WO2006076863A1 - The synergistically pharmaceutical composition for inhibiting tumor - Google Patents

Abstract

The present invention relates to a pharmaceutical composition having synergistical anti-cancer effect which comprising the compound of general formular (I) as followed and tumor chemotherapeutical medicament, such as cisplatin and/or 5-fluorouracil, also relates to the use of the compound with the general formular and the pharmaceutically acceptable salts thereof for manufacturing medicament: wherein, R is hydrogen or glucuronic radical.

Description

 Antitumor synergistic pharmaceutical composition

 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. However, 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.

 In order to reduce the side effects of chemotherapy drugs, improve the efficacy, reduce tumor recurrence and avoid the emergence of drug resistance, the combination of different chemotherapy drugs has become one of the important means of tumor chemotherapy. For example, 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 D2 Dl X D2

 CI = + + χ

 (Dx)l (Dx)2 (Dx)l x (Dx)2

 Wherein, 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.

 Two drugs that are independent of each other α = 0; and drugs that are not independent of each other α = 1.

When CI < 1 , it is synergistic, CI - 1 is additive; when CI > 1 , it is antagonistic Function.

 According to the animal model of anti-tumor screening established by the National Cancer Institute in 1983, 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.

 The traditional Chinese medicine Scutellaria baicalensis Georgi is first published in Shennong Bencao, also known as Huang Wen, Wu Qi and so on. Its pharmacological effect is bitter, cold, functional effluent fire, dehumidification heat, with antibacterial, heat removal, detoxification, sedation, blood pressure, gallbladder and so on.

 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).

The chemical structure of 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 „, molecular weight 446.37.

In recent years, it has been reported in the literature that Astragalus and Astragalus membranaceus have an inhibitory effect on the growth of breast cancer cells cultured in vitro (So FV, et al. Cancer Lett., 112: 127-133, 1997). There are also patent reports that Astragalus and Astragalus membranaceus have significant killing effects on esophageal cancer and gastric cancer cells (CN 03109933.5; CN 03109942.4). So far, no reports have been made about the synergistic effect of Astragalus and/or Astragalus on tumor chemotherapy drugs. Summary of the invention

 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:

 Wherein R represents hydrogen or a glucuronic acid group.

 Wherein the tumor is a solid tumor; preferably a melanoma.

 In a preferred embodiment of the present invention, when R represents hydrogen, the compound is xanthine, the molar ratio of the cisplatin and xanthine is 1:2.5 to 1:10;

 In another preferred embodiment of the present invention, when R represents a glucuronic acid group, the compound is xanthine, and 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.

 In a preferred embodiment of the present invention, when R represents hydrogen, the compound is xanthine, and the molar ratio of the cisplatin to xanthine is from 1:1 to 1:10:

 When the tumor is gastric cancer, 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.

 In another preferred embodiment of the present invention, when R represents a glucuronic acid group, the compound is xanthine, and the molar ratio of the cisplatin to xanthine is 1:2.5 to 1:10:

When the tumor is gastric cancer, the molar ratio of cisplatin to xanthine is 1:2.5 to 1:10; When the tumor is colorectal cancer or esophageal cancer, the molar ratio of the cisplatin to xanthine is 1:5 to 1:10;

 When the tumor is liver cancer or lung cancer, 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.

 Wherein the tumor is a solid tumor; preferably a melanoma.

 In a preferred embodiment of the present invention, 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;

 In another preferred embodiment of the present invention, when R represents a glucuronic acid group, the compound is xanthine, and 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.

 In a preferred embodiment of the present invention, when R represents hydrogen, the compound is xanthine, and the molar ratio of the 5-fluorouracil to xanthine is 1:2 to 2:1:

 When the tumor is liver cancer, colon cancer, gastric cancer, esophageal cancer or breast cancer, the molar ratio of the 5-fluorouracil to xanthine is 1:2 to 2:1.

 In another preferred embodiment of the present invention, when R represents a glucuronic acid group, the compound is xanthine, and the molar ratio of the 5-fluorouracil to xanthine is 1:1 to 1:4:

 When the tumor is colorectal cancer, gastric cancer, esophageal cancer or breast cancer, the molar ratio of the 5-fluorouracil to xanthine is 1: 1 to 1: 2;

When the tumor is liver cancer, the molar ratio of the 5-fluorouracil to xanthine is from 1:2 to 1:4. 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).

 Specific embodiments of the invention are set forth in the following sections. Other features, objects, and advantages of the invention will be apparent from the description. detailed description:

 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.

Some of the flavonoids of the formula (I) of the present invention are naturally occurring and can be isolated from plants. For example, 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. Methods for the preparation of synthetic chemical transformations and group protection (deprotection) of the flavonoids of the invention are well known to those skilled in the art, see R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989). TW Green and PGM Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed., John Wiley and Sons (1999), L. Fieser and M. Fieser, Fieser and Fieser s 'Reagents for Organic Synthesis, John Wiley and Sons (1994) And L. Paquette, ed" Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and its follow-up.

 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.

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. Further, 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. 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. Related useful carriers or solvents include mannitol, water, Ringer's solution, isotonic sodium chloride, and the like. In addition, 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. Thus the suppository dissolves in the rectum and releases the active ingredient. Such 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) can be directly used in the affected area. 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. Further, 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. In addition, 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 α-, β- and γ -cyclodextrin or its chemistry Modified derivatives such as hydroxyalkyl cyclodextrin such as 2- and 3-hydroxypropyl-β-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). As two commonly used tumor chemotherapy drugs, 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.

 One of ordinary skill in the art will know how to prepare the present invention by mixing the xanthine with xanthine, cisplatin or 5-fluorouracil according to the conventional techniques in the art, according to the molar ratio of the present invention. A synergistic anti-tumor pharmaceutical composition.

 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

 Synergistic effect of Astragalus membranaceus or Astragalus membranaceus combined with cisplatin (CDDP) on growth inhibition of human tumor cell lines in vitro

Cells of various human tumor cell lines were suspended in a cell culture medium containing 10% (small) bovine fetal serum, and seeded in a 96-well cell culture dish at 5 x 10 ³ /well. After 24 hours of cultivation, he added Huang Qiyuan (product of Kunming Tongzhi Pharmaceutical Co., Ltd.), Huangqi (Sichuan Superman Phytochemical Development Co., Ltd.), and added it to the culture solution at different concentration ratios with cisplatin (Sigma product). . MTT assay was performed after 72 hours of culture. 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. . When CI < 1 , it is synergistic, when CI = 1 , it is additive; when CI > 1, it is antagonistic.

The cell proliferation inhibition rate when the drug is administered alone or in combination, and the combined drug index values are shown in Table 1-5.

Human liver cancer cell line HepG2 Table 1

Human large intestine HCT116 Table 2 Human lung cancer cell line A549

Human gastric cancer cell line M N45

Human esophageal cancer cell line TE2

 Table 1

Single-dose drug concentration combined drug concentration concentration cell growth inhibition rate combined drug coefficient value

(μηι) (μπι) (%) (CI)

Huang Yuan 2.5 0.2

Huang Yuan 5 17.43±1.2

Huang Yuan 10 40.5±2

Huang Yuan 20 59.8±3

Huang Yuan 40 91±2.5

Huang Wei 5 0.1

黄甙 10 5±0.2

黄甙 20 25.2±2

黄甙 40 75.2±3

 Ptl 2±0.5

 Pt2 30±3

 Pt4 33±3

 Pt8 77.5±2.5

 Pt'l+黄元 2.5 5±2 1.32

 Pt2+ Huang Yuan 5 37.8±3 0.96

 Pt4+黄元 10 95±2.7 0.47

 Ptl+黄元 5 21.2±2 0.78

 Pt2+ Huang Yuan 10 42.9±3 0.98

 Pt4+黄元 20 85±2 0.98

 Ptl+黄元 10 35±3 0.9

 Pt2+ Huang Yuan 20 73.3±1.2 0.98

 Pt4+黄元 40 95.5±2 0.88

Ptl+黄甙7.5 10±1.5 1.07 Pt2+ jaundice 15 59.2±2.5 0.875

 Pt4+黄甙 30 92±3 0.85

Ptl+黄甙 10 11.2±2 1.2

Pt2+ jaundice 20 65±3 0.958

Pt4+黄甙 40 95±2 0.9 Table 2

Ptl+黄甙 5 28.75±2 1.1

Ptl+黄甙5 28.75±2 1.1

 Pt2+ jaundice 10 62.9±3.2 0.736

 Pt4+黄甙 20 88±2 0.626

 Ptl+黄甙 10 44.32±3 0.95

 Pt2+ jaundice 20 67.76±1.2 0.85

 Pt4+黄甙 40 95±2 0.42 Table 3

Single-dose drug concentration combined drug concentration concentration cell growth inhibition combined drug coefficient value

(μηι) (μηι) rate ⁰ / ₀ (CI)

Huang Yuan 5 1±0.5

Huang Yuan 10 17.43±3

Huang Yuan 20 38±2

Huang Yuan 40 91.2±1

黄甙 5 5±1

黄甙 10 10.3±2

黄甙 20 35.8±2

黄甙 40 62.1±3

 Ptl 31±2.5

 Pt2 42.3±3

 Pt4 49±3

 Ptl + Huang Yuan 2.5 15±2 5.8

 Pt2+ Huang Yuan 5 52.5±3 0.661

 Pt4+黄元 10 66±3 0.677

 Ptl+黄元 5 19±1 3.7

 Pt2+ Huang Yuan 10 59.5±2.5 0.69

 Pt4+黄元 20 90.2±2 0.515

 Pt 1+黄元 10 67±3 0.47

Pt2+ Huang Yuan 20 85±2 0.6 Pt4+ Huang Yuan 40 95±2 0.79

 Ptl+黄甙 7.5 26.7±2 2

 Pt2+ jaundice 15 55.7±3.1 0.762

 Pt4+黄甙 30 78±2 0.578

 Ptl+黄甙 10 29.8±2.1 1.15

 Pt2+ jaundice 20 61.9±2.1 0.7025

 Pt4+黄甙 40 82.7±3 0.6 Table 4

Single-dose drug concentration combined with drug concentration cytostatic inhibition combined drug coefficient value (μιη) (μ∞) rate% (CI)

Huang Yuan 1 5±0.5

Huang Yuan 2 17.6±2

Huang Yuan 4 21.5±2

Huang Yuan 8 43±3

Huang Yuan 16 51.25±3

黄甙 2.5 0.01

Yellow it 5 23.6±2

黄甙 10 40·25±3

黄甙 20 47.87±3

黄甙 40 82.78±3

 Ptl 5±0.5

 Pt2 29.67±3

 Pt4 43.3±3

 Pt8 51.5±2.5

 Ptl+黄元 1 10.02±2 1.8

 Pt2+ Huang Yuan 2 37±3 0.769

 Pt4+黄元 4 55±2 0.88

Pt8+ Huangyuan 8 77.12±2 0.7727 Ptl+黄元2.5 19±3 1.28

 Pt2+ Huang Yuan 5 55士 2 0.628

 Pt4+黄元 10 65±3 0.8838

 Pt 1+黄元 5 22.2±2 1.26

 Pt2+ Huang Yuan 10 57±2 0.89

 Pt4+黄元 20 85±2 0.505

 Ptl+黄元 10 52±3 0.9

 Pt2+ Huang Yuan 20 82±3 0.49

 Pt4+黄元 40 95±2 0.272

 Ptl+ jaundice 2.5 10.2±2 1.0625

 Pt2+ jaundice 5 51.3±3 0.605

 Pt4+黄甙 10 67.2±2 0.863

 Ptl+黄甙 5 ' 23.22±3 0.783

 Pt2+ jaundice 10 55.35±1.2 0.819

 Pt4+黄甙 20 85±2 0.91

 PU+黄甙 10 45.65±2 0.772

 Pt2+ jaundice 20 76.7±3 0.4825

 Pt4+黄甙 40 95±2 1

Single-dose drug concentration combined with drug action concentration cell growth inhibition rate combined drug coefficient value (μιη) % (CI)

Huang Yuan 5 0.9

Huang Yuan 10 16.8±1.7

Huang Yuan 20 49±2

Huang Yuan 40 91.3±3

黄甙 5 1

黄甙 10 9±1

黄甙20 45.2±3 黄甙40 71.2±3

 Ptl 8.8±0.5

 Pt2 31.99±3

 Pt4 44.42±3

 Pt8 75±2.5

 Ptl+黄元 2.5 12±3 1.13

 Pt2+ Huang Yuan 5 32.2±2 1.12

 Pt4+黄元 10 70±2.7 0.98

 Pt8+黄元 20 92±3 0.91

 Pt 1+黄元 5 22±2 0.95

 Pt2+ Huang Yuan 10 52±2 0.988

 Pt4+黄元 20 86±3 0.91

 Ptl+黄元 10 38±3 0.95

 Pt2+ Huang Yuan 20 71±3 0.99

 Pt4+黄元 40 95±4.2 0.932

 Ptl+黄甙 5 11±1 0.9

 Pt2+ jaundice 10 49.5±3 0.9

 Pt4+黄甙 20 82.35±3 0.82

 Ptl + jaundice 10 32.5±2.5 0.926

 Pt2+ jaundice 20 69.8±3 0.876

 Pt4+黄甙 40 95±2 0.69

Huang Yuan = Huang Weiyuan, Huang Wei = Huang Wei

Inhibition rate %; mean ±SD, n=3

When CI<1, it is synergistic, when CI=1, it is additive; when CI>1, it is antagonistic.

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

 After 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 (Sichuan Superman Phytochemical Development Co., Ltd.) and grouped with cisplatin (Sigma products) by separate administration, combined administration, etc. Anti-tumor test. There were 10 experimental animals in each group. 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. The tumor inhibition rate was determined according to the calculation formula; the tumor inhibition rate = (1 - treatment group tumor weight / blank control group tumor weight) χΐοο% calculated tumor weight inhibition rate and performed statistical (t test) treatment.

 The test results are shown in Table 6.

 Table 6 Results of animal test for transplanted B16 melanoma when administered alone or in combination with cisplatin Group Dosing Administration Weight loss rate Tumor weight (g) Tumor inhibition rate Animal mg/kg Schedule % Mean SD %

(only) start/end control group <0 2.63±0.27 10/10 cisplatin 2 2-4, 8-10 <5 1·58±0·3 39.9 10/10 Huang Yuan 5 2-4,8-10 <5 2.55±0.3 3 10/10 Huang Yuan 10 2-4,8-10 <5 2.35±0.187 10.6 10/10 Huang Yuan 20 2-4,8-10 <5 2.22±0.225 15.58 10/10 Huang Wei 8.25 2-4,8-10 <5 2.57±0.18 2.2 10/10 Astragalus 16.5 2-4,8-10 <5 2.37±0.15 9.9 10/10 Astragalus 33 2-4,8-10 <5 2.23±0.12 15.2 10/10 Cisplatin + Huang Yuan 2+5 2-4, 8-10 <5 1.2±0.2 54.37** 10/10 Cisplatin + Huang Yuan 2+ 10 2-4, 8-10 <5 1.15±0.2 56.27** 10/10 cisplatin + yellow 2+20 2-4, 8-10 <7 1·05±0.15 60** 10/10 顺Platinum + Astragalus 2+8.25 2-4, 8-10 <5 1.42±0.18 45.6 10/10 Cisplatin + Astragalus 2+ 16.5 2-4, 8-10 <5 1.35±0.23 48.67* 10/10 Cisplatin +黄甙2+33 2-4, 8-10 <5 1·15±0.08 56.27** 10/10 , Huang Yuan = Huang Yiyuan, Huang Wei = Huang Wei

Mode of administration: cisplatin; abdominal cavity, xanthine and jaundice; intraperitoneal administration

 * Compared with cisplatin alone Ρ<0.05

**Compared with cisplatin alone Ρ<0.01

 The results showed that the combination of Astragalus and Cisplatin showed significant anti-tumor synergy. Cisplatin + Astragalus 5 mg/kg, cisplatin + xanthine 10 mg/kg, cisplatin + xanthine 20 mg/kg each group had statistically significant differences compared with the single cisplatin group. The results of the animal test clearly supported the results of the in vitro test, that is, the cisplatin pair and the xanthine have a relatively synergistic effect in the vicinity of the concentration ratio of 1:2.5 to 1:10.

Astragalus and cisplatin also showed significant synergistic effects when used together. Cisplatin + baicalin 16.5mg / kg, and cisplatin + baicalin 33m _g / kg of cisplatin alone compared to have statistically significant difference. The results of the animal test clearly supported the results of the in vitro test, that is, the cisplatin pair and the xanthine have a relatively synergistic effect in the vicinity of the concentration ratio of 1:5 to 1:10.

 It can be seen from the changes in animal body weight that no toxicity enhancement trend was observed in each of the combined groups.

 Comprehensive animal experiments can be seen; Astragalus or Astragalus and Cisplatin have a good synergistic anti-tumor effect. Example 3 Synergistic effect of xanthene or xanthine combined with 5-fluorouracil (5-FU) on growth inhibition of human tumor cell lines in vitro

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. 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. CalcSyn statistical software and combined drug index value (CI) method were used. Perform data analysis. When CI < 1 , it is synergistic, when CI = 1 , it is additive; when CI > 1, it is antagonistic.

 The cell proliferation inhibition rate when the drug is administered alone or in combination, and the combined drug index values are shown in Table 7-12 for each human tumor cell line;

 Human hepatoma cell line HepG2 Table 7

 Human large intestine (colon, rectum) HCT116 Table 8

 Human gastric cancer cell line MKN45 Table 9

 Human esophageal cancer cell line TE2 Table 10

 Human breast cancer cell line MCF-7 Table 11 Table 7

Single-dose drug concentration combined drug concentration concentration cell growth inhibition rate combined drug coefficient value

(μ∞) (μηι) (%) (CI)

Huang Yuan 2.5 0.2

Huang Yuan 5 17.43±1.2

Huang Yuan 10 40.5±2

Huang Yuan 20 59.8±3

Huang Yuan 40 91±2.5

Huang Wei 5 0.1

黄甙 10 5±0.2

黄甙 20 25.2±2

黄甙 40 75.2±3

 5-Fu 5 8±2

 5-Fu 10 20.2±3.5

 5-Fu 20 48±2.78

5-Fu40 87.72±1.7 5-Fu 10+ Huang Yuan 5 35±3 0.98

 5-Fu 20+黄元 10 69±2 1

 5-Fu 40+黄元 20 95 0.85

 5-Fu 5+黄元 5 18±2 0.755

 5-Fu 10+黄元 10 48.2±2 0.98

 5-Fu 20+黄元 20 88 0.98

 5-Fu 5+黄元 10 35±3 0.95

 5-Fu 10+ Huang Yuan 20 75±3 0.98

 5-Fu 20+黄元 40 98±3 0.79

 5-Fu 5+黄甙 10 12±2.5 1.2

 5-Fu 10+黄甙 20 77±2 0.85

 5-Fu 20+黄甙 40 92.5±3 1

 5-Fu 2.5+黄甙 10 11±1.5 0.962

 5-Fu 5+黄甙 20 57±3 0.91

 5-Fu 10+黄甙 40 91.7±3 0.947 Table 8

Single-dose drug concentration combined drug concentration concentration cell growth inhibition rate% combined drug coefficient value

(μηι) (μιη) (CI)

Huang Yuan 5 24.43±1.5

Huang Yuan 10 35.933±3

Huang Yuan 20 57.02±2

Huang Yuan 40 72±1

黄甙 5 27.62±2

黄甙 10 33.25±2

黄甙 20 37.65±3

黄甙 40 68.7±3

 5-Fu 5 25.8±2

5-Fu 10 61.5士3.5 -Fu 20 68.5±2.78

 5-Fu 2.5+ Huang Yuan 5 28.2±3 1.31

 5-Fu 5+黄元 10 62.5±2 0.7

 5-Fu 10+ Huang Yuan 20 77.1±2.7 0.8

 5-Fu 20+黄元 40 91.2±2.79 0.37

 5-Fu 2.5+ Huang Yuan 2.5 21.2±1.9 1.275

 5-Fu 5+黄元 5 49.2±3 0.86

 5-Fu 10+黄元 10 75.2±3 0.662

 5-Fu 20+黄元 20 91.2±2.7 0.485

 5-Fu 5+黄元 2.5 38±2.2 1

 5-Fu 10+黄元 5 63.21±2 0.882

 5-Fu 20+黄元 10 82.67±3.2 0.78

 5-Fu 2.5+ jaundice 2.5 20.5±2.5 1.37

 5-Fu 5+黄甙 5 38.9±2 1.1

 5-Fu 10+黄甙 10 75.2±3 0.56

 5-Fu 20+黄甙 20 87.6±4 0.55

 5-Fu 2.5+黄甙 5 23.7±2 1.49

 5-Fu 5+黄甙 10 52.7±3 0.88

 5-Fu 10+黄甙 20 82.65±3 0.45 Table 9

Single-dose drug concentration combined with drug concentration concentration cell growth inhibition combined drug coefficient value (μιη) (μηι) rate ⁰ / ₀ (CI)

 Huang Yuan 1 5±0.5

 Huang Yuan 2 17.6±2

 Huang Yuan 4 21.5±2

 Huang Yuan 8 43±3

 Huang Yuan 16 51.25±3

Astragalus 2.5" 0.01 Astragalus 5 23.6±2 Astragalus 10 40.25±3

黄甙 20 47.87±3

黄甙 40 82.78±3

 5-Fu 5 25.2±2

 5-Fu 10 48.91±3.5

 5-Fu 20 65.32±2.78

 5-Fu 5+黄元 2.5 29.8±2 1.32

5-Fu 10+黄元 5 61.8±3 0.84

5-Fu 20+黄元 10 82±3.2 0.7

5-Fu 10+黄元 5 90 05±2 0.42

5-Fu 2.5+ Huang Yuan 2.5 22.5±3 1.23

5-Fu 5+黄元 5 47±3 0.92

5-Fu 10+黄元 10 72±3 0.727

5-Fu 20+黄元 20 87.8±2 0.6

5-Fu 2.5+黄元 5 29±2 1.38

5-Fu 5+黄元 10 61.5±3 0.8

5-Fu 10 yellow yuan 20 75±3 0.749

5-Fu 2.5+ jaundice 2.5 17.2±3 0.9655

5-Fu 5+黄甙 5 37.7±3 0.9568

5-Fu 10+黄甙 10 71±3 0.857

5-Fu 20+黄甙 20 0.91

5-Fu 2.5+黄甙 5 28.2±2.7 0.81

5-Fu 5+黄甙 10 57.2±3 0.85

5-Fu 10+黄甙 20 81.5±3 0.98

Table 10 Single-dose drug concentration combined with drug action concentrated cell growth inhibition rate combined drug coefficient value

(μιη) Degree (μιη) % (CI)

Huang Yuan 5 0.9

Huang Yuan 10 16.8±1.7

Huang Yuan 20 49±2

Huang Yuan 40 91.3±3

Yellow i 5 1

黄甙 10 9±1

黄甙 20 45.2±3

黄甙 40 71.2±3

 5-Fu 5 7.2±2

 5-Fu 10 13.9±3.5

 5-Fu 20 39.08d=2.78

 5-Fu 40 44.2±1.7

 5-Fu 5+黄元 2.5 8±2.8 1.22

 5-Fu 10+黄元 5 25.8±2 0.95

 5-Fu 20+黄元 10 65.2±3 0.725

 5-Fu 40+黄元 20 92.2±3 0.62

 5-Fu 5+黄元 5 12.5±2 1.1

 5-Fu 10+ Huang Yuan 10 42.2±3 0.9

 5-Fu 20+黄元 20 74.2±3 0.97

 5-Fu 5+黄元 10 22.5±2 1.1

 5-Fu 10+ Huang Yuan 20 67±3 0.98

 5-Fu 20+黄元 40 95±3 0.9

 5-Fu 5+黄甙 5 11.2±1.5 1.12

 5-Fu 10+黄甙 10 40.7±2 0.8

 5-Fu 20+黄甙 20 75.5±3 0.717

 5-Fu 5+黄甙 10 21.2±2 1

5-Fu 10+黄甙20 65.8±3 0.767 5-Fu 20+黄甙40 95±2 0.57

Table 11

Single-dose drug combination combined drug concentration (μηι) Cell growth inhibition combined drug coefficient concentration (μιη) rate ⁰ / ₀ (CI)

Huang Yuan 2.5 1±0.5

Huang Yuan 5 8.7±3

Huang Yuan 10 37.7±2

Huang Yuan 20 55.8±1

黄甙 5 5±1

黄甙 10 21.5±2

黄甙 40 85.2±3

 5-Fu5 22.5±2

 5-FulO 45.2±3

 5-Fu20 65.2±2

 5-Fu40 82.7±1.8

 5-Fu 5+黄元 2.5 25±3 1.18

 5-Fu 10+黄元 5 55.8±2.2 0.97

 5-Fu 20+ Huang Yuan 10 82.1±2.1 0.83

 5-Fu 40+黄元 20 95±2 0.72

 5-Fu 5+黄元 5 25±3 1.41

 5-Fu 10+ Huang Yuan 10 67.8±2 0.93

 5-Fu 20+ yellow 20 90.2±2 0.8

 5-Fu 5+黄元 10 36.5±4 1.3

 5-Fu 10+黄元 20 82±2 0.93

 5-Fu 20+黄元 40 95 0.769

 5-Fu 5+黄甙 5 22.5±2.5 1.5

5-Fu 10+黄甙10 65.2±2 0.825 5-Fu 20+黄甙20 87.2±3 0.84

 5-Fu 5+黄甙 10 35.2±2 1.36

 5-Fu 10+黄甙 20 79.8±3 0.877

 5-Fu 20+黄甙 40 95±5.7 0.76

Huang Yuan = Huang Qiyuan; Huang Qi = Huang Qi; 5Fu = 5-fluorouracil

Inhibition rate %; mean ±SD, n=3

When CI < 1 , it is synergistic, when CI = 1 , it is additive; when CI > 1, it is antagonistic.

 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). Have 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

After the B16 melanoma cell line was cultured for two generations in vitro, it was inoculated subcutaneously into the experimental part of the female C57BIJ6 (weight of about 20 g) mouse 2x106 cells/only. The rats were randomized on the second day after inoculation and started to be administered at a dose of 0.1 ml/lOg. Huang Yuyuan (product of Kunming Tongzhi Pharmaceutical Co., Ltd.), Huang Wei (Sichuan Superman Phytochemical Development Co., Ltd.), and combined with 5-fluorouracil (Shanghai Xudong Haipu Pharmaceutical Co., Ltd.) Anti-tumor tests are carried out in groups by different modes of administration such as drugs. There were 10 experimental animals in each group. 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. The tumor inhibition rate was determined according to the calculation formula; the tumor inhibition rate = (1 - treatment group tumor weight / blank control group tumor weight) χΐοο% calculated tumor weight inhibition rate and performed statistical (t test) treatment. The test results are shown in Table 12.

 Table 12 Animal test results of transplanted B16 melanoma when administered alone and in combination with 5-fluorouracil Grouped dosing schedule Weight of tumor weight (g) Tumor suppressor rate Animals mg/lcg Decrease mean SD, % (only) Start/end

°/

Control group one <0 2.48±0.16 10/10

5Fu 10 subcutaneous 1-10 <5 1.55±0.2 37.5 10/10 Huang Yuan 2.5 abdominal cavity 1-10 <5 2.47±0.15 0.4 10/10 Huang Yuan 5 abdominal cavity 1-10 <5 2.28±0.127 8 10/10 Huang Yuan 10 Abdominal cavity 1-10 <5 2.22±0.12 10.5 10/10 Astragalus 8.25 Peritoneal cavity 1-10 <5 2.32±0.09 6.5 10/10 Astragalus 16.5 Abdominal cavity 1-10 <5 2.2±0.08 11.3 10/10

5Fu+Yellow 10+2.5 1-10 <5 1.32±0.09 46.77** 10/10

5Fu+黄元 10+5 1-10 <5 1.21±0.1 51.2** 10/10

5Fu+黄元 10+ 10 1-10 <5 0.81±0.11 67.3** 10/10

5Fu+黄甙 10+8.25 1-10 <5 1.25±0.11 49.6** 10/10

10/10 黄元 =黄芩甙元； 黄甙 ₌黄芩甙； 5Fu=5-氟脲嘧啶 5Fu+黄甙10+ 16.5 1-10 <5 1.12±0.11

10/10 Huang Yuan = Huang Qiyuan; Huang Qi ₌ Huang Qi; 5Fu = 5-fluorouracil

Mode of administration: 5-fluorouracil; subcutaneous administration, astragalus and jaundice; intraperitoneal administration

 **Compared with 5-fluorouracil group alone P<0.01

The results showed that the combination of xanthine and 5-fluorouracil showed significant anti-tumor synergy. 5-fluorouracil + xanthine 2.5mg/kg, 5-fluorouracil + xanthine 5mg/kg, cisplatin + xanthine 10m _g /kg each group compared with 5-fluorouracil group Both have statistically significant differences. The results of the animal test clearly supported the results of the in vitro test, that is, the 5-fluorouracil pair and the xanthine have a relatively synergistic effect in the vicinity of the concentration ratio of 1:2 to 2:1.

Astragalus and 5-fluorouracil also showed significant synergistic effects. 5-fluorouracil + xanthine 8.25 mg / kg, cisplatin + xanthine 16.5 mg / kg were statistically significantly different from the 5-fluorouracil alone and the group. Animal test results clearly support the results of in vitro tests, namely 5-fluorouracil It has obvious synergistic drug effect on the area near the concentration ratio of 芩甙1 to 1:2. It can be seen from the changes in animal body weight that no toxicity enhancement trend was observed in each of the combined groups.

 Comprehensive animal tests can be seen; Astragalus or Astragalus and 5-fluorouracil have a good synergistic anti-tumor effect. Each of the above-referenced documents is hereby incorporated by reference in its entirety in its entirety in its entirety. The various aspects of the present invention are set forth above. However, it is to be understood that any modifications to the above description are possible without departing from the spirit and scope of the invention. Similarly, similar situations are included in the claims.

Claims

Rights request A pharmaceutical composition having a synergistic antitumor effect, the composition comprising cisplatin and a compound of the following formula (I), characterized in that the molar ratio of the cisplatin to the compound of the formula (I) is 1:2.5 to 1:10:

Wherein R represents hydrogen or a glucuronic acid group.  2. The pharmaceutical composition of claim 1, wherein the tumor is a solid tumor.  3. The pharmaceutical composition of claim 1, wherein the tumor is melanoma.  The pharmaceutical composition according to claim 1 or 2 or 3, wherein when R represents hydrogen, the compound is xanthine, and the molar ratio of the cisplatin to xanthine is from 1:2.5 to 1:10.  The pharmaceutical composition according to claim 1 or 2 or 3, wherein when R represents a glucuronic acid group, the compound is xanthine, and the molar ratio of the cisplatin to xanthine is 1:5 to 1:10.  6. Use of a compound of the following formula (I) and a pharmaceutically acceptable salt thereof for the preparation of an antitumor drug having synergistic effect on cisplatin -

 Wherein R represents hydrogen or a glucuronic acid group.  7. The use of claim 6, wherein the tumor is selected from the group consisting of liver cancer, colorectal cancer, lung cancer, gastric cancer or esophageal cancer.  The use according to claim 6 or 7, wherein 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 use according to claim 8, wherein when the tumor is gastric cancer, the molar ratio of the cisplatin to the xanthine is from 1:1 to 1:10. 10. The use of claim 8, wherein when the tumor is liver cancer, colon cancer, lung cancer or esophageal cancer, The molar ratio of the cisplatin to the xanthine is from 1:2.5 to 1:10.  The use according to claim 6 or 7, wherein when R represents a glucuronic acid group, the compound is xanthine, and the molar ratio of the cisplatin to xanthine is 1:2.5 to 1:10.  The use according to claim 11, wherein when said tumor is gastric cancer, said cisplatin and xanthine have a molar concentration ratio of 1:2.5 to 1:10.  The use according to claim 11, wherein when the tumor is colorectal cancer or esophageal cancer, the molar concentration ratio of the cisplatin to xanthine is 1:5 to 1:10.  The use according to claim 11, wherein when the tumor is liver cancer or lung cancer, the molar concentration ratio of the cisplatin to xanthine is 1:7.5 to 1:10.  A pharmaceutical composition having a synergistic antitumor effect, comprising 5-fluorouracil and a compound of the following formula (I), characterized in that the molar concentration of the 5-fluorouracil and the compound of the formula (I) The ratio is 1:2 to 2:1:

Wherein R represents hydrogen or a glucuronic acid group.  16. The pharmaceutical composition of claim 15 wherein the tumor is a solid tumor.  17. The pharmaceutical composition of claim 15, wherein the tumor is melanoma.  The pharmaceutical composition according to claim 15 or 16 or 17, wherein 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 pharmaceutical composition according to claim 15 or 16 or 17, wherein when R represents a glucuronic acid group, the compound is xanthine, and the molar ratio of the 5-fluorouracil to xanthine is 1:1 to 1:2.  20. Use of a compound of the following formula (I) and a pharmaceutically acceptable salt thereof for the preparation of an antitumor agent having synergistic effect on 5-fluorouracil:

Among them, it represents hydrogen or glucuronic acid groups.  21. The use of claim 20, wherein the tumor is selected from the group consisting of liver cancer, colorectal cancer, gastric cancer, esophageal cancer, or breast cancer.  The use according to claim 20 or 21, wherein 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.  The use according to claim 22, wherein when the tumor is liver cancer, colorectal cancer, gastric cancer, esophageal cancer or breast cancer, the molar concentration ratio of the 5-fluorouracil to xanthine is 1:2 to 2: 1.  The use according to Claim 20 or 21, wherein when R represents a glucuronic acid group, the compound is xanthine, and the molar ratio of the 5-fluorouracil to xanthine is from 1:1 to 1:4.  The use according to claim 24, wherein when the tumor is colorectal cancer, gastric cancer, esophageal cancer or breast cancer, the molar concentration ratio of the 5-fluorouracil to xanthine is 1:1 to 1:2.  The use according to claim 24, wherein when the tumor is liver cancer, the molar ratio of the 5-fluorouracil to xanthine is 1:2 to 1:4.