproplatin), lomustine (lomustine) (CCNU), macsfamide (macfosfamide), melphalan (mellan), dibromolactitol (linolctol), nimustine (acylustine) (ACUppyu), Nippon (npryon) NSphan-36, NCkinin-121, Nippon-C-12, nipuline (NCkinine), nipuline (NCkinine), Nippon-12-N-S-E (NCP-E) C-S-1, and N-S-E (NCP-S-1, N-S-2, and S-2, Semustine (semustine), Kurarin Schk (SmithKline) SK&F-101772, Yanogluca (Yakult Honsha) SN-22, (spiromustine), Tianbian (Tanabe Seiyaku) TA-077, (tauromustine) talozine, temozolomide (temozolomide), tirilone (teroxirone), tetrabenatin (tetraplatin), and trimelamol (trimelamol), as described in U.S. Pat. No. 7,446,122 to Chao et al, which is incorporated herein by reference. In particular toFor the treatment of glioblastoma multiforme, alkylating agents such as temozolomide (temozolomide), BCNU, CCNU and ACNU; all of these alkylating agents have an O-to-guanine effect on DNA⁶Cause damage while DAG is at N⁷Cross-linking occurs); an alternative is thus to use DAG in combination with an alkylating agent that causes damage to DNA at a different location than DAG. The alkylating agent may be a monofunctional alkylating agent or a difunctional alkylating agent. Monofunctional Alkylating Agents include, but are not limited to, carmustine, temozolomide and dacarbazine as described in "DNA Damage Induced by Alkylating Agents and Repair Pathways" J.Nucl.Acidsdoi:10.4061/2010/543531(2010), N.Kondo et al, which is incorporated herein by reference; monofunctional Alkylating Agents also include such Agents as methyl methanesulfonate, ethyl methanesulfonate and N-methyl-N-nitrosoguanidine, as described in J.M.walling and I.J.Stratford, "methylation by monoclonal Alkylating Agents" M radial. Oncol.biol.Phys.12: 1397-Across 1400(1986), which is incorporated herein by reference. Bifunctional alkylating agents include, but are not limited to, mechlorethamine phenylbutyrate, cyclophosphamide, butacaine sulfate (butalfan), nimustine, carmustine, lomustine, fotemustine, and bis- (2-chloroethyl) sulfide (N.Kondo et al (2010),supra). An important class of bifunctional alkylating agents includes O as guanine in DNA⁶An alkylating agent that is the target.

Anti-tubulin agents include, but are not limited to, vinca alkaloids, taxanes (taxanes), podophyllotoxins (podophylotoxin), halichondrin b (halichondrin b), and halichondrin b (homohalichondrin b).

Antimetabolites include, but are not limited to: amitrafolic acid, etidina (), 5-fluoropyrimidinedione, capecitabine, arabinoside, gemcitabine, 6-mercaptopurine (6-mertepurine), and pentostatin, alanosine, AG2037 (Pfizer), 5-FU-dione-fibrinogen (5-FU-fibrinogen), acanthoic acid (acanthofolinic acid), aminothiadiazole, brequinar sodium (brequinadonium), carmofur (carmofur), Ciba-Gedeoxygenigy CGP-30694, cyclopentylcytosine, arabinoside stearophosphate, arabinoside conjugate, lillan (DATHF), Meilin channel (Meilin-Dow) DDFC, deazaguanine (deazaguanine), dideoxyadenine (doxine), diphytidine (doxine), pentostatin (doxine), nordoxine (doxine), doxine (DMtrosine & doxine), doxine (DMtrosine & 015), doxine (doxine), doxine (Medoxine) and mexican (doxine (DMtrosine Co) Fazarabine (fazarabine), floxuridine (floxuridine), fludarabine phosphate (fludarabine phosphate), N- (2 '-tetrahydrofuryl) -5-fluoropyrimidinedione (N- (2' -furidinyl) -5-fluoroouracil), first drug (Daiichi Seiyaku) FO-152, isopropylpyrrolizine (isoproxylinazine), Li-188011, Li-264618, methoxazepine (methoxazpam), aminomethylfolic acid, Huikang MZPES, norspermidine (norspertidine), NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert (PALA), pirtricin (pirimicin), Wuxuri-propidin (788), thizamycin (Aciflavine), Taguanidium-L-8, Takara (Acrylamide-N), Trifluzine (Acrylamide), Trifludarabine (Aciflavine), Tributine (Aciflavine) PALA (Aciflavine), Tributine (Aciflavine) and Tributine (Aciflavine), Tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Roc pharmaceuticals (Taiho) UFT, and eugenol (uricysin).

Berberine has antibiotic activity and avoids and inhibits the expression of pro-inflammatory (pro-inflammatory) kinase and E-selectin, while also increasing the expression of adiponectin (adiponectin).

Apigenin is a flavone that reverses the undesirable effects of cyclosporine and has chemoprotective activity, either alone or in combination with a carbohydrate derivative.

Amonafide is a topoisomerase inhibitor and a DNA intercalator with antitumor activity.

Curcumin is believed to have anti-tumor, anti-inflammatory, antioxidant, anti-ischemic (anti-ischemic), anti-arthritic (anti-arthritic) and anti-amyloidogenic (anti-amyloid) properties and also has hepatoprotective activity.

NF-. kappa.B inhibitors include, but are not limited to, bortezomib (bortezomib).

Rosmarinic acid is a naturally occurring phenolic antioxidant that also has anti-inflammatory activity.

Mitoguazone is an inhibitor of poly-amino synthesis, S-adenosylmethionine, via competitive inhibition of S-adenosylmethionine decarboxylase.

Tetrandrine has the chemical structure 6,6',7, 12-tetramethoxy-2, 2' -dimethyl-1 β -cupramman (berbaman) and is a calcium channel blocker, which has anti-inflammatory, immunological and antiallergic effects, and also has antiarrhythmic effects similar to quinidine (quinidine). It has been isolated from the Stephania tetrandra (Stephania tetrandra) and other asian herbs.

VEGF inhibitors include bevacizumab (carcinostat), which is a monoclonal antibody to VEGF, itraconazole (itraconazole), and suramin (); and batimastat (batimastat) and marimastat (marimastat), which are inhibitors of matrix metalloproteinases (matrix metalloproteinases), and cannabinoids and derivatives thereof.

Cancer vaccines are being developed. Typically, cancer vaccines are based on an immune response by proteins or some proteins that appear in cancer cells but not in normal cells. Cancer vaccines include Provenge against metastatic hormone resistant prostate cancer; oncophage against kidney cancer; CimaVax-EGF for lung cancer; MOBILAN; neuvenge against Her 2/neu-expressing cancers such as breast, rectal, bladder and ovarian cancers; stimuvax for breast cancer, and others. Cancer Vaccines are described in "Cancer Vaccines: antigens and" Vaccines "of crit. rev. oncol.hematol.67:93-102(2008) by s.pejawar-Gaddy and o.finn, which is incorporated herein by reference.

Epithelial Growth Factor Receptors (EGFR) are present on the cell surface of mammalian cells and are activated by binding of the receptor to its specific ligand, including, but not limited to, epithelial growth factor and transforming growth factor alpha. When the receptor is activated by binding to its growth factor ligand, EGFR undergoes a transition from the inactive monomeric form to an active homodimer (homomodimer), although a preformed active dimer may be present prior to ligand binding. In addition to forming active homodimers upon ligand binding, EGFR may be paired with additional ErbB receptor family members, such as ErbB2/Her2/neu, to create activated heterodimers (heterodimmers). There is also evidence that clusters of activated EGFR will form, although it remains unknown whether this clustering behavior is important for activation itself or whether activation of dimers will ensue. EGFR dimerization triggers endogenous protein (intrinsic protein) -tyrosine kinase activity inside its cells. Thus, autophosphorylation occurs at various tyrosine residues in the carbonyl-terminal domain of EGFR. These residues include Y992, Y1045, Y1068, Y1148 and Y1171. This autophosphorylation causes downstream activation, and many other proteins associated with phosphorylated tyrosine residues signal through their own phosphotyrosine-binding SH2 domain. The signaling of these proteins associated with phosphotyrosine residues through their own phosphotyrosine-binding SH2 domain can then initiate multiple signal transduction cascades and trigger DNA synthesis and cell proliferation. The kinase domain of EGFR is also capable of cross-phosphorylating tyrosine residues of other co-aggregated receptors and itself can be activated in this way. EGFR is encoded by the c-erbB1 proto-oncogene and has a molecular weight of 170 kDa. EGFR is a transmembrane glycoprotein with an outer region rich in the cystine membrane and has an intracellular domain containing an uninterrupted tyrosine kinase site, and multiple autophosphorylation sites clustered at the end of the carbonyl terminus as described above. The extracellular portion has been divided into four domains: domains I and III, which have 37% sequence identity, are cysteine-poor and conformationally contain sites for ligand binding (EGF and transforming growth factor alpha (TGF α)). Cystine-rich domains II and IV contain N-linked glycosylation sites and disulfide bonds that determine the tertiary structure of the outer domain of the protein molecule. In many human cell lines, TGF α expression and EGFR overexpression are strongly correlated, and therefore TGF α is thought to act in an autocrine manner, stimulating cell proliferation, and to be produced in cells by activation of EGFR. Binding of stimulatory ligands to the extracellular domain of EGFR leads to receptor dimerization and initiation of intracellular signaling, the first step of which is activation of tyrosine kinases. The initial result of kinase activation is phosphorylation of its own tyrosine residues (autophosphorylation) as described above. Activation of the signaling entity then accompanies mitogenesis. Mutations that lead to EGFR expression or overactivity are implicated in several malignancies, including glioblastoma multiforme. Specific mutations of EGFR are known as the third variant of EGFR which is frequently observed in glioblastomas (C.T. Kuan et al, "EGF Mutant Receptor VIII as a Molecular Target in cancer Therapy," endo. Relat. cancer 8:83-96(2001), which is incorporated herein by reference). EGFR is considered an oncogene (oncogene). Inhibitors of EGFR include, but are not limited to, erlotinib (erlotinib), gefitinib (gefitinib), lapatinib (lapatinib), lapatinib tosylate, afatinib (afatinib), canertinib (canertinib), noratinib (neratinib), CP-724714, WHI-P154, TAK-285, AST-1306, ARRY-334543, ARRY-380, AG-1478, tyrphostin 9, dacomitinib (dacomitinib), desmethylerlotinib (desmethylleotinib), OSI-420, RLD 8931, AEE788, belitinib (pelitinib), CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, HCI, BMS-599626, BW 92, BILITI 35420, VaVATInib 724714 and OSI (OSI). Particularly preferred EGFR inhibitors include erlotinib, afatinib, and lapatinib.

Tyrosinase inhibitors include, but are not limited to, imatinib, gefitinib, erlotinib, sunitinib (sunitinib), sorafenib (sorafenib), nonrectinib (foretinib), cedatinib (cedeinib), axitinib (axitinib), fibula (carbozantinib), BIBF1120, covatinib (golvatinib), dasatinib (dovidinib), zmm 306416, ZM 323881HCI, SAR 131675, sibirib (semaxinib), tiratinib (telatinib), pazopanib (pazopanib), ponatinib (ponatinib), crenolanib (crenolanib), tivatinib (tivatiib), tilidinib (tiratinib), ibrib (soratinib), tanatinib (soratinib), tanariunib (sorafenib), taratinib (troginib), tanicinib (troginib), tanicinfitinib (troginib), tanicinib (troginib), tanicinficinib (troginib), tanicinib (troginib), tanicinfib (troginib), tanicinfigub), tanicidinib (troginib), tanicinfigub), tanib (troginib), tanicidinib (troginib), tanicib), tanicidinib), tanici. These tyrosine kinase inhibitors may inhibit tyrosine kinases associated with one or more of the following receptors: VEGFR, EGFR, PDGFR, c-Kit, c-Met, Her-2, FGFR, FLT-3, IGF-1R, ALK, c-RET and Tie-2. When the activity of the Epithelial Growth Factor Receptor (EGFR) is related to the activity of tyrosine kinases, the class of tyrosine kinase inhibitors is duplicated by the species of EGFR inhibitors. Several tyrosine kinase inhibitors inhibit the activity of EGFR and at least one other tyrosine kinase. In general, tyrosine kinase inhibitors can be controlled by four different mechanisms: competes with Adenosine Triphosphate (ATP) and is used by tyrosine kinase to perform phosphorylation reaction; competition with the substrate; competition with ATP and substrate; or allosteric inhibition (allosteric inhibition). The activity of these Inhibitors is disclosed in "Blocking of EGF-Dependent Cell promotion by EGF Receptor Kinase Inhibitors" Science242:933-935(1988) by P.Yaish et al; garzit et al, "tyrphos.2. heterocyclic and oi-subdivided conjugated quinonedienemalononitrile genera as post Inhibitors of EGFRReceptor and ErbB2/neu Tyrosine Kinases" J.Med.chem.34:1896-1907 (1991); "Selective Inhibition of the epidemic Growth Factor and HER2/neu Receptors by Tyrphostins" J.biol.chem.268:11134-11142(1993) by Osherov et al; and "tyrphosins and Other Tyrosine Kinase Inhibitors" Annu. Rev. biochem.75:93-109(2006) by A.Levitzki and E.Mishani, all of which are incorporated herein by reference.

In an alternative, when the pharmaceutical composition is formulated with an alkylating agent, the alkylating agent can be an alkylating agent selected from the group consisting of BCNU, BCNU implant (Gliadel), ACNU, CCNU, bendamustine (Treanda), lomustine, and temozolomide () (Temodar).

When the improvement results from chemosensitization, the chemosensitization may include, but is not limited to, the use of a substituted hexitol derivative as a chemosensitizer in combination with an agent selected from the group consisting of:

(a) a topoisomerase inhibitor;

(b) a pseudonucleoside;

(c) a pseudonucleotide;

(d) a thymidylate synthase inhibitor;

(e) a signal transmission inhibitor;

(f) cisplatin or platinum analogs;

(g) an alkylating agent;

(h) an anti-tubulin agent;

(i) an antimetabolite;

(j) berberine;

(k) apigenin;

(l) Amonafide;

(m) vinca alkaloids;

(n) 5-fluoropyrimidinedione;

(o) curcumin;

(p) NF- κ B inhibitors;

(q) rosmarinic acid;

(r) mitoguazone;

(s) tetrandrine;

(t) tyrosine kinase inhibitors;

(u) an EGFR inhibitor; and

(v) PARP inhibitors.

When the improvement results from chemical potentiation, the chemical potentiation can include, but is not limited to, the use of substituted hexitol derivatives as chemical enhancers in combination with agents selected from the group consisting of:

(a) a topoisomerase inhibitor;

(b) a pseudonucleoside;

(c) a pseudonucleotide;

(d) a thymidylate synthase inhibitor;

(e) a signal transmission inhibitor;

(f) cisplatin or platinum analogs;

(g) an alkylating agent;

(h) an anti-tubulin agent;

(i) an antimetabolite;

(j) berberine;

(k) apigenin;

(l) Amonafide;

(m) vinca alkaloids;

(n) 5-fluoropyrimidinedione;

(o) curcumin;

(p) NF- κ B inhibitors;

(q) rosmarinic acid;

(r) mitoguazone; and

(s) tetrandrine;

(t) tyrosine kinase inhibitors;

(u) an EGFR inhibitor; and

(v) PARP inhibitors.

In an alternative, when the chemical potentiation involves the chemical potentiation of an alkylating agent by the activity of dianhydrogalactitol, the alkylating agent can be selected from the group consisting of BCNU, BCNU implant (Gliadel), CCNU, bendamustine (Treanda), lomustine, ACNU, and temozolomide (Temodar).

When improvement results from post-treatment management, the post-treatment management can be, but is not limited to, a method selected from the group consisting of:

(a) treatment associated with pain management;

(b) administering an antiemetic agent;

(c) treatment for nausea;

(d) administering an anti-inflammatory agent;

(e) administering an antipyretic agent; and

(f) an immunostimulant is administered.

When improvement results from alternative therapy/post-treatment support, the alternative therapy/post-treatment support can be, but is not limited to, a method selected from the group consisting of:

(a) hypnosis;

(b) acupuncture and moxibustion;

(c) meditation;

(d) herbs prepared synthetically or by extraction; and

(e) muscle dynamics are applied.

In an alternative, when the method is synthetically or through-extraction prepared herbal medicine, the synthetically or through-extraction prepared herbal medicine may be selected from the group consisting of:

(a) NF- κ B inhibitor;

(b) natural anti-inflammatory agents;

(c) an immune stimulant;

(d) an antibacterial agent; and

(e) flavonoids, isoflavones and flavones.

When the herb prepared synthetically or by extraction is an NF- κ B inhibitor, the NF- κ B inhibitor may be selected from the group consisting of parthenolide, curcumin and rosmarinic acid. When the herb prepared synthetically or by extraction is a natural anti-inflammatory agent, the natural anti-inflammatory agent may be selected from the group consisting of rhein and parthenolide. When the herb prepared synthetically or by extraction is an immunostimulant, the immunostimulant may be a product found in or isolated from echinacea. When synthetically or through extraction made herbal medicines are the anti-bacterial agent, the anti-bacterial agent may be berberine. When the synthetically or through extraction prepared herbs are flavonoids, isoflavonoids and flavones, the flavonoids, isoflavonoids and flavones may be selected from the group consisting of apigenin, trihydroxyisoflavone, genistein, 6 "-O-malonyl genistein, 6" -O-acetyl genistein, daidzein, daidzin, 6 "-O-malonyl daidzin, 6" -O-acetyl trihydroxyisoflavone, glycitein, glycitin, 6 "-O-malonyl glycitin and 6-O-acetyl glycitin.

When an improvement results from a bulk drug product improvement, the bulk drug product improvement can be, but is not limited to, a bulk drug product improvement selected from the group consisting of:

(a) salt formation;

(b) prepared into a homogeneous crystalline structure;

(c) preparation of the pure isomers;

(d) increased purity;

(e) preparation of lower solvent residue content; and

(f) preparation of low heavy metal residue content.

When the improvement results from the use of a diluent, the diluent may be, but is not limited to, a diluent selected from the group consisting of:

(a) an emulsifier;

(b) dimethylsulfoxide (DMSO);

(c) n-methylformamide (NMF);

(d) dimethylformamide;

(e) ethanol;

(f) benzyl alcohol;

(g) water for injection containing glucose;

(h) cremophor;

(i) a cyclodextrin; and

(j)PEG。

when the improvement results from the use of a solvent system, the solvent system can be, but is not limited to, a solvent system selected from the group consisting of:

(a) an emulsifier;

(b) dimethylsulfoxide (DMSO);

(c) n-methylformamide (NMF);

(d) dimethylformamide;

(e) ethanol;

(f) benzyl alcohol;

(g) water for injection containing glucose;

(h) cremophor;

(i) a cyclodextrin; and

(j)PEG。

when the improvement results from the use of an excipient, the excipient may be, but is not limited to, an excipient selected from the group consisting of:

(a) mannitol;

(b) albumin;

(c)EDTA；

(d) sodium bisulfite;

(e) benzyl alcohol;

(f) a carbonate buffer; and

(g) phosphate buffer.

When the improvement results from the use of a dosage form, the dosage form may be, but is not limited to, a dosage form selected from the group consisting of:

(a) a lozenge;

(b) a sachet;

(c) a topical gel;

(d) topical emulsions;

(e) pasting a piece;

(f) suppositories; and

(g) a filling agent of a freeze-dried preparation.

The formulation of pharmaceutical compositions in lozenges, sachets, and topical gels, creams or suppositories is well known in the art and is described, for example, in U.S. patent application publication No. 2004/0023290 to Griffin et al, which is incorporated herein by reference.

The formulation of pharmaceutical compositions into patches, such as transdermal patches, is well known in the art and is described, for example, in U.S. patent No. 7,728,042 to Eros et al, which is incorporated herein by reference.

Lyophilized fillers are also well known in the art. A method for preparing the filler of the lyophilized dosage form, which can be used with dianhydrogalactitol and derivatives thereof, comprises the following steps:

(1) the drug was dissolved in water for injection pre-cooled to below 10 ℃. It was diluted to final volume with cold water for injection to obtain a 40mg/mL solution.

(2) Under sterile conditions, the bulk solution was filtered through a 0.2-micron (μm) filter into a receiving vessel. The formulation and filtration need to be completed in one hour.

(3) Under aseptic conditions, a nominal volume of 1.0mL of filtrate was filled into a sterilized glass vial within a controlled target range.

(4) After filling, all vials were placed with rubber stoppers inserted in the "freeze drying position" and loaded into the pre-frozen freeze dryer. For the freeze dryer, the shelf plate (shelf) temperature was set at +5 ℃ for 1 hour; the shelf temperature was then adjusted to-5 ℃ for 1 hour, the condenser temperature was set at-60 ℃ and then the machine was started.

(5) The vial is then frozen to 30 ℃ or less and maintained for not less than 3 hours, usually 4 hours.

(6) Then starting vacuum, adjusting the temperature of the shed plate to-5 ℃, and continuing primary drying for 8 hours; the shelf temperature was again adjusted to-5 ℃ and drying was performed for at least 5 hours.

(7) Secondary drying was started after turning on the condenser (set at-60 ℃ C.) and vacuum. In secondary drying, the shelf temperature is controlled at +5 ℃ for 1 to 3 hours, typically 1.5 hours, followed by 25 ℃ for 1 to 3 hours, typically 1.5 hours, and finally at 35 to 40 ℃ for at least 5 hours, typically 9 hours, or until the product is completely dried.

(8) The vacuum is broken by filtering an inert gas such as nitrogen. The vials in the freeze dryer were stoppered.

(9) The vial was removed from the lyophilization chamber and sealed with an aluminum flip top. Visual inspection of all vials was performed and labeled with approved labels.

When the improvement results from the use of a dosage kit and package, the dosage kit and package may be, but are not limited to, selected from the group consisting of the use of brown bottles to avoid light and the use of specially coated bottle stoppers to increase shelf life stability.

When the improvement results from the use of a drug delivery system, the drug delivery system may be a drug delivery system selected from the group consisting of:

(a) nano-crystallization;

(b) a bioerodible polymer;

(c) a liposome;

(d) a slow release injectable gel; and

(e) microspheres.

Nanocrystals are described in U.S. patent No. 7,101,576 to Hovey et al, which is incorporated herein by reference.

Bioerodible polymers are described in U.S. patent No. 7,318,931 to Okumu et al, which is incorporated herein by reference. Bioerodible polymers are degraded when placed in vivo, e.g., as measured by the decrease in molecular weight of the polymer over time. Polymer molecular weight can be determined using a variety of methods, including Size Exclusion Chromatography (SEC), and is typically expressed as an average weight or an average number. A polymer is bioerodible if it has a phosphate buffered saline solution at pH 7.4, temperature 37 ℃ and a weight average molecular weight that decreases by at least 25% over a period of 6 months, when measured by SEC. Useful bioerodible polymers include polyesters such as polycaprolactone, polyglycolic acid, polylactic acid, and polyhydroxybutyrate: polyanhydrides, such as polyanhydrides and polymaleic anhydrides; polydioxanone (polydioxanone); polyamines; polyamides; polyurethanes; polyesteramides; polyorthoesters; polyacetals; polyketones (polyketals); polycarbonates; polyorthocarbonates (polyorthocarbonates); polyphosphazenes (polyphosphazenes); polymalic acid; a polyamino acid; polyvinylpyrrolidone (polyvinylpyrrolidone); polymethyl vinyl ether; polyalkylene oxalates (poly (alkylene oxides)); polyalkylene succinates (poly (alkylene succinates)); polyhydroxycellulose; chitin; chitosan; and copolymers and mixtures thereof.

Liposomes are well known as drug delivery vehicles. Preparation of liposomes is described in Weng et al, European patent application publication No. EP 1332755, which is incorporated herein by reference.

Sustained Release injectable gels are known in the art and are described, for example, in "Drug releaseefficient injectable thermosensive Hydrogel of PEG-PLGA-PEGTriblock copolymers" J.controlled Release 63: 155-.

The use of Microspheres for Drug Delivery is known in the art and is described, for example, in "Biodegradable Microspheres in Drug Delivery" crit. rev. ther. Drug carriers.12: 1-99(1995) by h.okada and h.taguchi, which are incorporated herein by reference.

When the improvement results from the use of a drug conjugated form, the drug conjugated form can be, but is not limited to, a drug conjugated form selected from the group consisting of:

(a) a polymer system;

(b) polylactic acid;

(c) polyglycolic acid;

(d) an amino acid;

(e) peptides; and

(f) a multi-valent bond chain group.

Polylactic acid Conjugates are well known in the art and are described, for example, in "Controlled Synthesis of catalytic-polylactic Conjugates and Nano-polymers" biocompatible Chem.21:111-121(2010), by R.Tong and C.Cheng, which are incorporated herein by reference.

Polyglycolic acid conjugates are well known in the art and are described, for example, in PCT patent application publication No. WO 2003/070823 to Elmaleh et al, which is incorporated herein by reference.

Multivalent bond chain groups are well known in the art and are described, for example, in U.S. patent application publication No. 2007/0207952 to Silva et al, which is incorporated herein by reference. For example, a multivalent linker group may comprise a thiophilic group(s) to react with an active cysteine, as well as a plurality of nucleophilic groups (e.g., NH or OH) or electrophilic groups (e.g., activated esters) that allow a plurality of biologically active moieties to be attached to the linker group.

Combinations suitable for crosslinking a number of functional groups are known in the art. For example, electrophilic groups can react with a number of functional groups, including those present in proteins or polypeptides. Combinations of various reactive amino acids and electrophilic groups are known in the art and can be used. For example, an N-terminal cysteine containing a thiol group may be reacted with a halogen or a maleimide. Thiol groups are known and a large number of coupling agents are reactive, such as alkyl halides, halogenated acetyl derivatives, maleimides, ethyleneimines (aziridines), acryloyl derivatives (acryloyl derivitives), arylating agents, such as aryl halides and others. These are described in "Bioconjugate Techniques" (Academic Press, San Diego,1996), pp.146-150, by G.T. Hermanson, which is incorporated herein by reference. The reactivity of cysteine residues can be optimized by appropriate selection of their adjacent amino acid residues. For example, a histidine residue adjacent to a cysteine residue will increase the reactivity of the cysteine residue. Combinations of other reactive amino acids and electrophilic reactants are known in the art. For example, maleimide can react with amino groups, such as the epsilon amino group of the lysine side chain, especially at higher pH ranges. Aryl halides can react with such amino groups. Halogenated acetyl derivatives can react with the nitrogen of the imidazolyl side chain of histidine, the thioether group of the methionine side chain and the epsilon-amino group of the lysine side chain. Many other electrophilic reactants are known to react the epsilon amino group of lysine side chains, including, but not limited to, isothiocyanates, isocyanates, acyl azides (acyl azides), N-hydroxysuccinimide esters (N-hydroxysuccinimide esters), chlorosulfonyl chlorides, epoxides, oxiranes, carbonates, imines, carbodiimides, and anhydrides. These are described in "Bioconjugate Techniques" (Academic Press, San Diego,1996), pp.137-146, by G.T. Hermanson, which is incorporated herein by reference. Furthermore, electrophilic reactants are known to react with carboxylate side chains such as aspartate and glutamate, such as diazoalkanes and diazoacetyl compounds, carbonyldiimidazole and carbodiimide. These are described in "Bioconjugate Techniques" by g.t.hermanson (Academic Press, San Diego,1996), pp.152-154, which is incorporated herein by reference. Even more, electrophiles are alkyl halide derivatives known to react with hydroxyl groups such as serine and threonine side chains, including reactivity. These are described in "Bioconjugate Techniques" by G.T. Hermanson (Academic Press, San Diego,1996), pp.154-158, which is incorporated herein by reference. In further embodiments, the relative positions of the electrophilic group and the nucleophilic group (i.e., the molecule reactive with the electrophilic group) are reversed such that the protein has an amino acid residue with the electrophilic group reactive with the nucleophilic group, and the target molecule includes the nucleophilic group therein. As noted above, this includes the reaction of aldehydes (the electrophilic group) and hydroxylamines (the nucleophilic group), but is more common than the reaction; other groups may be used as electrophilic and nucleophilic groups. Suitable groups are well known in organic chemistry and need not be described in further detail.

Additional combinations of reactive groups for crosslinking are known in the art. For example, amino groups can be reacted with isothiocyanates, isocyanates, acyl azides, N-hydroxysuccinimide (NHS) esters, chlorinated sulphonyl, aldehydes, glyoxals, epoxides, oxiranes, carbonates, alkylating agents, iminates, carbodiimides, and anhydrides. The thiol group can be reacted with halogenated acetyl or alkyl halide derivatives, maleimides, ethyleneimines, acryloyl derivatives, acylating agents or other thiol groups by oxidation to form mixed disulfides. The carboxyl group can react with diazoalkanes, diazoacetyl compounds, carbonyldiimidazole and carbodiimide. The hydroxyl group may be reacted with an epoxide, ethylene oxide, carbonyldiimidazole, N' -disuccinimidyl carbonate, N-hydroxysuccinimide chloroformate, periodate (for oxidation), alkyl halide, or isocyanate. The aldehyde and ketone groups may be reacted with hydrazine, Schiff base-forming reagent and other groups in a reductive amination reaction or Mannich condensation reaction. Still other reactions suitable for crosslinking reactions are known in the art. For example, cross-linking agents and reactions are described in "g.t. hermanson," Bioconjugate Techniques "(academic press, San Diego 1996), which is incorporated herein by reference.

When the improvement results from a prodrug system, the prodrug system may be, but is not limited to, a prodrug system selected from the group consisting of:

(a) use of enzyme sensitive esters;

(b) use of a dimer;

(c) using a Schiff base;

(d) use of pyridoxal complexes; and

(e) caffeine complexes are used.

The use of the prodrug system is described at T.

"Design and pharmaceutical Applications of Prodrugs" by et al are in the Drug Discovery Handbook (S.C. Gad, ed., Wiley-Interscience, Hoboken, NJ,2005), Chapter 17, pages 733 to 796, which is incorporated herein by reference. This publication describes the use of enzyme sensitive esters as prodrugs. The use of dimers as prodrugs is described in Allegretti et al, U.S. Pat. No. 7,879,896, which is incorporated herein by reference. The use of peptides as prodrugs is described in "delivery Multiple Anticancer peptides a Single Prodrug use Lysyl-Lysine as a drug Linker" J.peptide Sci.13:458-467(2007) by S.Prasad et al, which is incorporated herein by reference. The use of Schiff bases as prodrugs is described in Epstein et al, U.S. Pat. No. 7,619,005, which is incorporated herein by reference. The use of caffeine as a prodrug is described in U.S. patent No. 6,443,898 to Unger et al, which is incorporated herein by reference.

When the improvement results from the use of a multidrug system, the multidrug system can be, but is not limited to, a multidrug system selected from the group consisting of:

(a) the use of multiple drug resistance inhibitors;

(b) use of specific drug resistance inhibitors;

(c) specific inhibitors using selective enzymes;

(d) use of a signalling inhibitor;

(e) using repair inhibition; and

(f) topoisomerase inhibitors with non-overlapping side effects are used.

Multiple drug resistance inhibitors are described in U.S. patent No. 6,011,069 to Inomata et al, which is incorporated herein by reference.

Specific drug resistance inhibitors are described in "The ProteasomeInhibitor PS-341 inhibitors Growth, industries Apoptosis, and Overcomes drug resistance in Human Multiple Myeloma Cells" Cancer Res.61:3071-3076(2001) by T.Hideshima et al, which is incorporated herein by reference.

Repair Inhibition is described in "DNA Repair Inhibition and cancer therapy" J.Photochem.Photobiol.B 63:162-170(2001) by N.M.Martin, which is incorporated herein by reference.

When the improvement results from a biotherapeutic enhancement, the biotherapeutic enhancement may be performed by the combined use of a sensitizer/enhancer and a therapeutic agent or technique, which may be, but is not limited to, a therapeutic agent or technique selected from the group consisting of:

(a) a cytokine;

(b) a lymphokine;

(c) a therapeutic antibody;

(d) antisense therapy;

(e) gene therapy;

(f) a ribozyme;

(g) RNA interference; and

(h) a vaccine.

Antisense Therapy is described, for example, in "Antisense RNA Gene Therapy for studying and Modulating Biological Processes" cell. mol. Life Sci.55:334-358(1999), by B.Weiss et al, which is incorporated herein by reference.

Ribozymes are described, for example, in "RNA-Based therapeutics", by S.Pasco, in Drug discovery handbook (S.C. Gad, ed., Wiley-Interscience, Hoboken, NJ,2005), Chapter 27, pages 1273 to 1278, which is incorporated herein by reference.

RNA interference is described, for example, in "RNA-Based therapeutics" by s.pascolo in drug discovery Handbook (s.c. gad, ed., Wiley-Interscience, Hoboken, NJ,2005), chapter 27, pages 1278 to 1283, which is incorporated herein by reference.

As mentioned above, cancer vaccines are generally based on an immune response against a protein or proteins that are present in cancer cells but not in normal cells. Cancer vaccines include Provenge against metastatic hormone resistant prostate cancer; oncophage against kidney cancer; CimaVax-EGF for lung cancer; MOBILAN; neuvenge against Her 2/neu-expressing cancers such as breast, rectal, bladder and ovarian cancers; stimuvax for breast cancer; and others. Cancer vaccines are described in s.pejawar-Gaddy and o.finn, (2008), supra.

When the biotherapeutic boost is performed by a sensitizer/booster in combination with a therapeutic antibody, the therapeutic antibody may be, but is not limited to, a therapeutic antibody selected from the group consisting of bevacizumab (carcinostat), rituximab (rituximab), trastuzumab (a \ -h \), and cetuximab (cetuximab) (erbitux \).

When the improvement results from the use of a biotherapeutic resistance modulation, the biotherapeutic resistance modulation can be, but is not limited to, the use of glioblastoma multiforme or medulloblastoma that is resistant to a therapeutic agent or technique selected from the group consisting of:

(a) a biological response modifier;

(b) a cytokine;

(c) a lymphokine;

(d) a therapeutic antibody;

(e) antisense therapy;

(f) gene therapy;

(g) a ribozyme;

(h) RNA interference; and

(i) a vaccine.

When biotherapeutic resistance modulation is used against tumors that are resistant to the therapeutic antibody, the therapeutic antibody may be, but is not limited to, selected from the group consisting of bevacizumab (carcinostat), rituximab (rituximab), trastuzumab (haxate), and cetuximab (erbitux).

When the improvement results from a radiation therapy potentiation, the radiation therapy potentiation can be, but is not limited to, a radiation potentiating agent or technique selected from the group consisting of:

(a) hypoxic cell sensitizers;

(b) radiosensitizer/protectant;

(c) a photosensitizer;

(d) an inhibitor of radiation repair;

(e) a thiol depleting agent;

(f) a vascular targeting agent;

(g) a DNA repair inhibitor;

(h) a radioactive species;

(i) a radioactive isotope;

(j) a radiolabelled antibody; and

(k) and (4) performing brachytherapy.

Substituted hexitol derivatives such as dianhydrogalactitol may be used in combination with radiation to treat glioblastoma multiforme or medulloblastoma.

Hypoxic cell sensitizers are described in "The Effect of Hypoxic CellSensitizers at Different Irradiation Dose Rates" Radiation Res.109:396-406(1987) by C.C. Link et al, which is incorporated herein by reference. Radiosensitizers are described in "Radiation Sensitizers and Targeted therapeutics" Oncology 17 (supply.13) 23-28(2003) by t.s.lawrence, which is incorporated herein by reference. Radioprotectants are described in "Evaluation of D-Methionine as a Novel organic Radiation detector for prediction of music" Clin. cancer Res.14:2161-2170(2008) by S.B. Vuyuri et al, which is incorporated herein by reference. Photosensitizers are described in "oncogenic Photodynamics therapy Photosensizers: A Clinical Review", Photognosis Photodynamics therapeutics 7:61-75(2010), by R.R.Allison and C.H.Sibata, which is incorporated herein by reference. Radiation Repair inhibitors and DNA Repair inhibitors are described in "Evaluation of Repair of Radiation-Induced DNADADAMAGE ENHANCES Expression from feedback-Defective additive Vectors" Cancer Res.68:9771-9778(2008) by M.Hingorani et al, which is incorporated herein by reference. Thiol Depleting agents are described in "position transduction of Mammalian Cells by the thiol-Depleting Agent" Radiation Res.127:75-80(1991) by K.D. Held et al, which is incorporated herein by reference. Vascular targeting agents are described in "Tumor necrosis Factor oil media Homogeneous Distribution of lipids in MurinElelanema thaat lipids to a beer Tumor Response" Cancer Res.67:9455-9462(2007) by A.L. Seynhaeve et al. As mentioned above, radiation therapy is often used to treat glioblastoma multiforme and medulloblastoma, so that radiation therapy potentiation is of paramount importance for both malignancies.

When the improvement results from the use of a novel effector, the novel effector may be, but is not limited to, a novel effector that is and is selected from the therapeutic interaction of targets and effectors consisting of:

(a) adenosine diphosphate ribose polymerase inhibitors;

(b) agents that affect vascularity or vasodilation;

(c) an oncogenic targeting agent;

(d) a signal transmission inhibitor;

(e) EGFR inhibition;

(f) inhibition of protein kinase C;

(g) down regulation of phospholipid lipolytic enzyme C;

(h) jun is regulated and controlled downwards;

(i) a histone gene;

(j)VEGF；

(k) ornithine decarboxylase;

(I) ubiquitin C;

(m)Jun D；

(n)v-Jun；

(o)GPCR；

(p) protein kinase a;

(q) protein kinases other than protein kinase a;

(r) prostate specific genes;

(s) telomerase;

(t) histone deacetylases; and

(u) tyrosine kinase inhibitors.

EGFR inhibition is described in "EGFR Inhibitors: WhatHave We left from the Treatment of Lung Cancer" nat. Clin. Pract. Oncol.11:554-561(2005) by G.Giacone and J.A.Rodriguez, which is incorporated herein by reference. Protein Kinase C inhibition is described in "Protein Kinase C Inhibitors" curr. oncol. rep.4:37-46(2002) by h.c. swannie and s.b. kaye, which are incorporated herein by reference. Phospholipid lipolytic enzyme C down-regulation Is described in "Phosphoinositide signalling in nucleic acid of Friend Cells: phospholipases C.beta.downward regulation Related to Cell Differentiation" Cancer Res.54:2536-2540(1994) by A.M. Martelli et al, which Is incorporated herein by reference. Down-regulation of Jun (specifically c-Jun) is described in "Down regulation of c-Jun Expression and Cell cycle regulation Molecules in the enzyme Myeloid Leucomia Cell Up CD44 Ligation" Oncogene 22:2296-2308(2003) by A.A.P.Zada et al, which is incorporated herein by reference. The role of histone Genes as targets for therapeutic intervention (therapeutic intervention) is described in "alternative expression of G1-Specific Genes in Human major animal Cells" Proc. Natl. Acad. Sci. USA 83:1495-1498(1986) by B.Calabretta et al. The role of VEGF as a target for therapeutic intervention is described in "VEGF-Mediated Angiogenesis of Human Pheochromocytomas IsAssociation to Maliganic and Inhibited by anti-VEGF Antibodies in Experimental turbines" Surgery 132: 1056-. The role of ornithine Decarboxylase as a target for therapeutic intervention is described in "targeting Ornithine Decarboxylase in Myc-Induced lymphoma growth Prevents Mobile Format" Cancer Cell 7:433-444(2005) by J.A. Nilsson et al, which is incorporated herein by reference. The role of ubiquitin C as a target for therapeutic intervention is described in "A Phase I Trial of the novelProteonomer Inhibitor PS341in Advanced Sol, C.Aghajanian et alid Tumor Maiignanes "Clin. cancer Res.8: 2505-. The role of Jun D as a target for therapeutic intervention Is described in "Jun Is infused in the therapeutic efficacy of Δ⁹Tetrahydrocannibol on Human Breast Cancer Cells "Oncogene 27: 5033-. The role of v-Jun as a target for therapeutic intervention is described in "Differencetic and anticancer Effects of v-Jun and c-Jun" cancer Res.56:4229-4235(1996) by M.Gao et al, which is incorporated herein by reference. The role of Protein Kinase A as a target for therapeutic intervention is described in "Elevation of Protein Kinase A and Protein Kinase C in Malignant as shared With Normal Breast Tissue" Eur.J. cancer 12: 2120. 2126(1996), by P.C. Gordge et al, which is incorporated herein by reference. The role of telomerase as a Target for therapeutic intervention is described in "TeIomerase as a Novel and functional Target for Cancer Chemotherapy" Ann. Med.35:466-475(2003) by E.K. Parkinson et al, which is incorporated herein by reference. The role of Histone Deacetylases as Targets for Therapeutic intervention is described in Histone Deacetylases as Therapeutic Targets in Therapeutic Maliances, Curr. Opin. Hematol.9:322-332(2002) by A.Melnick and J.D.Licht, which are incorporated herein by reference.

When the improvement results from use of a selective target cell population therapy, the use of the selective target cell population therapy can be, but is not limited to, use selected from the group consisting of:

(a) using cells that are resistant to radiation sensitivity;

(b) using radiation resistant cells; and

(c) cells resistant to energy depletion are used.

The improvement can also result from the use of a combination of dianhydrogalactitol and free radiation.

In another aspect of the invention, the composition is directed to a suboptimal drug-administered treatment with a substituted hexitol derivative for treating glioblastoma multiforme or medulloblastoma, improving efficacy and/or reducing side effects, comprising an alternative selected from the group consisting of:

(i) a therapeutically effective amount of a modified substituted hexitol derivative, or a substituted hexitol derivative or a derivative, analog, or prodrug of a modified substituted hexitol derivative, wherein the modified substituted hexitol derivative, or a derivative, analog, or prodrug of a modified substituted hexitol derivative has increased therapeutic efficacy or reduced side effects in the treatment of glioblastoma multiforme or medulloblastoma compared to the use of an unmodified substituted hexitol derivative;

(ii) the composition comprises:

(a) a therapeutically effective amount of a substituted hexitol derivative, modified substituted hexitol derivative, or substituted hexitol derivative or derivative, analog, or prodrug of a modified substituted hexitol derivative; and

(b) at least one additional therapeutic agent, a therapeutic agent affected by chemosensitization, a therapeutic agent affected by chemopotentiation, a diluent, an excipient, a solvent system, or a drug delivery system, wherein the composition has increased therapeutic efficacy or reduced side effects in treating glioblastoma multiforme or medulloblastoma compared to the use of the unmodified substituted hexitol derivative;

(iii) a therapeutically effective amount of a substituted hexitol derivative, a modified substituted hexitol derivative, or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative incorporated into a dosage form, wherein the substituted hexitol derivative, modified substituted hexitol derivative, or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative incorporated into the dosage form has increased therapeutic efficacy or reduced side effects in the treatment of glioblastoma multiforme or medulloblastoma as compared to an unmodified substituted hexitol derivative;

(iv) a therapeutically effective amount of a substituted hexitol derivative, a modified substituted hexitol derivative, or a substituted hexitol derivative or a derivative, analog, or prodrug of a modified substituted hexitol derivative incorporated into a dosage kit and packaging, wherein the substituted hexitol derivative, modified substituted hexitol derivative, or derivative, analog, or prodrug of a modified substituted hexitol derivative incorporated into the dosage kit and packaging has increased efficacy or reduced side effects in the treatment of glioblastoma multiforme or medulloblastoma as compared to an unmodified substituted hexitol derivative; and

(v) a therapeutically effective amount of a substituted hexitol derivative, a modified substituted hexitol derivative, or a derivative, analog, or prodrug of a substituted hexitol derivative or a modified substituted hexitol derivative that is affected by modification of a drug substance product, wherein the substituted hexitol derivative, modified substituted hexitol derivative, or derivative, analog, or prodrug of a modified substituted hexitol derivative that is affected by modification of a drug substance product has increased therapeutic efficacy or reduced side effects in the treatment of glioblastoma multiforme or medulloblastoma as compared to an unmodified substituted hexitol derivative.

As detailed above, typically the unmodified substituted hexitol is selected from the group consisting of dianhydrogalactitol, a dianhydrogalactitol derivative, diacetyldianhydrogalactitol, a diacetyldianhydrogalactitol derivative, dibromodulcitol and a dibromodulcitol derivative. Preferably, the unmodified substituted hexitol is dianhydrogalactitol.

In one alternative, the composition comprises a pharmaceutical composition comprising:

(i) substituted hexitol derivatives; and

(ii) an additional therapeutic agent selected from the group consisting of:

(a) a topoisomerase inhibitor;

(b) a pseudonucleoside;

(c) a pseudonucleotide;

(d) a thymidylate synthase inhibitor;

(e) a signal transmission inhibitor;

(f) cisplatin or platinum analogs;

(g) an alkylating agent;

(h) an anti-tubulin agent;

(i) an antimetabolite;

(j) berberine;

(k) apigenin;

(l) Amonafide;

(m) vinca alkaloids;

(n) 5-fluoropyrimidinedione;

(o) curcumin;

(p) NF- κ B inhibitors;

(q) rosmarinic acid;

(r) mitoguazone;

(s) tetrandrine;

(t) tyrosine kinase inhibitors;

(u) an EGFR inhibitor; and

(v) PARP inhibitors.

In these alternatives, when the additional therapeutic agent is an alkylating agent, the alkylating agent can be, but is not limited to, an alkylating agent selected from the group consisting of BCNU, BCNU implants, CCNU, bendamustine (Treanda), and temozolomide (Temodar).

In a further alternative, the composition comprises a pharmaceutical composition comprising:

(i) substituted hexitol derivatives; and

(ii) a therapeutic agent additionally affected by chemosensitization, selected from the group consisting of:

(a) a topoisomerase inhibitor;

(b) a pseudonucleoside;

(c) a pseudonucleotide;

(d) a thymidylate synthase inhibitor;

(e) a signal transmission inhibitor;

(f) cisplatin or platinum analogs;

(g) an alkylating agent;

(h) an anti-tubulin agent;

(i) an antimetabolite;

(j) berberine;

(k) apigenin;

(l) Amonafide;

(m) vinca alkaloids;

(n) 5-fluoropyrimidinedione;

(o) curcumin;

(p) NF- κ B inhibitors;

(q) rosmarinic acid;

(r) mitoguazone;

(s) tetrandrine;

(t) tyrosine kinase inhibitors;

(u) an EGFR inhibitor; and

(v) PARP inhibitors constitute agents of the group,

wherein the substituted hexitol derivative is acting as a chemosensitizer.

In yet further alternatives, the composition comprises:

(i) substituted hexitol derivatives; and

(ii) a therapeutic agent affected by chemopotentiation selected from the group consisting of:

(a) a topoisomerase inhibitor;

(b) a pseudonucleoside;

(c) a pseudonucleotide;

(d) a thymidylate synthase inhibitor;

(e) a signal transmission inhibitor;

(f) cisplatin or platinum analogs;

(g) an alkylating agent;

(h) an anti-tubulin agent;

(i) an antimetabolite;

(j) berberine;

(k) apigenin;

(l) Amonafide;

(m) vinca alkaloids;

(n) 5-fluoropyrimidinedione;

(o) curcumin;

(p) NF- κ B inhibitors;

(q) rosmarinic acid;

(r) mitoguazone;

(s) tetrandrine;

(t) a biotherapeutic agent;

(u) tyrosine kinase inhibitors;

(v) an EGFR inhibitor; and

(w) PARP inhibitors;

wherein the substituted hexitol derivative is used as a chemical enhancer.

In these alternatives, where the additional therapeutic agent is a biologic therapeutic agent, the biologic therapeutic agent can be, but is not limited to, a biologic therapeutic agent selected from the group consisting of carcinostat, haxapin, rituximab, and erbitux.

In yet other alternatives, the substituted hexitol derivative is affected by a drug substance product modification, wherein the drug substance product modification is selected from the group consisting of:

(a) salt formation;

(b) preparing a homogeneous crystal structure;

(c) preparing a purified isomer;

(d) the purity is increased;

(e) preparation of lower solvent residue content; and

(f) preparation of low heavy metal residue content.

In still yet other alternatives, the composition comprises a substituted hexitol derivative and a diluent, wherein the diluent is selected from the group consisting of:

(a) an emulsifier;

(b) dimethylsulfoxide (DMSO);

(c) n-methylformamide (NMF);

(d) dimethylformamide;

(e) ethanol;

(f) benzyl alcohol;

(g) water for injection containing glucose;

(h) cremophor;

(i) a cyclodextrin; and

(j)PEG。

in still yet other alternatives, the composition comprises a substituted hexitol derivative and a solvent system, wherein the solvent system is selected from the group consisting of:

(a) an emulsifier;

(b) dimethylsulfoxide (DMSO);

(c) n-methylformamide (NMF);

(d) dimethylformamide;

(e) ethanol;

(f) benzyl alcohol;

(g) water for injection containing glucose;

(h) cremophor;

(i) a cyclodextrin; and

(j)PEG。

in yet a further alternative, the composition comprises a substituted hexitol derivative and an excipient, wherein the excipient is selected from the group consisting of:

(a) mannitol;

(b) albumin;

(c)EDTA；

(d) sodium bisulfite;

(e) benzyl alcohol;

(f) a carbonate buffer; and

(g) phosphate buffer.

In yet a further alternative, the substituted hexitol derivative is incorporated into a dosage form selected from the group consisting of:

(a) a lozenge;

(b) a sachet;

(c) a topical gel;

(d) topical emulsions;

(e) pasting a piece;

(f) suppositories; and

(g) a filling agent of a freeze-dried preparation.

In yet other alternatives, the dianhydrogalactitol is included in a dosage kit and package selected from the group consisting of protection from light with brown bottles and increased shelf-life stability with specially coated stoppers.

In still other alternatives, the composition comprises a dianhydrogalactitol and a drug delivery system selected from the group consisting of:

(a) nano-crystallization;

(b) a bioerodible polymer;

(c) a liposome;

(d) a slow release injectable gel; and

(e) microspheres.

In still other alternatives, the substituted hexitol derivative is present in the composition in a conjugated form with a drug selected from the group consisting of:

(a) a polymer system;

(b) polylactic acid;

(c) polyglycolic acid;

(d) an amino acid;

(e) peptides; and

(f) a multi-valent bond chain group.

In yet a further alternative, the therapeutic agent is a modified substituted hexitol derivative, and the modification is selected from the group consisting of:

(a) altering the side chain to increase or decrease lipophilicity;

(b) adding additional chemical functional groups to alter a property selected from the group consisting of reactivity, electron affinity, and bonding ability; and

(c) changing the salt form.

In yet other alternatives, the substituted hexitol derivative is in the form of a prodrug system, wherein the prodrug system is selected from the group consisting of:

(a) use of enzyme sensitive esters;

(b) use of a dimer;

(c) using a Schiff base;

(d) use of pyridoxal complexes; and

(e) caffeine complexes are used.

In yet a further alternative, the composition comprises a substituted hexitol derivative and at least one additional therapeutic agent to form a multi-drug system, wherein the at least one additional therapeutic agent is selected from the group consisting of:

(a) the use of multiple drug resistance inhibitors;

(b) use of specific drug resistance inhibitors;

(c) specific inhibitors using selective enzymes;

(d) use of a signalling inhibitor;

(e) inhibitors of repair enzymes; and

(f) topoisomerase inhibitors with non-overlapping side effects are used.

When a pharmaceutical composition according to the invention includes a prodrug, the prodrug and active metabolite of the compound may be distinguished using techniques conventional in the art. See, e.g., Bertolini et al, published in j.med.chem.,40,2011-2016 (1997); shann et al, published in J.pharm.Sci.,86(7), 765-767; bagshawe, published in Drug Dev.Res.,34, 220-; bodor, published in Advances in Drug Res.,13, 224-; bundgaard published in Design of Prodrugs (Elsevier Press 1985); larsen published in Design and application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al, eds., Harwood Academic Publishers, 1991); dear et al, J.Chromatogr.B,748,281-293 (2000); spraul et al, published in J.pharmaceutical & Biomedical Analysis,10,601-605 (1992); and Prox et al, in Xenobiol, 3,103-112 (1992).

When the pharmacologically active compound in the pharmaceutical composition according to the present invention has sufficient acidic functional groups, sufficient basic functional groups, or both sufficient acidic and basic functional groups, the functional group or groups may be reacted with any of a variety of inorganic or organic bases, and inorganic or organic acids, respectively, to form a pharmaceutically acceptable salt. Typical pharmaceutically acceptable salts include those prepared by reacting a pharmacologically active compound with a mineral or organic acid or an inorganic base, and include sulfates, disulfates, bisulfates, sulfites, bisulfites, phosphates, hydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, sebacates, octanoates, acrylates, formates, isobutyrates, caproates, pimelates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1, 4-diacids, hexyne-1, 6-diacids, benzoates, chlorobenzates, methylbenzates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β -hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelates (mantles). If the pharmacologically active compound has one or more basic functional groups, the desired pharmaceutically acceptable salts may be prepared by methods suitable in the art, for example by treatment with a free base inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid (such as glucuronic acid) or galacturonic acid (galacic acid), alpha-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid) or the like, the desired pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, by treating the free acid with an inorganic or organic base and, for example, an amine (primary, secondary or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide or the like. Illustrative examples of suitable salts include organic salts derived from amino acids (e.g., glycine and arginine), ammonia, primary, secondary or tertiary amines, and cyclic amines (e.g., piperidine, morpholine, and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

In the case of solid agents, it will be appreciated by those skilled in the art that the compounds and salts of the present invention may exist in different crystalline or allotropic forms, all of which are intended to be within the scope and specific formulation of the present invention.

The amount of a given pharmaceutically active agent, such as a substituted hexitol derivative (dianhydrogalactitol or an analog or derivative of dianhydrogalactitol as described above), included in a unit dose of a pharmaceutical composition according to the invention will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., body weight) of the subject in need of treatment, but can nevertheless be routinely determined by those skilled in the art. Typically, the pharmaceutical composition comprises a therapeutically effective amount of a pharmacologically active agent and an inert pharmaceutically acceptable carrier or diluent. Typically, these compositions are formulated in unit dosage forms suitable for the chosen route of administration, such as oral or parenteral. The pharmacologically active agents described above may be administered in conventional dosage forms by combining a therapeutically effective amount of such pharmacologically active agent as the active ingredient with a suitable pharmaceutical carrier or diluent according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients, depending on the desired formulation. The pharmaceutical carrier used may be a solid or a liquid. Typical solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia (acacia), magnesium stearate, stearic acid and the like. Typical liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time-delay or time-release materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.

A wide variety of pharmaceutical forms are available. Thus, if a solid carrier is used, the formulation may be in the form of a tablet, a powder or granules in a hard gelatin capsule, or a tablet (troche) or lozenge (lozenge). The amount of solid carrier can vary, but will generally be from about 25mg to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial, or non-aqueous liquid suspension.

To achieve a stable aqueous formulation, the pharmaceutically acceptable salts of the pharmacologically active agents described above are dissolved in an aqueous solution of an organic or inorganic acid, such as a solution of 0.3M (molar concentration) succinic acid or citric acid. If a soluble salt form cannot be used, the agent may be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co-solvents include, but are not limited to, alcohols, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerol and the like, at concentrations ranging from 0 to 60% of the total volume. In a typical embodiment, the compound of formula I is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of the salt form of the active ingredient in a suitable aqueous carrier, such as water or isotonic saline or dextrose solution.

It will be appreciated that the actual dosage of the agent used in the compositions of the invention will vary depending upon the particular complex, formulation usedThe specific composition formulated, the mode of administration and the specific site, host and disease and/or symptom to be treated vary. The actual dosage concentration (dosage level) of the active ingredient in the compositions of the invention may be varied so that the active ingredient is in an amount effective to achieve the desired therapeutic response for a particular subject, composition, mode of administration, and is not toxic to the subject. The selected dosage concentration is based on a variety of pharmacokinetic factors including the activity of the particular therapeutic agent, the route of administration, the time of administration, the rate of excretion of the particular compound used, the severity of the condition, other health considerations affecting the subject, and the renal and hepatic functional status of the subject. It also depends on the duration of the treatment, the drug, compound and/or substance used in combination with the particular therapeutic agent, and the age, weight, condition, general health and prior medical history of the subject to be treated, and other similar factors. The optimal dosage is determined as described herein, e.g., Remington: The Science and Practice of pharmacy, Mack Publishing Co.,20^thed., 2000. Those skilled in the art can determine their optimal dosage for a given set of conditions based on experimental data for the agent using routine dose-decision tests. For oral administration, a typical daily dose is generally about 0.001 to about 3000 mg per kg of body weight, with repeated courses of treatment at appropriate intervals. In some embodiments, the daily dose is about 1 to 3000 mg per kg of body weight.

A typical daily dose for a patient may be anywhere between about 500 to about 3000 mg, given once or twice daily, e.g. 3000 mg twice a day, to a total dose of 6000 mg. In one embodiment, the dosage is between about 1000 to about 3000 mg. In another embodiment, the dose is between about 1500 to about 2800 milligrams. In another embodiment, the dose is between about 2000 to about 3000 mg. Typically, the dosage is about 1mg/m²To about 40mg/m². Preferably, the dose is about 5mg/m²To about 25mg/m²。

The plasma concentration of the subject may be between about 100 μ M to about 1000 μ M. In some embodiments, the plasma concentration may be between about 200 μ M to about 800 μ M. In other embodiments, the concentration may be between about 300 μ M and about 600 μ M. In yet another embodiment, the plasma concentration may be between about 400 to about 800 μ M. In other embodiments, the plasma concentration may be between about 0.5 μ M to about 20 μ M, typically 1 μ M to about 10 μ M. The administration of the prodrug is typically at a weight-scale adjusted dose, which is a weight-scale that is chemically equivalent to the intact active form.

The compositions of the present invention may be manufactured using techniques commonly known for the preparation of pharmaceutical compositions, e.g., by conventional techniques such as mixing, dissolving, granulating, dragee-making, suspending, emulsifying, encapsulating, entrapping or lyophilizing. The pharmaceutical composition may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate the entry of the active ingredients into the formulation , which may be used pharmaceutically.

The appropriate formulation is based on the chosen route of administration. For injection, the formulations of the invention may be formulated as aqueous solutions, preferably in physiologically compatible buffered solutions, such as Hanks 'solution, Ringer's solution, or buffered saline solution. For transmucosal (transmucosal) administration, penetrants appropriate to the permeation barrier are used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be readily formulated using combinations of the active ingredients and pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as lozenges, pills, dragees, sachets, liquids, gels, syrups, slurries, solutions, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be prepared by mixing together solid excipients and the active ingredient(s), optionally grinding the resulting mixture, and processing the mixture of granules, if desired after adding suitable auxiliaries, to give tablets or dragee cores. Suitable excipients include: fillers, such as saccharides, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gums, methylcellulose, hydroxypropylmethylcellulose, sodium hydroxymethylcellulose or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

Dragees are provided with suitable coatings. For this purpose, it is possible to use concentrated sugar solutions, which optionally comprise gum arabic (gum acacia), polyvinylpyrrolidone, carbomer (Carbopol gel), polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the pastilles or dragees in order to identify or characterize combinations of different active agents.

Pharmaceutical preparations which can be used orally include push-fit capsules of gelatin, as well as soft, sealed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In the soft-cap portion, the active agent may be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, a stabilizer may be added. All formulations for oral administration should be within a dosage suitable for such administration. For buccal administration, the compositions may take the form of lozenges or pastilles which are formulated in conventional manner.

Pharmaceutical formulations for parenteral administration may include aqueous solutions or suspensions. Suitable lipophilic solvents or vehicles (vehicles) include fatty oils such as sesame oil, or fatty acid esters such as ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may contain suitable stabilizers or modifiers to increase the solubility or dispersibility of the composition to allow for the preparation of highly concentrated solutions, or may contain suspending or dispersing agents. Pharmaceutical preparations for oral use can be obtained by combining pharmacologically active ingredients with solid excipients, optionally grinding the resulting mixture, and processing the mixture of granules, if necessary after adding suitable auxiliaries, to obtain tablets or dragees. Suitable excipients are, inter alia, fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth (gum tragacanth), methyl cellulose, hydroxypropylmethyl-cellulose, sodium hydroxymethylcellulose or polyvinylpyrrolidone (PVP). If desired, disintegration-regulating agents such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added.

Other ingredients such as stabilizers, for example antioxidants, such as sodium citrate, ascorbyl palmitate, propyl gallate, reducing agents, ascorbic acid, vitamin E, sodium bisulfite, butylated hydroxytoluene, Butylated Hydroxyanisole (BHA), acetylcysteine, thioglycerol (monothioglycerol), phenyl-alpha-naphthylamine, or lecithin, may be used. Additionally, chelating agents such as EDTA may be used. Other conventional ingredients used in the pharmaceutical composition and formulation arts, such as lubricants, colorants, or flavoring agents in tablets or pills, may be used. In addition, conventional pharmaceutical excipients or carriers may be used. Pharmaceutical excipients may include, but are not necessarily limited to, calcium carbonate, calcium phosphate, various sugars or starch types, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and physiologically compatible solvents. Other pharmaceutical excipients are well known in the art. Typical pharmaceutically acceptable carriers include, but are not limited to, any and/or all solvents, including aqueous and non-aqueous solvents, dispersion media, coatings, antibacterial and/or antifungal agents, isotonic and/or absorption delaying agents, and/or the like. The use of such media and/or agents for pharmacologically active substances is well known in the art. Except insofar as any conventional media, carrier, or agent is incompatible with the active ingredient or ingredients, its use in the compositions according to the invention is contemplated. Supplementary active ingredients may also be incorporated into the composition, especially as described above. For administration of any of the compounds used in the present invention, the formulation should meet sterility, pyrogenicity, general safety and purity Standards as required by the FDA Office of biological Standards or regulatory organization of other regulatory drugs.

For intranasal administration or administration by inhalation, the compounds for use according to the invention are conveniently delivered in the form of a vapour spray from pressurized packs or nebulisers, by use of suitable propellants, such as dichlorodifluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurizer aerosol, the dosage unit may be measured by providing a valve to deliver a metered amount. Sachets and cartridges of gelatin for use in an inhaler or insufflator and similar devices may be formulated containing a powdered mixture of the compounds and a suitable powdered base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, such as a single injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be presented prior to use in powder form with a suitable vehicle, such as sterile pyrogen-free water. The compounds may also be formulated in compositions for rectal use, such as suppositories or retention enemas (retention enemas), e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds may also be formulated as depot dosage forms. Such long acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., an emulsion in an acceptable oil) or ion exchange resins or derivatives such as sparingly soluble (e.g., a sparingly soluble salt).

A typical pharmaceutical carrier for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, an organic polymer miscible with water, and an aqueous phase. The co-solvent system may be a VPD co-solution system. VPD is a solution containing 3% weight/volume (w/v) benzyl alcohol, 8% w/v non-polar surfactant polysorbate 80 and 65% w/v polyethylene glycol 300, added to volume as absolute ethanol. The VPD co-solution system (VPD:5W) contained VPD diluted with 5% aqueous dextran solution at a 1:1 ratio. This co-solvent system dissolves hydrophobic compounds well and itself produces low toxicity in systemic administration. Naturally, the proportion of the cosolvent system can be varied widely without destroying its solvency and toxicity characteristics. Furthermore, the identity of the co-solvent system may vary: for example, other low toxicity non-polar surfactants may be used in place of polysorbate 80; the fractionation size (fraction size) of the polyethylene glycol may vary; other biocompatible polymers may replace polyethylene glycol; and other saccharides or polysaccharides may be substituted for the glucan.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are examples of known delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide solution can be used, although usually at the expense of greater toxicity. In addition, the compounds may be delivered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various sustained release materials are established and known to those skilled in the art. Depending on its chemical nature, a slow-release sachet may release the compound for weeks up to over 100 days; in other alternatives, release may occur over hours, days, weeks, or months, depending on the therapeutic agent and formulation used. Depending on the chemical nature and biological stability of the therapeutic, other strategies for protein stability may be used.

The pharmaceutical composition liquid may comprise a suitable carrier or excipient for the solid or gel phase (gel-phase). Examples of such carriers or excipients include calcium carbonate, calcium phosphate, saccharides, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

The pharmaceutical composition may be administered in a manner known in the art. The route and/or mode of administration will vary depending upon the desired result. Depending on the route of administration, the pharmacologically active agent may be coated with a material to protect the subject composition or other therapeutic agent from acids or other effects that may lead to inactivation of the agent. Conventional pharmaceutical practice may be employed to administer such pharmaceutical compositions to a subject, providing suitable formulations or compositions. Any suitable route of administration may be used, such as, but not limited to, intravenous, parenteral, intraperitoneal, intravenous, transdermal, subcutaneous, intramuscular, intraurethral, or oral administration. Depending on the severity of the malignancy or other disease, disorder or condition to be treated, either systemic or local delivery of the pharmaceutical composition may be used in the course of treatment. The pharmaceutical composition as described above may be administered with an additional pharmaceutical agent intended to treat a particular disease or condition, which may be the same as, a related disease or health condition, or even an unrelated disease or health condition that the pharmaceutical composition is intended to treat.

The pharmaceutical compositions according to the invention can be prepared according to methods well known and routinely practiced in the art. See, e.g., Remington, The Science and Practice of Pharmacy, Mack Publishing Co.,20^thed., 2000; and Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978. The pharmaceutical composition is preferably produced under GMP conditionsAnd (4) producing. Formulations for parenteral administration may comprise, for example, excipients, sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymers, lactide/glycolide copolymers or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other parenteral delivery systems that may have potential utility for the molecules of the present invention include ethylene-vinyl acetate copolymer particles, osmotic pumps, and implantable infusion systems. Formulations for inhalation may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether (polyoxyyethylene-9-lauryl ether), hepatocholate and deoxycholate, or may be oily solutions or gels for administration.

The pharmaceutical composition according to the present invention is often administered to a subject on multiple occasions. The interval of a single dose may be weekly, monthly or yearly. The intervals may also be irregular, as indicated by a therapeutic response or other indications known in the art. Alternatively, the pharmaceutical composition may be administered in a sustained release formulation, in which case less frequent administration is required. The dose and frequency will vary depending on the half-life of the pharmacologically active agent included in the pharmaceutical composition in the subject. The dosage and frequency of administration may vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, relatively low doses are administered at relatively infrequent intervals over a prolonged period of time. Some subjects may continue to receive treatment for the rest of their lives. In therapeutic applications, it is sometimes desirable to administer relatively high doses at relatively short intervals until the progression of the disease is slowed or terminated, and preferably until the subject exhibits partial or complete improvement in disease symptoms. Thereafter, the subject may be administered a prophylactic project (prophylactic region).

For the purposes of this application, treatment may be monitored by observing one or more improved symptoms associated with the disease, disorder or condition to be treated, or by observing one or more improved clinical parameters associated with the disease, disorder or condition to be treated. In the case of glioblastoma multiforme and medulloblastoma, clinical parameters may include, but are not limited to, reduced tumor burden (tumor burden), reduced pain, reduced brain edema, reduced frequency and severity of seizures, reduced frequency and severity of vomiting, reduced frequency and severity of headache, reduced memory impairment, reduced neurological impairment, and reduced incidence of tumor spread or metastasis. As used herein, the terms "treating" or "treatment" or equivalent terms are not intended to imply a permanent cure for the disease, disorder or condition being treated. The compositions and methods according to the present invention are not limited to the treatment of humans, but may be applied to the treatment of animals of social or economic importance, such as dogs, cats, horses, cattle, sheep, goats, pigs and other species of animals of social or economic importance. Unless specifically noted, meaning that compositions and methods according to the invention are not limited to human treatment.

Sustained release formulations or controlled release formulations are well known in the art. For example, a sustained or controlled release formulation can be (1) an oral matrix sustained or controlled release formulation; (2) oral multi-layered sustained or controlled release lozenge formulations; (3) oral multiparticulate (multiparticulate) sustained or controlled release formulations; (4) oral osmotic sustained release or controlled release formulations; (5) sustained or controlled release formulations of chewable tablets (chewable) for oral administration; or (6) a patch formulation for sustained or controlled release of skin.

The Pharmacokinetic control of Drug Delivery systems is described, for example, in "pharmaceutical/pharmaceutical administration Basis of Controlled Drug Delivery" of B.M.Silber et al, Fundamentals and Applications (J.R.Robinson & V.H.L.Lee, eds,2ded, Marcel Dekker, New York,1987), Chapter 5, pages 213 to 251, which is incorporated herein by reference.

One of ordinary skill in the art can readily prepare Controlled or sustained Release formulations containing the pharmacologically active agents according to the present invention by adjusting the above formulations, such as according to the principles disclosed in "InfIumene of Drug Properties and Routes of Drug Administration on the Design of Sustanated and Controlled Release Systems" of V.H.K.Li et al, in Controlled Drug Delivery: fuels and Applications (J.R.Robinson & V.H.L.Lee, eds,2d ed., Mardecekker, New York,1987), Chapter 1, pages 3 through 94, which are incorporated herein by reference. This preparation procedure generally takes into account the physicochemical properties of the pharmacologically active agents, such as aqueous solubility, partitioning coefficient, molecular size, stability, nonspecific binding to proteins and other biological macromolecules. The preparation process also takes into account biological factors such as absorption, distribution, metabolism of the pharmacologically active agent, duration of action, possible side effects and safety margins (margin of safety). Thus, one of ordinary skill in the art can adjust the formulation to have the desired properties described above for a particular application.

U.S. patent No. 6,573,292 to Nardella, U.S. patent No. 6,921,722 to Nardella, U.S. patent No. 7,314,886 to Chao et al, and U.S. patent No. 7,446,122 to Chao et al, all of which are incorporated herein by reference, disclose methods and compositions for using various pharmacologically active agents for the treatment of certain diseases and conditions, including cancer, and for determining the therapeutic benefit of the pharmacologically active agents and pharmaceutical compositions.

Based on the results reported in the examples below, another aspect of the present invention is a method of treating a malignant tumor selected from the group consisting of glioblastoma multiforme and medulloblastoma, comprising the step of administering a therapeutically effective amount of a substituted hexitol derivative, such as dianhydrogalactitol, to a patient suffering from the malignant tumor.

Typically, when the substituted hexitol derivative is dianhydrogalactitol, the therapeutically effective amount of dianhydrogalactitol is about 1mg/m²To about 40mg/m². Preferably, the therapeutically effective amount of dianhydrogalactitol is 5mg/m²To about 25mg/m². The therapeutically active amount of other substituted hexitol derivatives other than dianhydrogalactitol (thereuticalyactive quality) can be determined by one of ordinary skill in the art using the molecular weight of the particular substituted hexitol derivative and the activity of the particular substituted hexitol derivativeSexual assays, such as the in vitro activity of substituted hexitol derivatives against standard cell lines.

Typically, substituted hexitol derivatives, such as dianhydrogalactitol, are administered by a route selected from the group consisting of intravenous and oral. Preferably, the substituted hexitol derivative, such as dianhydrogalactitol, is administered intravenously.

The method may further comprise the step of administering a therapeutically effective dose of free radiation. If the malignancy to be treated is glioblastoma multiforme, the method may further comprise the step of administering a therapeutically effective amount of temozolomide, bevacizumab or a corticosteroid. If the malignancy to be treated is medulloblastoma, the method may further comprise the step of administering a therapeutically effective amount of at least one chemotherapeutic agent selected from the group consisting of lomustine, cisplatin, carboplatin, vincristine, and cyclophosphamide.

Typically, substituted hexitol derivatives such as dianhydrogalactitol substantially inhibit the growth of cancer stem cells. Typically, the inhibition of growth of cancer stem cells is at least 50%. Preferably, the inhibition of growth of cancer stem cells is at least 99%.

Typically, substituted hexitol derivatives such as dianhydrogalactitol have O for inhibition⁶-ethylguanine-DNA methyltransferase (MGMT) driven growth of drug resistant cancer cells is efficient. In general, substituted hexitol derivatives such as dianhydrogalactitol are also effective in inhibiting the growth of anti-temozolomide cancer cells.

The method may further comprise administering a therapeutically effective amount of a tyrosine kinase inhibitor as described above.

The method may further comprise administering a therapeutically effective amount of an Epithelial Growth Factor Receptor (EGFR) inhibitor as described above. EGFR inhibitors may affect the binding positions of wild-type or mutated binding positions, including the third variant of EGFR, as described above.

The invention is illustrated by the following examples. This example is included for illustrative purposes only and is not intended to limit the present invention.