阅读说明：本技术 左氧氟沙星类抗生素作为制备抗癌药物增敏药物的应用及其抗癌药物 (Application of levofloxacin antibiotic in preparing anti-cancer drug sensitizing drug and anti-cancer drug thereof ) 是由 贺小琼 于 2019-11-22 设计创作，主要内容包括：本发明涉及左氧氟沙星类抗生素作为制备抗癌药物增敏药物的应用及其抗癌药物,属于药物研究技术领域。左氧氟沙星类抗生素对人类多种癌症具有显著性的体外、体内抗癌作用；其抗癌作用具有明显的剂量-效应、时间-效应关系；左氧氟沙星类抗生素与其它抗癌药物联合应用时,能显著性提升抗癌药物对各种癌症的抗癌作用,二者具有协同或相加联合抗癌作用。在有效的体内抗癌剂量下,左氧氟沙星不会显著性影响动物体重发育。结果显示,左氧氟沙星类抗生素可作为广谱抗癌药物；特别是作为其它抗癌药物的增敏药物,可与其它抗癌药物联合应用,或与其它抗癌药物形成联合抗癌药物组合物；或作为保健品进行癌症辅助治疗。(The invention relates to application of levofloxacin antibiotic in preparing an anti-cancer drug sensitizing drug and an anti-cancer drug thereof, belonging to the technical field of drug research. The levofloxacin antibiotic has significant in-vitro and in-vivo anticancer effects on various human cancers; the anticancer effect has obvious dose-effect and time-effect relationship; when the levofloxacin antibiotic is combined with other anti-cancer drugs for use, the anti-cancer effect of the anti-cancer drugs on various cancers can be remarkably improved, and the levofloxacin antibiotic and the other anti-cancer drugs have synergistic or additive combined anti-cancer effect. At effective in vivo anti-cancer doses, levofloxacin does not significantly affect animal weight development. The results show that the levofloxacin antibiotics can be used as broad-spectrum anticancer drugs; in particular, the derivative can be used as a sensitizing medicament of other anticancer medicaments and can be combined with other anticancer medicaments for application or form a combined anticancer medicament composition with other anticancer medicaments; or used as health product for adjuvant treatment of cancer.)

1. The levofloxacin antibiotic is applied to the preparation of broad-spectrum anticancer drugs, anticancer drug sensitizing drugs, combined anticancer drug compositions or auxiliary anticancer health care products.

2. The use of levofloxacin antibiotics according to claim 1 in the preparation of broad-spectrum anticancer drugs, anticancer drug sensitizers, combined anticancer drug compositions or auxiliary anticancer health products, wherein the broad-spectrum anticancer drugs, anticancer drug sensitizers, combined anticancer drug compositions include drugs against gastric cancer, colon cancer, leukemia, lymphoma, glioma, nasopharyngeal carcinoma, esophageal cancer, cervical cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, cholangiocarcinoma, pancreatic cancer, bladder cancer, renal cancer, prostate cancer, osteosarcoma, melanoma.

3. The use of levofloxacin antibiotic according to claim 1 in the preparation of a broad-spectrum anticancer drug, an anticancer drug sensitizing drug, a combined anticancer drug composition or an auxiliary anticancer health product, wherein the combined anticancer drug composition is a drug formed by combining levofloxacin antibiotic with other anticancer drugs.

4. The use of levofloxacin antibiotic according to claim 1 in the preparation of a broad-spectrum anticancer drug, an anticancer drug-sensitizing drug, a combination anticancer drug combination or an auxiliary anticancer health product, wherein the anticancer drug-sensitizing drug is a drug capable of enhancing the anticancer drug efficacy of various anticancer drugs clinically used for the treatment of cancer patients.

5. The broad-spectrum anticancer medicine is characterized in that the active component comprises levofloxacin antibiotic.

6. The anti-cancer drug sensitization drug is characterized in that the active component is levofloxacin antibiotic.

7. A combined anticancer medicine composition is characterized in that the active ingredients comprise at least one of other clinical anticancer drugs such as cisplatin, 5-fluorouracil and the like besides levofloxacin antibiotics.

8. The anticancer drug according to claim 5, the anticancer drug sensitizer according to claim 6, or the combined anticancer pharmaceutical composition according to claim 7, wherein the pharmaceutical dosage form is injection, powder injection, tablet, oral liquid, capsule, granule, or granule.

9. An auxiliary anticancer health product is characterized in that the active component comprises levofloxacin antibiotic.

10. The auxiliary anticancer health product of claim 9, wherein the dosage form is tablet, oral liquid, capsule, granule or granule.

Technical Field

The invention belongs to the technical field of medicine research, and particularly relates to application of levofloxacin antibiotic in preparing broad-spectrum anticancer drugs, application in preparing sensitizing drugs of other clinical anticancer drugs, application in preparing a combined anticancer drug composition, and an auxiliary anticancer health-care product.

Background

Malignant tumor is a serious disease seriously threatening human health and life safety, and is now the main cause of death of human beings and seriously threatening human health and life safety. Data published by Globocan of the international cancer institute of the world health organization show that 1266.1 ten thousand new cancer cases and 756.4 ten thousand deaths occur worldwide in 2008. In 2012, the number of newly added cancer cases is 1410 ten thousand, the death is 820 ten thousand, and 3260 thousands of people live with tumors. In 2015, 1750 ten thousand new cancer cases and 870 ten thousand deaths occur worldwide. The number of cancer cases and the number of deaths are increasing, and the number of new cancer cases is estimated to reach 1900 ten thousand in 2025 and 2400 ten thousand in 2035. The data show that the incidence of malignant tumors is rapidly increasing with the aging population, the aggravation of environmental pollution and the change of life patterns.

Cancer is still an incurable disease in the world at present. Chemotherapy for cancer plays an important role in cancer treatment as a systemic therapeutic measure, and is a promising approach to complete cancer treatment in the future. Most of the clinically used cancer chemotherapy drugs have the problems of great toxic and side effects, uncertain curative effect, poor selectivity, weak targeting property, cancer cell drug resistance and the like, so that the clinical application and effect of cancer chemotherapy drug treatment are greatly limited. Therefore, the development of new chemotherapeutic drugs with definite curative effect and sensitization drugs capable of improving the anticancer effect of clinical anticancer drugs has important value for the chemotherapy of cancer.

Disclosure of Invention

The invention aims to solve the defects of the prior art and provides the application of levofloxacin antibiotic in preparing broad-spectrum anticancer drugs, the application in preparing combined anticancer drug compositions, the application in serving as clinical anticancer drug sensitizing drugs, anticancer drugs thereof and auxiliary anticancer health care products.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

the levofloxacin antibiotic can be used in preparing broad-spectrum anticancer drugs, combined anticancer drug compositions, and anticancer drug sensitizing drugs or auxiliary anticancer health products.

Further, preferably, the broad spectrum anticancer drugs include drugs against gastric cancer, colon cancer, leukemia, lymphoma, glioma, nasopharyngeal carcinoma, esophageal cancer, cervical cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, bile duct cancer, pancreatic cancer, bladder cancer, renal cancer, prostate cancer, osteosarcoma, and melanoma.

The levofloxacin antibiotic has significant anticancer effect on human gastric cancer, colon cancer, leukemia, lymphoma, glioma, nasopharyngeal carcinoma, esophageal cancer, cervical cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, cholangiocarcinoma, pancreatic cancer, bladder cancer, renal cancer, prostate cancer, osteosarcoma, melanoma and the like. Levofloxacin antibiotics are broad-spectrum anticancer drugs, and have obvious dose-effect and time-effect relationships in anticancer effect.

A broad-spectrum anticancer medicine or the sensitizing medicine of anticancer medicine contains levofloxacin as active component. The levofloxacin antibiotic can significantly improve the anticancer drug effect of clinical anticancer drugs, and has synergistic or additive combined anticancer effect with the clinical anticancer drugs.

A combined anticancer medicinal composition contains levofloxacin antibiotic as active ingredient, and at least one of cisplatin, 5-fluorouracil and other clinical anticancer drugs.

Further, preferably, the medicament formulation is injection, powder injection, tablets, oral liquid, capsules, granules or electuary.

The active ingredients of the broad-spectrum anticancer drug and the anticancer drug sensitizing drug can be levofloxacin antibiotic only or a combined anticancer drug composition which comprises the levofloxacin antibiotic as one of the active ingredients. When the compound is a combined pharmaceutical composition, the compound has anticancer activity and also comprises at least one of other clinical anticancer drugs such as cisplatin, 5-fluorouracil and the like besides levofloxacin antibiotics. The levofloxacin antibiotic and other anticancer drugs in the combined anticancer drug composition have additive action or synergistic action in cancer treatment, and can improve clinical anticancer effect, reduce the dosage of the anticancer drugs and reduce toxic and side effects.

It will be appreciated by those skilled in the art that the anticancer drug, the anti-cancer drug sensitizing agent of the present invention may further comprise a pharmaceutically acceptable carrier in addition to the active ingredient.

The specific therapeutically effective amount of levofloxacin in the pharmaceutical composition may be determined by those skilled in the art based on the subject to be administered and the type of cancer. In some embodiments, an effective amount of levofloxacin may range from 1 to 99.99%, preferably from 10 to 99%, more preferably from 50 to 99% by weight of the composition.

An auxiliary anticancer health product contains levofloxacin antibiotic as active ingredient.

Further, the dosage form is preferably a tablet, an oral liquid, a capsule, a granule or a granule.

It will be appreciated by those skilled in the art that the levofloxacin antibiotics having anticancer activity of the present invention include various generations of quinolone antibiotics currently used in clinical practice, and are not limited to the ones indicated in the examples.

Compared with the prior art, the invention has the beneficial effects that:

the levofloxacin antibiotic of the invention is a clinical common antibacterial drug, can be purchased from the market, and can also be chemically synthesized. The levofloxacin antibiotic can be used as a chemotherapeutic drug for various cancers of human beings, or as a sensitizing drug for other clinical anticancer drugs, or as an anticancer drug composition of active ingredients of anticancer drugs, or as a component of a combined anticancer drug composition, and as an active ingredient of a health care product for assisting anticancer.

The levofloxacin antibiotic can remarkably kill and/or inhibit various human cancer cells in vitro, such as gastric cancer cells SGC-7901, colon cancer cells HCT-116, leukemia cells K-562, lymphomas L-428 and BJAB, glioma cells U-251, liver cancer cells HepG2 and QGY-7703, nasopharyngeal cancer cells CNE2, lung cancer cells A-549 and XWLC-05, esophageal cancer cells CaEs-17, cervical cancer cells Hela, ovarian cancer SKOV-3, bile duct cancer cells QBC-939, pancreatic cancer PANC-1, bladder cancer cells T-24, renal cancer cells ACHN, prostate cancer PC-3, osteosarcoma MNNG, breast cancer MCF-7 and MDA-MB-231, melanoma A-375 and the like.

The levofloxacin antibiotic has obvious growth inhibition effect on human cancers transplanted to balb/c nude mice in vivo. The levofloxacin antibiotic and clinically used anticancer chemotherapeutic drugs such as cisplatin, 5-fluorouracil and the like have significant synergistic or additive combined anticancer effects on various human cancers in vitro and/or in vivo, and can be combined and applied as an anticancer drug composition for cancer chemotherapy or as a sensitizing drug in cancer treatment.

Drawings

FIG. 1 shows the in vitro anticancer effect of levofloxacin hydrochloride on different cancer cell lines;

FIG. 2 shows the in vitro anticancer effect of levofloxacin lactate on different cancer cell lines;

FIG. 3 is a graph showing the relationship between dose-effect and time-effect of levofloxacin hydrochloride in vitro against nasopharyngeal carcinoma;

FIG. 4 shows the in vitro selective anticancer effect of levofloxacin hydrochloride;

FIG. 5 is a graph showing the in vivo anti-nasopharyngeal carcinoma effect (relative tumor volume, RTV) of levofloxacin hydrochloride;

FIG. 6 shows the in vivo anti-nasopharyngeal carcinoma effect (relative tumor proliferation rate, RPR,%) of levofloxacin hydrochloride;

FIG. 7 shows the in vivo anti-nasopharyngeal cancer effect (tumor weight, TW) of levofloxacin hydrochloride;

FIG. 8 shows the in vitro combined anticancer effects of levofloxacin hydrochloride and cisplatin;

FIG. 9 shows the in vitro combined anticancer effects of levofloxacin hydrochloride and 5-fluorouracil;

FIG. 10 shows the in vivo combined anti-nasopharyngeal effect (relative tumor volume) of levofloxacin hydrochloride and cisplatin;

FIG. 11 shows the combined anti-nasopharyngeal effect (relative tumor proliferation rate) of levofloxacin hydrochloride and cisplatin in vivo;

FIG. 12 shows the in vivo combined anti-nasopharyngeal effect (mean tumor weight) of levofloxacin hydrochloride and cisplatin;

FIG. 13 shows the cytotoxic effect of levofloxacin hydrochloride on normal cells;

FIG. 14 shows that levofloxacin hydrochloride affects the cytotoxic effects of cisplatin on normal cells (NO-free levofloxacin, LH-levofloxacin hydrochloride);

FIG. 15 is a graph of the effect of various doses of levofloxacin hydrochloride on tumor-bearing body weight in animals;

FIG. 16 shows the effect of levofloxacin hydrochloride in combination with cisplatin on tumor-bearing body weight in mice;

FIG. 17 is a graph comparing the in vitro anti-cancer effects of Levofloxacin Hydrochloride (LH) and Levofloxacin Lactate (LL);

note: the overlapping of characters and lines in the figure does not affect the expression meaning.

Detailed Description

The present invention will be described in further detail with reference to examples.

It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples do not specify particular techniques or conditions, and are performed according to the techniques or conditions described in the literature in the art or according to the product specifications. The materials or equipment used are not indicated by manufacturers, and all are conventional products available by purchase.

Definition of terms

Unless otherwise indicated, the terms used in the present invention have the following meanings:

the chemical name of the levofloxacin antibiotics is as follows: (S) - (-) -9-fluoro-2, 3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1, 2, 3-de ] - [1, 4] benzoxazine-6-carboxylic acid hemihydrate, belonging to quinolone antibiotics. Including all the various levofloxacin antibiotic preparations used clinically.

As used herein, "pharmaceutical composition" refers to a formulation of a levofloxacin antibiotic of the present application with a vehicle commonly accepted in the art for delivery of biologically active compounds to mammals, such as humans. Such media include all pharmaceutically acceptable carriers.

The combined anticancer medicine composition is the combined anticancer medicine comprising levofloxacin antibiotic and other clinical anticancer medicine.

The 'sensitization effect' in the application refers to that when the levofloxacin antibiotic is combined with other anticancer drugs, the drug effect of the other anticancer drugs can be obviously improved, and the anticancer effect of the combined application is stronger than that of a single anticancer drug.

As used herein, "pharmaceutically acceptable carrier" is intended to include, but is not limited to, any adjuvant, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, disintegrating agent, solvent, or emulsifying agent that has been recognized by the united states Food and Drug Administration (FDA) as being useful in humans or animals in a variety of forms that have no adverse effects on the resulting pharmaceutical composition.

The term "treating" means administering the medicament of the present invention to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition;

(ii) inhibiting the disease or disease state, i.e., arresting its development;

(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition.

The auxiliary anticancer health product is used for auxiliary treatment of cancer patients in the treatment process of the cancer patients, and may have sensitization effect on the treatment of the cancer patients, but the health product is not used for treatment.