WO2006076863A1 - Composition pharmaceutique synergique destinee a inhiber une tumeur - Google Patents

Composition pharmaceutique synergique destinee a inhiber une tumeur Download PDF

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Publication number
WO2006076863A1
WO2006076863A1 PCT/CN2006/000091 CN2006000091W WO2006076863A1 WO 2006076863 A1 WO2006076863 A1 WO 2006076863A1 CN 2006000091 W CN2006000091 W CN 2006000091W WO 2006076863 A1 WO2006076863 A1 WO 2006076863A1
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xanthine
tumor
cancer
cisplatin
compound
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PCT/CN2006/000091
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Chinese (zh)
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Yixin Wu
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Shanghai Gloriayx Biopharmaceuticals Co., Ltd
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Publication of WO2006076863A1 publication Critical patent/WO2006076863A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to a synergistic antitumor pharmaceutical composition, and in particular to a synergistic antitumor pharmaceutical composition comprising a xanthone compound and a tumor chemotherapeutic drug.
  • the invention also relates to the pharmaceutical use of the flavonoids. Background technique
  • Chemotherapy is short for "chemical drug treatment.”
  • the current concept of chemotherapy is generally understood as “the treatment of tumors", that is, the use of anti-tumor chemicals, and the use of certain measures and protocols to treat tumors.
  • common chemotherapeutic drugs such as vincristine, cisplatin, methotrexate, cyclophosphamide, 5-fluorouracil (5-Fu) can produce local pain, venous thromboembolism, myelosuppression, and gastrointestinal reactions. , peripheral neuropathy and other toxic side effects.
  • cisplatin is clinically used in combination with 5-Fu, bleomycin or epipodophyllotoxin to treat esophageal cancer.
  • “Synergistic Effect” refers to the sum of the effects of the two drugs when they are used in combination with the two drugs when they are used alone. According to the principle of medium effect (Joseph R. Bertino, Ting-Chao Chou, Chemotherapy: Synergism and Antagonism, Encyclopedia of Cancer, 1996, Academic Press, Inc.), the effect of the combination of the two drugs can be achieved through the "combination index” (Combination) Index, CI) to judge:
  • Dl and D2 are the drug concentrations when the cell proliferation inhibition rate reaches x% when the drugs 1 and 2 are used alone; (Dx), (Dx) 2 is the drug 1 in the mixture when the same cell proliferation inhibition rate is reached. And the concentration of drug 2.
  • transplanted tumor strains in mice include: mouse melanoma cell line B16, mouse fibrosarcoma cell line M5076 and other solid tumors. (solid tumor) tumor strain; mouse leukemia cell line L1210 and other blood tumor tumor strains. Therefore, those skilled in the art often use a certain tumor tumor strain as an in vivo test mode for transplanted tumors: For example, a mouse animal test using mouse melanoma cell line B16 is used as an animal test for solid tumors. Mode; Mouse animal test of mouse leukemia cell line L1210 was used as an in vivo test mode for blood line tumors. It is judged whether the substance to be tested has an antitumor effect by combining the results of the test in vitro and in vivo.
  • Astragalus and Astragalus membranaceus are the main flavonoids contained in the roots of Astragalus membranaceus, both of which have the same flavonoid structure -
  • Astragalus membranaceus is one of the main active constituents of Astragalus membranaceus. Its molecular formula C 15 H 1() 0 5 , molecular weight 270.25, can be obtained by hydrolysis of Astragalus. Its chemical structure is: 5, 6, 7 three hydrogen groups (-H) are substituted by hydroxyl groups (-OH).
  • Astragalus membranaceus is as follows: 5, 6 two hydrogen groups (-H) are substituted by hydroxyl group (-OH), and hydroxyl group (-OH) at 7 is condensed with glucuronic acid, ie Huangqiyuan-7 -0-glucuronic acid, molecular formula C 12 H 18 0 classroom, molecular weight 446.37.
  • the advent of the present invention is based on the discovery that xanthine and/or xanthine have synergistic effects on cisplatin or 5-fluorouracil, which can significantly enhance the killing activity of the latter on tumor cells; Or a pharmaceutical composition of xanthine with cisplatin and/or 5-fluorouracil having an enhanced antitumor effect and a pharmaceutical composition comprising only a single xanthine, xanthine, cisplatin or 5-fluorouracil More effective.
  • One aspect of the present invention relates to a pharmaceutical composition having a synergistic antitumor effect, the composition comprising cisplatin and a compound of the following formula (I), wherein the molar concentration ratio of the cisplatin to the compound of the formula (I) is 1:2.5 to 1:10:
  • R represents hydrogen or a glucuronic acid group.
  • the tumor is a solid tumor; preferably a melanoma.
  • the compound when R represents hydrogen, the compound is xanthine, the molar ratio of the cisplatin and xanthine is 1:2.5 to 1:10;
  • R represents a glucuronic acid group
  • the compound is xanthine
  • the molar ratio of the cisplatin to xanthine is 1:5 to 1:10.
  • Another aspect of the invention relates to the use of a compound of the above formula (I) and a pharmaceutically acceptable salt thereof for the preparation of an antitumor agent having a synergistic effect on cisplatin; wherein the tumor is selected from the group consisting of liver cancer, colon cancer, lung cancer, Gastric cancer or esophageal cancer.
  • the compound when R represents hydrogen, the compound is xanthine, and the molar ratio of the cisplatin to xanthine is from 1:1 to 1:10:
  • the molar ratio of the cisplatin to the xanthine is 1:1 to 1:10; when the tumor is liver cancer, colorectal cancer, lung cancer or esophageal cancer, the cisplatin and The molar ratio of xanthine is 1:2.5 to 1:10.
  • R represents a glucuronic acid group
  • the compound is xanthine
  • the molar ratio of the cisplatin to xanthine is 1:2.5 to 1:10:
  • the molar ratio of cisplatin to xanthine is 1:2.5 to 1:10;
  • the molar ratio of the cisplatin to xanthine is 1:5 to 1:10;
  • the molar concentration ratio of the cisplatin to xanthine is 1:7.5 to 1:10.
  • Another aspect of the present invention relates to a pharmaceutical composition having a synergistic antitumor effect, comprising 5-fluorouracil and a compound of the above formula (I), wherein the 5-fluorouracil and the formula (I The compound has a molar concentration ratio of 1:2 to 2:1.
  • the tumor is a solid tumor; preferably a melanoma.
  • the compound when R represents hydrogen, the compound is xanthine, and the molar ratio of the 5-fluorouracil to xanthine is from 1:2 to 2:1;
  • R represents a glucuronic acid group
  • the compound is xanthine
  • the molar concentration ratio of the 5-fluorouracil to xanthine is 1:1 to 1:2.
  • Another aspect of the invention relates to the use of a compound of the above formula (I) and a pharmaceutically acceptable salt thereof for the preparation of an antitumor agent having a synergistic effect on 5-fluorouracil; wherein the tumor is selected from the group consisting of liver cancer and colorectal cancer , stomach cancer, esophageal cancer or breast cancer.
  • the compound when R represents hydrogen, the compound is xanthine, and the molar ratio of the 5-fluorouracil to xanthine is 1:2 to 2:1:
  • the molar ratio of the 5-fluorouracil to xanthine is 1:2 to 2:1.
  • R represents a glucuronic acid group
  • the compound is xanthine
  • the molar ratio of the 5-fluorouracil to xanthine is 1:1 to 1:4:
  • the molar ratio of the 5-fluorouracil to xanthine is 1: 1 to 1: 2;
  • Tumor chemotherapy drugs useful in the present invention include, but are not limited to: cisplatin, mitomycin C, irinotecan, docetaxel, paclitaxel > table ghost Podophyllotoxin, vincristine (VCR), plicamycin, daunorubicin (DNR), dactinomycin (DACT), doxorubicin (doxorubicin, Adriamycin, ADM), 5-fluorouracil, Hormones, hormone antagonists, and cytokines (such as interleukin-2 and beta transforming growth factors).
  • VCR vincristine
  • DNR daunorubicin
  • DACT dactinomycin
  • doxorubicin doxorubicin, Adriamycin, ADM
  • 5-fluorouracil Hormones, hormone antagonists, and cytokines (such as interleukin-2 and beta transforming growth factors).
  • the present inventors have found that when the flavonoid compound of the formula (I) of the present invention is administered simultaneously with a tumor chemotherapeutic drug, the antitumor activity of the chemotherapeutic drug can be markedly enhanced and has a synergistic effect. This can reduce the amount of chemotherapy drugs and reduce their side effects. Therefore, the flavonoid compound of the formula (I) of the present invention can be used for the preparation of a drug having a synergistic effect on a tumor chemotherapy drug.
  • flavonoids of the formula (I) of the present invention are naturally occurring and can be isolated from plants.
  • Astragalus and Astragalus can be extracted from the roots of Scutdlaria baicalensis GeorgO.
  • the compounds of the invention are also commercially available or can be made by conventional synthetic techniques in the art.
  • Chemicals for isolating or synthesizing the flavonoid compounds of the present invention include solvents, reagents, catalysts, protecting group reagents, deprotecting group reagents.
  • the separation and synthesis may also include the step of adding or removing a suitable protecting group to ultimately obtain the desired flavonoid.
  • the pharmaceutically acceptable salts of the flavonoids of the present invention include various inorganic or organic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, citrates, lactates, tartrates, maleates. , fumarate, mandelate and oxalate; various inorganic or organic base salts such as sodium hydroxide, trimethylolaminomethane (TRIS, tromethane) and N-methyl-glucosamine.
  • various inorganic or organic acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, citrates, lactates, tartrates, maleates. , fumarate, mandelate and oxalate
  • various inorganic or organic base salts such as sodium hydroxide, trimethylolaminomethane (TRIS, tromethane) and N-methyl-glucosamine.
  • Chemotherapy drugs useful in the present invention have been described in the "Summary of the Invention" section. See also Isselbacher et al “Harrison's Principles of Internal Medicine 13 th , McGraw-Hill, 1994. These chemotherapeutic drugs are commercially available or can be made by techniques well known in the art. The criteria for selecting a suitable chemotherapeutic drug are based, for example, on the type of tumor, the tumor marker, and the age and general health of the patient.
  • the flavonoid compound of the present invention can be administered simultaneously or non-simultaneously with a tumor chemotherapy drug; it can be administered by the intestinal or parenteral route.
  • Formulations for enteral administration include pills, granules, capsules, suspensions or solutions.
  • Formulations for parenteral administration include injections, creams, ointments, patches or sprays.
  • Parenteral routes of administration include subcutaneous, intradermal, arterial, venous, intramuscular, joint, synovial, sternal, intrathecal, intralesional, intracranial injection or instillation. Other routes of administration may include topical, rectal, nasal, buccal, vaginal, sublingual, mucosal, tracheal or urethral.
  • the flavonoid compound of the present invention can also be administered by aerosol inhalation or implantation accumulation or acupuncture.
  • Formulations for enteral administration of the flavonoids of the present invention include, but are not limited to, capsules, tablets, emulsions, aqueous suspensions, colloidal solutions, solutions, microcapsules, pills, troches, granules, powders.
  • Pharmaceutically acceptable carriers commonly used in tablets include lactose and corn starch. A lubricant such as magnesium stearate is usually added.
  • Pharmaceutically acceptable carriers commonly used in capsules include lactose and dried cornstarch.
  • the flavonoids When formulated as oral suspensions and/or emulsions, the flavonoids can be suspended or dissolved in the oil phase and combined with emulsifying or suspending agents. If desired, some sweeteners and/or flavoring agents and/or coloring agents may also be added.
  • the flavonoid drug of the present invention can be formulated into a sterile injectable preparation such as a sterile aqueous phase or an oil phase suspension.
  • This suspension can be prepared by a conventional method in the art using a suitable dispersing or wetting agent (e.g., Tween SO), a suspending agent, or the like. It may also be an aqueous solution or suspension in a non-toxic diluent or solvent for parenteral administration, such as a solution in 1, 3-butanediol.
  • a suitable dispersing or wetting agent e.g., Tween SO
  • a suspending agent e.g., a suspending agent
  • It may also be an aqueous solution or suspension in a non-toxic diluent or solvent for parenteral administration, such as a solution in 1, 3-butanediol.
  • Related useful carriers or solvents include mannitol, water, Ringer's solution, isotonic sodium chloride
  • bland fixed oils are often used as a vehicle for solvents or suspending agents, and thus a wide variety of mildly fixed oils including synthetic monoglycerides or diglycerides are suitable.
  • a fatty acid such as oleic acid and a glyceride derivative thereof (e.g., olive oil or castor oil, especially a polyoxyethylene derivative thereof) and the like can be used for the preparation of the injection.
  • the oil solution or suspension may also contain a long chain ethanol diluent or dispersant or carboxymethyl cellulose or similar other dispersing agents which are commonly used in the preparation of pharmaceutically acceptable emulsions and/or suspending agents.
  • Surfactants commonly used in other formulations such as Tweens or Spans and/or other similar emulsifiers or bioavailability enhancers, etc., are also useful in the preparation of the formulations.
  • the flavonoids of the present invention can be formulated as a suppository for rectal administration by mixing the flavonoid compound with a suitable non-irritating excipient which is solid at room temperature and liquid at the rectal temperature.
  • a suitable non-irritating excipient which is solid at room temperature and liquid at the rectal temperature.
  • excipients include, but are not limited to, cocoa butter, beeswax, and polyethylene.
  • the topical preparation of the flavonoid compound of the present invention e.g., ointment
  • Such topical formulations contain the active ingredient and a pharmaceutically acceptable carrier including, but not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene or polyoxypropylene compound, emulsified wax or water.
  • a pharmaceutically acceptable carrier including, but not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene or polyoxypropylene compound, emulsified wax or water.
  • the flavonoid compound of the present invention can also be used as a lotion or an oil. Suitable carriers include, but are not limited to, mineral oil, sorbitol monostearate, polysorbate 60, whale ester, cetyl alcohol, 2-octadecanol, benzyl alcohol or water.
  • the flavonoid compound of the present invention can also be used as an enema or the like for local administration in the rectum. Topical transdermal patches are also within the scope of the invention.
  • the flavonoids of the invention may also be administered by nasal spray or by inhalation, i.e., using benzyl alcohol or other preservatives, absorption enhancers, fluorocarbons and/or other solubilizing or dispersing agents, in accordance with conventional methods in the art.
  • a salt solution was prepared.
  • the flavonoids of the invention may also be administered by implantation.
  • the effect of the sustained release of the flavonoid compound of the present invention in the body of the drug can be achieved by the implantation method.
  • implanted administration can also be administered in local tissue and organ localization (Negrin et al., Biomaterials 22 (6): 563, 2001).
  • Timed release techniques can also be used in the administration of the flavonoids of the present invention, such as Timed release capsules of polymer technology, sustained release techniques and formulation encapsulation techniques (eg, polymers and liposomes).
  • Patches are also included within the scope of the present invention. It includes a base layer (e.g., a polymer, cloth, yarn, and bandage) and a pharmaceutical composition of the present invention. One side of the base layer may be provided with a protective layer to prevent the active ingredient from flowing out.
  • the patch may further contain a binder for immobilization, and the latter may be a natural or synthetic substance which temporarily adheres to the skin when it comes into contact with the skin of the subject to be administered.
  • the adhesive can be waterproof.
  • the "pharmaceutically acceptable carrier” does not destroy the pharmaceutical activity of the flavonoid compound of the present invention, and the effective amount thereof, that is, the amount which can be used as a drug carrier, is not toxic to the human body.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, ion exchange materials, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as dc-vitamin E polyethylene glycol 1000 succinate, Tween Surfactant for pharmaceutical preparations such as Tweens or other similar polymerization media, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, saturated glycerides of saturated vegetable fatty acids, water , salts, electrolytes such as protamine, dihydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium silicate, and the like.
  • Polyvinylpyrrolidone cellulosic material, polyvinyl alcohol, sodium carboxymethylcellulose, polyacrylate, ethylene-polyoxyethylene-block polymer and lanolin, cyclodextrin such as ⁇ -, ⁇ - and ⁇ -cyclodextrin or its chemistry
  • cyclodextrin such as ⁇ -, ⁇ - and ⁇ -cyclodextrin or its chemistry
  • Modified derivatives such as hydroxyalkyl cyclodextrin such as 2- and 3-hydroxypropyl- ⁇ -cyclodextrin or other soluble derivatives and the like can be used to promote drug delivery of the flavonoid compounds of the present invention.
  • the effective range (molar ratio) of the synergistic action of the flavonoids of the present invention with cisplatin or 5-fluorouracil has been verified by a suitable in vitro assay ( ⁇ Wtro assay).
  • ⁇ Wtro assay a suitable in vitro assay
  • the usual dosages and routes of administration of cisplatin and 5-fluorouracil are as follows: cisplatin 20-150 mg/day, intravenous drip or arteriovenous infusion; 5-fluorouracil 500- 1000mg / day, intravenous drip or arteriovenous infusion; 5-fluorouracil 200-300mg / day, orally. There have been no reports of clinical antitumor doses of Huangqiyuan and Astragalus and their appropriate routes of administration.
  • Example 1 In order to facilitate the understanding of the present invention, the following examples are specifically enumerated. It is to be understood that the invention is not to be construed as limiting the invention.
  • Example 1
  • the inhibition rate of cell proliferation was measured by tetrazolium salt (MTT) method and the cell proliferation was measured by single or combined use of xanthine or xanthine and cisplatin.
  • CalcuSyn statistical software and combined drug index value (CI) method were used for data analysis. .
  • Huang Yuan Huang Weiyuan
  • Huang Wei Huang Wei
  • Table 1-5 shows that the molar ratio of IC50 of cisplatin to xanthine to each cell line is about (1:5), and shows the area near this concentration ratio (1:2.5 to 1:10).
  • Table 1-5 shows that the molar ratio of IC50 of cisplatin to xanthine to each cell line is about (1:5), and shows the area near this concentration ratio (1:2.5 to 1:10).
  • There is a good combined drug index which can clearly indicate that Huangqiyuan and Cisplatin are different for each human tumor cell line; human hepatoma cell line HepG2, human large intestine HCT116, human lung cancer cell line A549, human gastric cancer cell line MKN45, esophageal cancer
  • the cell line TE2 has a good combined drug effect.
  • the molar ratio of IC50 of cisplatin and xanthine to each cell line was about (1:5-7.5), and it showed that there was a good combination in the vicinity of this concentration ratio (1:5 ⁇ 1:10).
  • the index can clearly indicate that Astragalus and Cisplatin have good associations with human tumor cell lines; human liver cancer cell line HepG2, human large intestine HCT116, human lung cancer cell line A549, human gastric cancer cell line MKN45, and esophageal cancer cell line TE2. Medication effect.
  • Example 2 Anti-tumor synergistic effect of xanthine or xanthine combined with cisplatin (CDDP) on transplanted tumors
  • the B16 melanoma cell line was cultured for two generations in vitro, it was inoculated subcutaneously into the experimental female female C57BL/6 (body weight of about 20 g) at 2x106 cells/only.
  • the rats were randomly divided into the next day after inoculation and administered at a dose of O.lml/lOg.
  • Huang Yuyuan product of Kunming Tongzhi Pharmaceutical Co., Ltd.
  • Huang Wei Suduan Superman Phytochemical Development Co., Ltd.
  • cisplatin Sigma products
  • the body weight of the animals was measured before administration, and the body weight of the animals was weighed on the 15th day after the test, and the tissue was removed and weighed.
  • Cells of various human tumor cell lines were suspended in a cell culture medium containing 10% (small) bovine fetal serum, and seeded at 5 x 103 / well in a 96-well cell culture dish. After 24 hours of cultivation, add Huang Qiyuan (product of Kunming Tongzhi Pharmaceutical Co., Ltd.), or Huangqi (Sichuan Superman Phytochemical Development Co., Ltd.), and with 5-Fu (Sigma product) Mix into the culture solution at different concentration ratios. MTT assay was performed after 72 hours of culture.
  • Huang Qiyuan product of Kunming Tongzhi Pharmaceutical Co., Ltd.
  • Huangqi Suduan Superman Phytochemical Development Co., Ltd.
  • the rate of inhibition of cell proliferation was measured by tetrazolium salt (MTT) method and the cell proliferation was measured by single-use and combination of xanthine or xanthine and 5-fluorouracil.
  • Huang Yuan Huang Qiyuan
  • Huang Qi Huang Qi
  • 5Fu 5-fluorouracil
  • Table 7-11 shows that the molar ratio of IC50 in each cell line of Astragalus and 5Fu is about (1:1), and it is shown in the vicinity of this concentration ratio (2:1 to 1:2).
  • a good combination drug index can clearly indicate that Huangqiyuan and 5Fu on each human tumor cell line; human liver cancer cell line HepG2, human large intestine HCT116, human gastric cancer cell line MKN45, human esophageal cancer cell line TE2, human breast cancer
  • the cell line MCF-7 has a good combined drug effect.
  • the molar concentration ratio of Astragalus and 5Fu to IC50 of each cell line except HepG2 is about (1:1), and it shows that there is a good combination in this concentration ratio (1:1 ⁇ 1:2). Medication index. In the HepG2 cell line, there was a good combination index in the molar concentration ratio range of 1:2 to 1:4.
  • the above can clearly indicate that each of the human tumor cell lines of Astragalus and 5Fu; human hepatoma cell line HepG2, human large intestine HCT116, human gastric cancer cell line M N45, human esophageal cancer cell line TE2, human breast cancer cell line MCF-7 has a good combination of drug effects.
  • Example 4 Anti-tumor synergy effect of xanthine or xanthine combined with 5-fluorouracil (5-FU) on transplanted tumors
  • the body weight of the animals was measured before administration, and the body weight of the animals was weighed on the 15th day after the test, and the tissue was removed and weighed.
  • Control group one ⁇ 0 2.48 ⁇ 0.16 10/10
  • Mode of administration 5-fluorouracil; subcutaneous administration, astragalus and jaundice; intraperitoneal administration

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Abstract

La présente invention concerne une composition pharmaceutique dotée d'un effet anticancéreux synergique, qui comprend le composé de formule générale (I) telle que ci-dessous et un médicament chimiothérapeutique tel que le cisplatine et/ou le 5-fluorouracile. Cette invention concerne également l'utilisation dudit composé de formule générale et des sels pharmaceutiquement acceptables de celui-ci pour la fabrication du médicament: où R est un radical hydrogène ou glucuronique.
PCT/CN2006/000091 2005-01-20 2006-01-20 Composition pharmaceutique synergique destinee a inhiber une tumeur WO2006076863A1 (fr)

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CNA2005100234679A CN1679539A (zh) 2005-01-20 2005-01-20 抗肿瘤的协同药物组合物

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IT202200007988A1 (it) 2022-04-22 2023-10-22 Fondazione St Italiano Tecnologia Derivati del 4-cromone come inibitori della polimerasi ¿ come agenti antitumorali e metodo per la loro preparazione
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