阅读说明：本技术 替加色罗在制备抗肿瘤药物中的应用 (Application of tegaserod in preparing anti-tumor medicine ) 是由 杨金波 宋巧玲 赵晨阳 吴丽娟 赵俊 唐宇 徐锡明 于 2020-04-17 设计创作，主要内容包括：本发明公开了替加色罗或其药学上可接受的盐作为JAK-STAT3信号通路抑制剂、免疫调节剂及其在制备抗肿瘤药物中的应用。替加色罗及其药学上可接受的盐在体内外对多种肿瘤细胞的生长有非常好的抑制效果,可望用于多种癌症的治疗。(The invention discloses tegaserod or pharmaceutically acceptable salts thereof serving as a JAK-STAT3 signal pathway inhibitor and an immunomodulator and application thereof in preparing antitumor drugs. The tegaserod and the pharmaceutically acceptable salt thereof have very good inhibition effects on the growth of various tumor cells in vitro and in vivo, and are expected to be used for treating various cancers.)

1. Application of tegaserod or pharmaceutically acceptable salt thereof in preparing antitumor drugs.

2. The use of claim 1, wherein the tumor presents an abnormal activation of the JAK-STAT3 signaling pathway.

3. The use of claim 2, wherein the aberrant activation of the JAK-STAT3 signaling pathway is in the form of elevated phosphorylation levels of JAK1, JAK2, JAK3, Tyk2, or STAT 3.

4. The use of claim 3, wherein said increase in phosphorylation is an increase in phosphorylation at the JAK1Tyr1022/1023 site, the JAK2Tyr1007/1008 site, the TYK2Tyr1054/1055 site, or the STAT3Tyr705 site.

5. The use of claim 1, wherein the anti-neoplastic agent activates and/or enhances an immune response.

6. The use of claim 5, wherein the immune response is a mammalian immune response.

7. The use of claim 6, wherein the immune response comprises a peripheral immune response and/or an immune response in a tumor microenvironment.

8. The use of claim 1, wherein the pharmaceutically acceptable salt is tegaserod maleate.

9. The use of any one of claims 1 to 8, wherein the tumor is a brain tumor, a tumor of the genitourinary system, a tumor of the lymphatic system, a gastric cancer, a laryngeal cancer, a nasopharyngeal cancer, a skin cancer, a bone cancer, a blood cancer, a leukemia, a breast cancer, a histiocytic lymphoma, a non-small cell lung cancer, a lung adenocarcinoma, a lung squamous carcinoma, a pancreatic cancer, a prostate cancer, a cervical cancer, a liver cancer, a skin cancer or an epithelial cell cancer.

10. The use of claim 9, wherein the tumor is prostate cancer, lung cancer or colon cancer.

Technical Field

The invention belongs to the field of medical application, and relates to a new medical application of tegaserod, in particular to a medicine which is used as a JAK-STAT3 signal pathway inhibitor and an immunomodulator and can be used for preparing antitumor drugs.

Background

Tumors are the first killers of human health and life at present, clinical medication is far from meeting the requirements of patients, and research and development of anti-tumor drugs are extremely important research directions in the current drug research and development field.

JAK-STATs signals in cells are crucial to cell signal transduction and various physiological activities, and abnormalities of the family signals can cause a plurality of diseases, including cancer and immune-related diseases. The JAKs family includes four members of JAK1, JAK2, JAK3 and Tyk 2. While the STATs family downstream of JAKs contains 7 members, STAT3 is an important family member that is constitutively activated by upstream aberrant tyrosine kinases in a number of tumor cell lines and human tumors. Aberrant STAT3 signaling is involved in the development and progression of human tumors by stimulating cell proliferation, promoting angiogenesis, and inhibiting apoptosis. Therefore, inhibition of the JAK-STAT3 signaling pathway is a potentially viable clinical treatment strategy for tumors.

The current clinical treatment strategies for inhibiting the JAK-STAT3 signal pathway mainly include the following categories: one is a tyrosine kinase inhibitor directed against the STAT3 upstream signaling molecule, including JAK kinase family inhibitors; secondly, STAT3 gene expression or protein function is blocked, such as RNAi interference is carried out through dominant-negative STAT protein or aiming at STAT 3; and thirdly, small molecules are used for inhibiting STAT3 activation and dimerization.

In recent years, with the rapid rise of the development cost of new drugs and the gradual decline of the success rate of drug development, most of the drug patents expire, and under the condition that the new backup drugs are difficult to follow up, pharmaceutical companies develop new patent protection drugs on the basis of the existing drugs. The new application of old drugs becomes a hot spot of international drug development.

Tegaserod (formula I), chemical name is 2- [ (5-methoxy-1H-indol-3-yl) methylene]-N-pentylcarbazepine, which is a selective 5-hydroxytryptamine 4 (5-HT)₄) Receptor agonists, the maleate salt of which was approved by the FDA in 2002, are used for the treatment of irritable bowel syndrome. In addition, tegaserod has therapeutic effects on a number of gastrointestinal disorders, including for example heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction and gastroesophageal reflux.

Disclosure of Invention

The invention unexpectedly discovers that tegaserod has inhibitory activity on JAK-STAT3 signal channel activity, can inhibit tumor growth, can activate peripheral immune response and immune response in a tumor microenvironment, and has in-vivo and in-vitro anti-tumor effects on various tumors.

Based on the discovery, the invention provides the application of tegaserod or a pharmaceutically acceptable salt thereof in preparing antitumor drugs.

In a preferred form of the invention, the tumour is a tumour in which there is abnormal activation of the JAK-STAT3 signalling pathway.

As a more preferred form of the invention, the abnormal activation of the JAK-STAT3 signaling pathway is in the form of an elevated phosphorylation level of JAK1, JAK2, JAK3, Tyk2 or STAT3, preferably in the form of an elevated phosphorylation level of JAK1Tyr1022/1023 site, JAK2Tyr1007/1008 site, TYK2Tyr1054/1055 site or STAT3Tyr705 site.

In a preferred form of the invention, the antineoplastic agent also activates and/or enhances an immune response.

In a more preferred form of the invention, the immune response is a mammalian immune response.

In a more preferred form of the invention, the immune response comprises a peripheral immune response and/or an immune response in the tumor microenvironment; more preferably, the activation and/or enhancement of a peripheral immune response comprises an increase in the number of one or more of leukocytes, neutrophils, lymphocytes and platelets in peripheral blood of the body; activating and/or enhancing anti-tumor immune responses in a tumor immune microenvironment, including increasing infiltration of immune cells (CD45+) within the tumor, or partially or fully increasing the proportion of one or more of killer T cells (CD8+), helper T cells (CD4+), activated T cells (CD4+ CD69+ and CD8+ CD69+), tumor-infiltrating inflammatory neutrophils (CD11b + Ly6G +), monocytes/macrophages (CD11b + Ly6C +), natural killer cells (CD335 +).

In a preferred form of the invention, the pharmaceutically acceptable salt is tegaserod maleate.

In a preferred form of the invention, the tumour is any one of: brain tumor, genitourinary system tumor, lymphatic system tumor, gastric cancer, laryngeal cancer, nasopharyngeal cancer, skin cancer, bone cancer, leukemia, breast cancer, histiocytic lymph cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, prostatic cancer, cervical cancer, liver cancer, skin cancer, epithelial cell cancer, etc., preferably prostatic cancer, lung cancer or colon cancer.

In addition, the tegaserod or a pharmaceutically acceptable salt thereof can also increase the clinical effect thereof by being combined with an anti-tumor drug currently used or under development.

The tegaserod and the pharmaceutically acceptable salt thereof have very good inhibition effects on the growth of various tumor cells in vitro and in vivo, and are expected to be used for treating various cancers. The invention provides a new candidate drug for treating tumor patients, which can further improve the curative effect of the patients and improve the prognosis of the patients.

Drawings

Figure 1 is a graph of the inhibitory effect of tegaserod maleate on reporter gene expression in a STAT3 luciferase drug screening system.

FIG. 2 is a graph showing that tegaserod can inhibit constitutive activation and IL-6 induced STAT3 activation by immunoblotting experiments.

Figure 3 is a schematic representation of tegaserod selectively inhibiting phosphorylation of JAK kinases as demonstrated by immunoblotting experiments.

FIG. 4 is a schematic of tegaserod inhibiting tumor cell growth in vitro.

Fig. 5 is a schematic representation of a xenograft tumor model in a549 nude mice demonstrating that intraperitoneal administration of tegaserod inhibits the growth of the transplantable tumor.

FIG. 6 oral tegaserod can effectively inhibit the growth of non-small cell lung cancer A549 nude mouse transplanted tumor.

Figure 7 oral tegaserod inhibits the growth of prostate cancer DU145 nude mouse transplantable tumors.

FIG. 8 oral administration of low dose and low frequency tegaserod is effective in inhibiting the growth of transplanted tumors in DU145 nude mice.

Figure 9 oral tegaserod activates immune responses in the peripheral and tumor microenvironment.

FIG. 10 Tegaserod activates the immune system inhibiting the growth of colorectal carcinoma MC38 allografts.

Detailed Description

The invention provides application of tegaserod, free forms of tegaserod, pharmaceutically acceptable salts, prodrugs and active metabolites of the tegaserod in preparing antitumor drugs.

The free form of a particular salt of tegaserod may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base, such as a dilute aqueous NaOH solution, a dilute aqueous potassium carbonate solution, dilute aqueous ammonia, and a dilute aqueous sodium bicarbonate solution. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.

The pharmaceutically acceptable salts of the present invention can be synthesized from tegaserod by conventional chemical methods. Typically, they are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of the inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Thus, pharmaceutically acceptable salts of tegaserod of the invention include the conventional non-toxic salts of the compounds of the invention formed by the reaction of tegaserod with an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-monobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid and the like, preferably the maleate salt.

The invention relates to tegaserod or pharmaceutically acceptable salts thereof serving as JAK-STAT3 signal path small molecule inhibitors and application thereof in preparation of antitumor drugs.

In one embodiment, the present application provides a method of treating hyperproliferative diseases or conditions, such as tumors, in humans and other mammals, using tegaserod or a pharmaceutically acceptable salt thereof.

In one embodiment, the compounds and pharmaceutically acceptable salts thereof referred to herein can be used for treating or controlling hyperproliferative diseases such as histiocytic lymphoma, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, prostate cancer, nasopharyngeal cancer, epidermal cell cancer, cervical cancer, oral cancer, human fibrosarcoma, leukemia, and the like.

Tegaserod and pharmaceutically acceptable salts thereof to which the present application relates may be used for the treatment of the following diseases as well as other diseases not listed below according to the following method:

1) a method of treating breast cancer in a human or other mammal using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Including but not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

2) A method of treating cancer of the respiratory tract in a human or other mammal using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Including but not limited to small cell, non-small cell lung cancer, and bronchial adenomas and pleuropulmonary blastoma.

3) A method of treating brain cancer in a human or other mammal using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Including but not limited to brain stem and sub-ocular gliomas, cerebellum and brain astrocytomas, ependymomas, and neuroectodermal and pineal tumor bodies.

4) A method of treating tumors of male and female reproductive organs in a human or other mammal using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Tumors of the male reproductive organs include, but are not limited to, prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal and vulvar cancers, as well as intrauterine tumors.

5) A method of treating tumors of the alimentary tract of a human or other mammal using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Including but not limited to anal, colon, linear colon, esophageal, gastric, pancreatic, rectal, small bowel or salivary gland cancer.

6) A method of treating a neoplasm of the urinary tract of a human or other mammal using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Including but not limited to bladder, penile, kidney, renal pelvis, ureter, bladder-infiltrating papillary urothelial, or urethral cancers.

7) A method of treating ocular cancer in a human or other mammal using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Including but not limited to intraocular melanoma and retinoblastoma.

8) A method of treating liver cancer in humans and other mammals using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Including but not limited to hepatoma (stem cell carcinoma with or without fibroplasia), cholangiocarcinoma (hepatobiliary carcinoma) and mixed hepatocellular cholangiocarcinoma.

9) A method of treating skin cancer in humans or other mammals using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Including but not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merck's cell skin cancer, and non-melanoma cell cancer.

10) A method of treating head and neck cancer in a human or other mammal using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Including but not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, and lip and oral cancer.

11) A method of treating lymphoma in a human or other mammal using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Including but not limited to AIDS-related lymphomas, non-Hodgkin's lymphomas, cutaneous T-cell lymphomas, Hodgson's disease, and central nervous system lymphomas.

12) A method of treating sarcoma in a human or other mammal using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Including but not limited to soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lype sarcomas, and rhabdomyosarcomas.

13) A method of treating leukemia in humans and other mammals using a pharmaceutical composition of tegaserod or a pharmaceutically acceptable salt thereof. Including but not limited to acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

Tegaserod or a pharmaceutically acceptable salt thereof according to the invention may be administered to a mammal, preferably a human, alone or in a pharmaceutical composition in combination with a pharmaceutically acceptable recipient, adjuvant or diluent, according to standard pharmaceutical techniques. Can be administered orally or subcutaneously, intramuscularly, intraperitoneally, intravenously, rectally, topically, ocularly, pulmonarily, nasally, parenterally.

Active metabolites of tegaserod or a pharmaceutically acceptable salt thereof to which the present application relates, and prodrugs which may be converted in vivo into the structure of the compounds to which the present application relates and pharmaceutically acceptable salts thereof, are also comprised in the claims of the present application.

The term "immune response" refers to the defense and recognition reactions of the body against the foreign or variant autologous components. Immune responses typically include both systemic and local immune responses, depending on the location in the body where the occurrence or action occurs.

The term "peripheral immune response" pertains to a systemic immune response, involving the widespread activation of the immune system "in a distance" from the tumor itself, including the response of immune cells circulating in the bloodstream to activation, phenotypic change or proliferation caused by the release of damp (danger associated Molecular pattern) from allogeneic or mutated autologous or autologous cells, and also including immune responses in lymphoid nodules, spleen or gut-associated lymphoid tissues.

The tumor microenvironment is composed of tumor cells, tumor infiltrating immune cells, new vessels and endothelial cells thereof, tumor-related fibroblasts and extracellular matrix, and can promote tumor deterioration, increase tumor invasiveness, avoid host immune function and resist treatment reaction. The term "immune response in the tumor microenvironment", pertains to a local immune response, and generally includes the composition, activity and function of immune cells in the tumor microenvironment. In the present invention, immune responses in the tumor microenvironment include changes in the levels of tumor-internal immune cells (CD45+), killer T cells (CD8+), helper T cells (CD4+), activated T cells (CD4+ CD69+ and CD8+ CD69+), and tumor-infiltrating inflammatory neutrophils (CD11b + Ly6G +), monocytes/macrophages (CD11b + Ly6C +), natural killer cells (CD335+), etc. Activating and/or enhancing an immune response in an immune tumor microenvironment refers to an increase in the number or proportion of all or part of the above cells.

Tegaserod may be used in combination with other drugs known to treat or ameliorate similar conditions. When the combination is administered, the mode and dosage of administration of the original drug is maintained, while tegaserod is taken simultaneously or subsequently. When tegaserod is to be taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition comprising both one or more known drugs and tegaserod. The combination also includes administration of tegaserod in an overlapping time period with one or more other known drugs. The dosage of tegaserod or a known drug may be lower when tegaserod is administered in combination with one or several other drugs than when they are administered alone.

Drugs or active ingredients that can be used in combination with tegaserod for the treatment of tumors include, but are not limited to:

estrogen receptor modulators, androgen receptor modulators, retinal-like receptor modulators, cytotoxins/cytostatics, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, agents that interfere with cell cycle checkpoints and apoptosis inducers, cytotoxic agents, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors, Met inhibitors, Raf inhibitors, MEK inhibitors, MMP inhibitors, topoisomerase inhibitors, histidine deacetylase inhibitors, protease inhibitors, CDK inhibitors, Bcl-2 family protein inhibitors, protein kinase inhibitors, and the like, MDM2 family protein inhibitors, IAP family protein inhibitors, STAT family protein inhibitors, PI3K inhibitors, AKT inhibitors, integrin blockers, interferon-alpha, interleukin-12, COX-2 inhibitors, p53, p53 activators, VEGF antibodies, EGF antibodies, and the like.

In one embodiment, the drug or active ingredient that may be used in combination with tegaserod for the treatment of tumors includes, but is not limited to: aldesleukin, alendronic acid, interferon, atrazine, allopurinol sodium, palonosetron hydrochloride, altretamine, aminoglutethimide, amifostine, amrubicin, ambridine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, anoxin, 5-azacytidine, azathioprine, bacillus calmette or tide bacillus calmette, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromouroxime, bortezomib, busulfan, calcitonin, alezomab injection, capecitabine, carboplatin, custard, cefetasone, simon, daunorubicin, cytarabine, dacarbazine, actinomycin, dexamethasone, daunorubicin, chlorambucil, cisplatin, cladribine, clorine phosphate, clorfurin, cyclophosphamide, alexan, alexin, dacarbazine, actinomycin, dexamethasone, and dexamethasone, Estradiol valerate, dinil interleukin 2, dipalmitate, deslorelin, delazoxan, diethylstilbestrol, Dafukang, docetaxel, doxifluridine, doxorubicin, dronabinol, azulene-166-chitosan complex, eligard, ramucinase, epirubicin hydrochloride, aprepitant, epirubicin, alfapentin, erythropoietin, eptaplatin, levamisole, estradiol formulations, 17-beta-estradiol, estramustine sodium phosphate, ethisterol, amifostine, hydroxyphosphoric acid, vaseline, etoposide, fazole, tamoxifen formulations, filgrastim, phenastidine, filristine, floxuridine, fluconazole, fludarabine, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil, flumetmesterodine, fulvestramustine, 1-beta-D-arabinoside-5 '-stearoyl-5' -monophosphate, 5-fluorouracil, flutolidine, flutamide, fulvestrant, 1-beta-D-arabinoside, Fotemustine, fulvestrant, gamma globulin, gemcitabine, gemtuzumab ozogamicin, imatinib mesylate, carmustine wafer capsule, goserelin, glanesilong hydrochloride, histrelin, and meclizine, hydrocortisone, erythro-hydroxynonyladenine, hydroxyurea, temozolomide, idarubicin, ifosfamide, interferon alpha 2A, interferon alpha 2B, interferon alpha n1, interferon alpha n3, interferon beta, interferon gamma 1a, interleukin 2, intron A, iressa, irinotecan, ketrey, lentinan sulfate, letrozole, leucovorin, leuprorelin acetate, levotetramisoimidazole, levofolinic acid calcium salt, levothyroxine sodium, Levothyroxine sodium formulation, lomustine, lonidamine, dronabinol, mechlorethamine, medroxyprogesterone acetate, megestrol acetate, melphalan, esterified estrogen, 6-ryylpurine, mesna, methotrexate, methyl aminoacetylpropionate, miltefosine, memantin, mitomycin C, mitotane, mitoxantrone, trilobatin, trilostane, doxorubicin citrate liposome, nedaplatin, polyglycolized filgrastim, alprenelafin, neuoprotein, nilutamide, tamoxifen, NSC-631570, recombinant human leukocyte 1-beta, octreotide, ondansetron hydrochloride, hydrocortisone oral solution, oxaliplatin, paclitaxel, prednisone sodium phosphate formulation, pemetrexed, protamine, streptolysin, pirocin hydrochloride, betalain hydrochloride, Precamycin, porfimer sodium, prednisone, seletholin, prednisone, bemeili, procarbazine, recombinant human erythropoietin, raltitrexed, Libi, rhenium-186 etidronate, rituximab, dygulonol-A, romopeptide, pilocarpine hydrochloride tablet, octreotide, sarmostim, semustine, Sizopyran, sobuzosin, sodium methylprednisolone, pafoscarnet, dry cell therapy, streptozocin, strontium chloride-89, levothyroxine sodium, tamoxifen, tamsulosin, tasolone, tasolane, taxotere, temozolomide, teniposide, testosterone propionate, methyltestosterone, thioguanine, thiotepa, thyrotropine, temiudronic acid, topotecan, tolimomab, tolytuzumab, tolytin, tretinomycin, tretinospora A, methotrexate, tretinomycin, and so, Trimethamide, trimetrexate, triptorelin acetate, triptorelin pamoate, eufordine, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vinblastine, vinorelbine, vilulizine, dexpropinimine, neat stastatin, vinflunine, paclitaxel protein stabilizing formulations, acolbifene, interferon r-lb, affinitak, aminopterin, azoxifene, ascorisil, atamestane, atrasentan, BAY43-9006, avastin, CCI-779, CDC-501, celecoxib, cetuximab, clinatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dstpm, dutasteride, eotarececarin, eflornithine, irinotecan, fenretinide, histamine, a dihydrochloride, a hydrogel of histidine, irinotecan-166 holmium diphosphate, holmium 166-holmium D, DOTMP, DOO, Interferon gamma, intron-PEG,

ixabepilone, keyhole limpet hemocyanin, L-651582, lanreotide, lasofoxifene, libra, lonafamib, mifepristoxifene, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, simvastatin, nolatrexed, orlimerson, onco-TCS, osidme, paclitaxel polyglutamate, pamoate, PN-

401. QS-21, quart, R-1549, raloxifene, ranpirnase, 13-cis retinoic acid, satraplatin, seocalcitol, T-138067, tarceva, taxol docosahexanoate, thymosin alpha 1, gazofurin, tipifarnib, tirapazamine, TLK-286, toremifene, trans MID-lo7R, varsnada, vapreotide, vatalanib, verteporfin, vinflunine, Z-100, and zoledronic acid, or combinations thereof.

The invention is further illustrated below in conjunction with specific examples, which are provided to aid in further understanding of the invention, wherein the particular materials, means, etc. used are illustrative of the invention and are not intended to limit the scope of the invention.