KR100844477B1 - Antitumor effect fortifier, antitumor agent and method of therapy for cancer - Google Patents

Abstract

A therapeutically effective amount of tegapur, containing an effective amount of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) as an active ingredient, an effective amount of anti-tumor effect-enhancing gimeracil, and an effective amount of odor for suppressing side effects Antitumor effect enhancers that enhance the antitumor activity of antitumor agents containing terasil potassium; A method for treating cancer, comprising administering to the mammal an effective amount of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) in order to enhance the antitumor agent and antitumor effect. Two or more separate components each comprising, alone or in any combination, an active ingredient consisting of tegapur, gimeracil, potassium terrasil, and cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) An anti-tumor agent and kit in the form of a formulation consisting of a formulation or in the form of a formulation comprising all active ingredients.

Tegapur, gimeracil, oterasyl potassium, antitumor effect enhancer, cis-oxalate platinum, cancer treatment method, antitumor agent, kit

Description

ANTITUMOR EFFECT FORTIFIER, ANTITUMOR AGENT AND METHOD OF THERAPY FOR CANCER}

The present invention relates to a method for treating cancer, an antitumor agent and a kit for treating cancer, aimed at enhancing antitumor effect by a novel combination administration of an antitumor effect enhancer and an antitumor agent.

Research and development of anti-tumor agents have been actively conducted in the past, and clinically, various excellent anti-tumor agents have been introduced into the treatment of malignant tumors. For example, tegafur is a drug that is activated in vivo and slowly releases the active body, 5-fluorouracil (hereinafter referred to as 5-FU), which reduces the toxicity or side effects of 5-FU. will be.

Moreover, the compounding agent (brand name: UFT, Tegapur: uracil (molar ratio) = 1: 4, Daiho Pharmaceutical Co., Ltd. product) of this tegapur and uracil is known. Usually 5-FU is rapidly metabolized and inactivated in vivo, and this formulation is used when uracil, which itself has no antitumor activity, uses tegapur alone by inhibiting 5-FU inactivation. It shows a markedly enhanced antitumor effect compared to

In addition, a three-agent combination of tegapur, gimeracil and oteracil potassium (trade name: TS-1, tegapur: gimeracil: oterasyl potassium (molar ratio) = 1: 0.4: 1 and Daiho Pharmaceutical Co., Ltd. are known. In this formulation, since gimerasil exhibits about 200-fold 5-FU degradation inhibitory activity of uracil, higher antitumor effect enhancement is expressed. In this formulation, the therapeutic effect is improved by specifically suppressing digestive tract toxicity, which is concerned that potassium orerasil potassium increases with antitumor effect caused by the two agents of tegafur and gimeracil. Thus, UFT and TS-1 contribute to the treatment of various malignancies.

However, there is a need for more therapeutic agents and therapies that extend the survival of cancer patients. To this end, as one of the oldest therapeutic methods, attempts have been made to improve therapeutic results (combination therapy) by administering a combination of a plurality of drugs having different types of antitumor mechanisms and side effects. Combination therapy contributes to the improvement of the therapeutic result (for example, refer patent documents 1, 2, 3, and 4). For example, oxaliplatin is used as a combination therapy with other agents because of its low antitumor effect in monotherapy, and as a combination therapy, a combination therapy of 5-fluorouracil and calcium phosphate ( FOLFOX) is widely used worldwide (see, for example, Non-Patent Documents 1, 2 and 3). However, since FOLFOX therapy is complicated, there are problems such as lower QOL and high cost of treatment due to restraint associated with continuous seizures. The establishment of better combination therapy using oxaliplatin is a worldwide problem. It is considered. For example, the combination therapy of capecitabine (Zeroda) and oxaliplatin (XELOX), an oral pyrimidine-based anticancer agent, has been reported to have an antitumor effect almost equivalent to that of FOLFOX (for example, non-patent literature). 4), a combination therapy with a higher therapeutic effect is needed.

Patent Document 1: Japanese Patent No. 2557303

Patent Document 2: Japanese Patent No. 2614164

Patent Document 3: Japanese Patent Application Laid-Open No. 8-169825

Patent Document 4: Japanese Patent Application Laid-Open No. 2002-205945

Non-Patent Document 1: Journal of Clinical Oncology, Vol. 22, 22-30, 2004

Non Patent Literature 2: Journal of Clinical Oncology, Vol. 21, 2059-2069, 2004

Non-Patent Document 3: Journal of Clinical Oncology, Vol. 18, 2938-2947, 2000

Non-Patent Document 4: Journal of Clinical Oncology, Vol. 22, 2084-2091, 2004

The present invention provides an anti-tumor effect enhancer of a tegapur, gimeracyl and orteracyl potassium formulation, a cancer treatment method that exhibits an excellent therapeutic effect by using another formulation in combination with the formulation, and the combination and the other formulation. The main aim is to provide antitumor agents and kits.

In view of this phenomenon, the present inventors have combined a novel combination of a three-agent combination of tegapur, gimeracil, and octeracyl potassium with other anti-tumor agents to develop cancer treatments that contribute more to patients' longer survival. As a result of the study of the combination therapy of the drug, cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) (general name: oxaliplatin, trade name: Eloxatin or Elplat) By using l-OHP hereinafter) in combination with the above-mentioned three-agent combination, it was found that the antitumor effect was remarkably enhanced without enhancing side effects. In addition , the combination therapy of tegapur and uracil formulations and d, l -folate, which are representative colorectal cancer standard chemotherapy, is effective for suppressing tumor growth by this new combination therapy (see Japanese Patent No. 2557303) and Tegapur. The present invention was confirmed to be superior to the effect of inhibiting tumor growth by the combination therapy of the uracil compound, d, l -folate and l-OHP (see US Patent No. 6602870).

That is, the present invention provides the following antitumor effect enhancers, cancer treatment methods, antitumor agents, antitumor agent kits, methods for enhancing antitumor effects, and the like.

Item 1. An effective amount of tegapur, anti, characterized in that it contains an effective amount of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) as an active ingredient for enhancing antitumor effect. An anti-tumor effect enhancer that enhances the anti-tumor activity of an anti-tumor agent containing an amount of gimeracil effective for enhancing tumor effect and an amount of oterasyl potassium effective for suppressing side effects.

Item 2. The anti-tumor according to Item 1, wherein the anti-tumor agent contains tegapur, gimeracil and potassium terasil in a molar ratio of tegapur: kimeracil: oterathyl potassium = 1: 0.4: 1. Effect enhancer.

Item 3. Effective amount of tegapur for treatment, amount of gimeracil for effective antitumor effect, amount of terasil potassium for effective side effects suppression, and amount of cis-oxalate effective for antitumor effect A cancer treatment method, comprising (1R, 2R-diaminocyclohexane) platinum (II) in combination to a mammal.

Item 4. The ratio of active ingredient is 0.1-5 mol of gimeracyl, 0.1-5 mol of potassium terasil, and cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) with respect to 1 mol of tegapur. The cancer treatment method of item 3 which is 0.1-5 mol.

Item 5. The molar ratio of the active ingredient is tegapur: gimeracil: oteracyl potassium: cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) = 1: 0.4: 1: 0.1 to 5 The cancer treatment method of Claim 4.

Item 6. A plurality of active ingredients each consisting of alone or in any combination, comprising an active ingredient consisting of tegapur, gimeracyl, octeryl potassium and cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) An anti-tumor agent which is in the form of a preparation consisting of a preparation or in the form of a preparation consisting of one preparation comprising all active ingredients.

Item 7. A combination formulation comprising three components of tegapur, gimeracyl, and octeracyl potassium as active ingredients, and cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) as active ingredients The anti-tumor agent according to item 6, which is in the form of a preparation consisting of a preparation.

Item 8. The ratio of active ingredient is 0.1-5 mol of gimeracil, 0.1-5 mol of potassium terrasil, and cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) with respect to 1 mol of tegapur. The anti-tumor agent according to item 6 or 7, which is 0.1 to 5 mol.

Item 9. The molar ratio of active ingredient is tegapur: gimeracil: oteracyl potassium: cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) = 1: 0.4: 1: 0.1 to 5 The antitumor agent according to item 8.

Item 10. (a) An anti-tumor composition comprising tegapur in an amount effective for treatment, an amount of gimeracil for enhancing antitumor effect and an amount of oterasyl potassium for suppressing side effects, and (b) A kit consisting of a combination of pharmaceutical compositions for the treatment of cancer in a mammal consisting of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) in an amount effective for enhancing antitumor effects.

SECTION 11.Efficacy of Tegapur in a therapeutically effective amount, antitumor effect when administered with an antitumor agent containing an amount of gimeracil to enhance antitumor effect and an amount of oterasyl potassium to inhibit side effects. A method of enhancing the antitumor effect of the antitumor agent, characterized in that it is administered in combination with an effective amount of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II).

Item 12. Simultaneous or before or after administration of a therapeutically effective amount of tegapur, an antitumor agent containing an amount of gimeracil for enhancing antitumor effect and an amount of oterasyl potassium for suppressing side effects. A method according to item 11, wherein cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) is administered within a time period.

Item 13.Tegapur in an amount effective for treatment, an amount of gimeracil effective for enhancing antitumor effect, and an agent for enhancing antitumor effect of an antitumor agent containing an amount of oterasyl potassium effective for suppressing side effects. Use of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) to prepare tumor effect enhancers.

Item 14. An effective anti-tumor effect in the manufacture of an anti-tumor agent containing tegapur in a therapeutically effective amount, gimeracil effective for enhancing antitumor effect, and an amount of oterasyl potassium effective for suppressing side effects. Use of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) to prepare an antitumor agent having

The antitumor effect enhancer of the present invention contains cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) as an active ingredient. According to the antitumor effect enhancer, it is possible to remarkably enhance the antitumor effect of the antitumor agent containing three components of tegapur, gimeracil and potassium terasil as active ingredients.

The method for treating cancer of the present invention is an amount of tegapur effective for treatment, an amount of gimeracil effective for enhancing antitumor effect, an amount of utereracil potassium effective for suppressing side effects, and an amount effective for enhancing antitumor effect. Cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) is co-administered to a mammal, It is characterized by the above-mentioned.

In addition, the anti-tumor agent of the present invention alone or in any combination of the active ingredients consisting of tegapur, gimeracil, potassium terasil, and cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II), respectively. It is characterized in that it is in the form of a preparation consisting of a plurality of preparations containing, or a preparation consisting of one preparation containing all active ingredients.

In addition, the kit of the present invention (a) an anti-tumor composition containing an amount of tegapur effective for treatment, an amount of gimeracil effective for enhancing antitumor effect, and an amount of oterasyl potassium effective for suppressing side effects, and ( b) a combination of a pharmaceutical composition for the treatment of cancer in a mammal comprising an effective amount of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) to enhance antitumor effect. .

In addition, the method of enhancing the anti-tumor effect of the present invention is an anti-tumor containing an amount of tegapur effective for treatment, an amount of gimeracil effective for enhancing the anti-tumor effect, and an amount of oterasyl potassium effective for suppressing side effects. When the agent is administered, an effective amount of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) is used in combination to enhance antitumor effect.

L-OHP used as an active ingredient of an anti-tumor effect enhancer is a compound known as a complex containing platinum. 1-OHP binds to the DNA of cancer cells, causing functional disorders of DNA and cleavage of DNA chains, and have the effect of killing cancer cells. l-OHP can be manufactured according to a well-known method, for example, the method of Unexamined-Japanese-Patent No. 60-41077.

Tegapur (common name, chemical name: 5-fluoro-1- (2-tetrahydrofuryl) -2,4- (1H, 3H) -pyrimidinedione, an active ingredient of an anti-tumor agent, hereinafter referred to as FT) Is a known compound, which is activated in vivo to release 5-FU, the body of anti-tumor activity. Tegapur can be manufactured according to a well-known method, for example, the method of Unexamined-Japanese-Patent No. 49-10510.

Gymeracyl (common name, chemical name: 2,4-dihydroxy-5-chloropyridine, sometimes referred to as CDHP) is also a known compound, which itself has no antitumor activity. It is to inhibit the FU metabolized and inactivated in vivo, and can enhance the antitumor effect.

Also known as potassium terasil (general name, chemical name: monopotassium 1,2,3,4-tetrahydro-2,4-dioxo-1,3,5-triazine-6-carboxylate, hereafter referred to as OXO) It is also a known compound, which itself does not have antitumor activity, but mainly distributed in the digestive tract, thereby inhibiting digestive tract obstruction by inhibiting the activation of 5-FU at the site.

The compounding ratio of each component in an anti-tumor agent containing three components of tegapur, gimeracyl, and octeracyl potassium as an active ingredient is, for example, a known compounding agent described in Japanese Patent No. 2614164. The range is preferably good, usually about 0.1 to 5 moles of gimerasil, preferably about 0.2 to 1.5 moles per 1 mole of tegapur, and about 0.1 to 5 moles of potassium terasil, preferably 0.2 What is necessary is just about-2 mol. Especially preferably, the blending ratio of the three components is tegapur: gimeracil: oterathyl potassium (molar ratio) = 1: 0.4: 1 (hereinafter, the blending agent of the blending ratio may be referred to as TS-1). .

An anti-tumor agent containing three components of tegapur, gimeracyl and oterasyl potassium as active ingredients is in the form of a preparation consisting of two or more preparations each containing each ingredient alone or in any combination, or the total active ingredient Either of the forms prepared with one formulation containing these may be sufficient. In either case, they form a formulation composition according to a conventional method using a suitable carrier for formulation. Examples of the carrier used herein include various kinds of agents commonly used in conventional medicines, for example, excipients, binders, disintegrating agents, lubricants, colorants, taste enhancers, flavor enhancers, surfactants, and the like. Can be.

When using an anti-tumor agent in the form of a formulation consisting of two or more agents described above, each component may be administered at the same time or at any other time before or after administration of one component. Preferably, the other component is administered at the same time or within 4 hours before and after the administration of one component, more preferably within 2 hours.

Antitumor effect enhancers of the present invention containing l-OHP as an active ingredient are formulated alone in various dosage unit forms. In this case, a formulation composition is prepared according to a conventional method using a carrier for a suitable formulation. As a carrier used here, various things general-purpose in a general medicine can be illustrated, for example, an excipient, a binder, a disintegrant, a lubricating agent, a coloring agent, a mating agent, a corrosive agent, a surfactant, and the like. The anti-tumor effect enhancer formulated in various dosage unit forms is an anti-tumor agent comprising three components of tegapur, gimeracyl and octeracyl potassium, which are also formulated in various dosage unit forms, respectively, separately or simultaneously. May be administered. That is, the anti-tumor effect enhancer of the present invention can be administered at any time before, after, or simultaneously with the administration of an anti-tumor agent comprising three components of tegapur, gimeracil and potassium terasil. Preferably at the same time or within 4 hours before and after the administration of the anti-tumor agent, more preferably within 2 hours.

When the anti-tumor effect enhancer of the present invention is administered separately or simultaneously with the anti-tumor agent containing the above three components of tegapur, gimeracyl and oterasyl potassium as active ingredients, for example, tegapur The amount of l-OHP per mole is preferably about 0.1 to 5 moles, preferably about 0.3 to 3 moles, more preferably about 0.4 to 1 mole.

The dosage unit form when the anti-tumor effect enhancer of the present invention is used for the purpose of treating malignant tumors in mammals including humans is not particularly limited, and may be appropriately selected according to the therapeutic purpose. Oral preparations such as suppositories, eye drops, ointments, aerosols, tablets, coated tablets, powders, granules, capsules, solutions, pills, suspensions, emulsions, and the like. Form. Such dosage agents are prepared by methods of formulation commonly known in the art.

In addition, in the present invention, an anti-tumor effect enhancer is further formulated by further combining l-OHP, an active ingredient of the anti-tumor efficacy enhancer, with an anti-tumor agent containing three components of tegapur, gimeracyl, and oterasyl potassium as active ingredients. It can be set as the combined antitumor agent. The anti-tumor agent is in the form of a formulation consisting of a plurality of formulations each comprising four or more of the above components alone or in any combination, or in the form of a formulation consisting of one formulation containing all active ingredients. That is, the antitumor agent of the present invention may be a one-part preparation containing all four components described above, or may be a multi-form preparation of a preparation containing one to three components and a preparation containing other components. Particularly preferred are two-component formulations in which a combination formulation comprising three components of tegapur, gimeracyl and oterasyl potassium as active ingredients and a formulation containing l-OHP as an active ingredient are separately prepared.

In the anti-tumor agent, the blending ratio of each component is not particularly limited, even if it is a one-part or a multi-part, but usually about 0.1 to 5 moles of gimerasil, preferably about 0.2 to 1.5 moles per 1 mole of tegafur, 0.1 to 5 moles of potassium terrasilyl, preferably about 0.2 to 2 moles, about 0.1 to 5 moles of l-OHP, preferably about 0.3 to 3 moles, and more preferably about 0.4 to 1 moles . In particular, it is preferable that the molar ratio of each component is tegapur: gimeracil: potassium terasil: l-OHP = 1: 0.4: 1: 0.1-5, and about 1: 0.4: 1: 0.3-3 mol. It is more preferable, and it is still more preferable that it is about 1: 0.4: 1: 0.4-1 mol. In the case of a two-part preparation having the above-mentioned combinations of three components of tegapur, gimeracyl and octeracyl potassium, which are preferred forms, as an active ingredient and a formulation having l-OHP as an active ingredient, Tegapur: gimeracil: potassium terrasil (molar ratio) = 1: 0.4: 1 with respect to 1 mole of tegapur, preferably about 0.1 to 5 moles, preferably about 0.3 to 3 moles, more preferably Preferably it is set as the formulation containing l-OHP about 0.4-1 mol.

These active ingredients are formulated according to conventional methods using a suitable carrier for the preparation. As a carrier used here, various things general-purpose in a general medicine can be illustrated, for example, an excipient, a binder, a disintegrant, a lubricating agent, a coloring agent, a mating agent, a corrosive agent, a surfactant, and the like.

In the case of using a multi-dose antitumor agent consisting of two or more agents described above, each component may be administered at the same time or at any time before or after administration of one component. Preferably, the other component is administered at the same time or within 4 hours before and after the administration of one component, more preferably within 2 hours.

In addition, in the present invention, a combination formulation of the above-described l-OHP-containing formulation and tegapur, gimeracil and potassium teracil,

(a) an anti-tumor composition containing an amount of tegapur effective for treatment, an amount of gimeracil effective for enhancing antitumor effect and an amount of oterasyl potassium effective for suppressing side effects, and

(b) a composition containing an amount of l-OHP effective to enhance antitumor effect

It can be set as the kit which consists of a combination of the pharmaceutical composition for cancer treatment in the mammal which consists of these. In the said kit, each composition which comprises this can be made into the well-known various formulation form, and generally each composition is accommodated in the various containers normally used according to the formulation form.

The kit may also be

(Iii) tegapur in an amount effective for treatment;

(Ii) an amount of gimeracil effective for enhancing antitumor effect,

(Iii) an anti-tumor composition containing an amount of oterasyl potassium effective for suppressing side effects, and

(Iii) an amount of l-OHP effective for enhancing antitumor effects

It can be set as the kit for cancer treatment in mammals which consists of at least 4 components which consist of these, and at least 2 container for these components, and which Tegapur and l-OHP are accommodated in another container. The components (i) to (iii) are preferably in the form of a formulation in combination with a pharmaceutically acceptable carrier. In the kit, the component (i) and component (i) may be housed in separate containers, and the components (ii) and (v) may be housed in containers separate from the two components, respectively. Or it may be mixed with (iii) component and accommodated in the same container. The kit which accommodated the formulation containing (iv)-(iv) component in one container, and contained the formulation containing (iv) component in the other container is preferable.

The dosage unit form when the anti-tumor agent of the present invention is used for the purpose of treatment of a mammal including a person suffering from a malignant tumor is not particularly limited, and may be appropriately selected according to the purpose of treatment. Oral preparations such as suppositories, eye drops, ointments, aerosols, tablets, coated tablets, powders, granules, capsules, solutions, pills, suspensions, emulsions. Such dosage agents are prepared by methods of formulation commonly known in the art.

In the antitumor effect enhancer or antitumor agent of the present invention, when preparing oral solid preparations such as tablets, powders and granules, as carriers, for example, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin , Excipients such as crystalline cellulose, silicic acid, methyl cellulose, glycerin, sodium alginate, gum arabic, sweet syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethyl cellulose, Binders such as ceramics, methyl cellulose, ethyl cellulose, water, ethanol, potassium phosphate, dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate Disintegrating agents such as monoglycerides, stearic acid, starch, lactose, sucrose, stearic acid, cacao butter, hydrogenated oil, etc. May be used such as sodium sulfate in the absorption accelerator, glycerol, humectants, such as starch, starch, lactose, kaolin, bentonite, colloidal silicic acid adsorbent such as, such as purified talc, stearates, boric acid powder, polyethylene glycol, and the like of the lubricant. In addition, tablets can be made into tablets which have been subjected to normal peeling as needed, for example, dragee tablets, gelatin coated tablets, enteric coated tablets, film coated tablets, double tablets, multilayer tablets, and the like.

In preparing the pills, for example, glucose, lactose, starch, cacao butter, excipients such as hardened vegetable oil, kaolin, tark, binders such as gum arabic, tragant powder, gelatin, laminaran and agar, etc. Agent etc. can be used.

Capsules are prepared by mixing the active ingredients with the various carriers exemplified above, filling hard gelatine capsules, soft capsules and the like.

In preparing suppositories, for example, polyethylene glycol, cacao butter, lanolin, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, witezole (registered trademark, Dynamite Nobel Co.) and the like can be used. .

At the time of preparation of injectables, diluents such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, sodium citrate , PH adjusters such as sodium acetate, sodium phosphate, buffers such as dipotassium phosphate, trisodium phosphate, sodium hydrogen phosphate, sodium citrate, stabilizers such as sodium pyrosulfite, EDTA, thioglycolic acid, thio lactic acid, and lyophilized As the molding agent for the above, sugars such as mannitol, inositol, maltose, sucrose, lactose and the like can be used. In this case, glucose or glycerin in an amount sufficient to adjust the isotonic solution may be contained in the pharmaceutical preparation, or a conventional dissolution aid, analgesic agent, local anesthetic, or the like may be added. These carriers can be added to produce subcutaneous, intramuscular, intravenous injectables by conventional methods.

The liquid formulations may be aqueous or oily suspensions, solutions, syrups, elixirs, and are prepared according to conventional methods using conventional additives.

When prepared in the form of ointments such as pastes, creams and gels, for example, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used.

The compounding amount of tegapur, gimeracyl, oterasyl potassium and l-OHP, which are active ingredients in the antitumor agent of the present invention, varies depending on the formulation, route of administration, dosing schedule, and the like, and is not particularly limited and may be appropriately selected. In general, the amount of the active ingredient in the formulation is preferably about 1 to 70% by weight.

The method of administration of the formulation of the present invention is not particularly limited and is determined according to various formulation forms, the age, sex, other conditions of the patient, the degree of symptoms of the patient, and the like. Enteral administration, oral administration, rectal administration, oral administration, artery Intra- and intravenous administration, transdermal administration, etc. are possible. For example, tablets, pills, solutions, suspensions, emulsions, granules, capsules and the like are administered orally, injections are administered intraarterally or intravenously, suppositories are administered rectally, ointments are applied to the skin, oral mucosa, etc. Is applied. In the formulation of the present invention, it is possible to orally administer, for example, a tegafur-gimeracyl-oteracyl potassium-containing formulation, and to intravenously administer an l-OHP formulation.

The dosage of each active ingredient in the present invention can be appropriately selected depending on the usage, the age, sex of the patient, the degree of disease, other conditions, and the like. The anti-tumor effect enhancer or anti-tumor agent of the present invention may be administered by dividing it about 1 to 4 times a day.

In the case of oral administration, the amount of tegapur is about 0.1-100 mg / kg / day, preferably about 0.2-40 mg / kg / day, more preferably about 0.5-20 mg / kg / day, gimerasil The amount of is about 0.02 to 30 mg / kg / day, preferably about 0.05 to 12 mg / kg / day, more preferably about 0.1 to 6 mg / kg / day, the amount of potassium terasil is 0.1 to 100 About mg / kg / day, preferably about 0.2 to 40 mg / kg / day, more preferably about 0.5 to 20 mg / kg / day, the amount of l-OHP is about 0.08 to 200 mg / kg / day, Preferably it is based on the quantity which becomes about 0.15-80 mg / kg / day, More preferably, about 0.4-40 mg / kg / day.

In the case of injectable drugs, the amount of tegapur per adult is usually about 0.1-100 mg / kg and the amount of l-OHP is about 0.08-200 mg / kg, if necessary, diluted with 5% glucose solution and slowly administered over 5 minutes. can do.

In the case of suppositories, about 0.1 to 100 mg / kg as an amount of tegapur per day and about 0.08 to 200 mg / kg as an amount of l-OHP once or twice a day for 6 to 12 hours per adult. It can be inserted and administered in the rectum.

The type of malignant tumor which can be treated by administering the agent of the present invention is not particularly limited as long as it exhibits susceptibility to 5-FU, which is an active body. For example, head and neck cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder and bile duct cancer, Pancreatic cancer, lung cancer, breast cancer, bladder cancer, prostate cancer, uterine cancer, pharyngeal cancer, esophageal cancer, kidney cancer, ovarian cancer, and the like. In particular, high effects can be expected for colon cancer, rectal cancer, breast cancer, esophageal cancer, stomach cancer, and head and neck cancer. In addition, a high effect can also be expected for tumors that are typically starting to become drug resistant or drug resistant.

Effects of the Invention

According to the antitumor effect enhancers, cancer therapies, antitumor agents, kits, and the like of the present invention, the known antitumor agents of tegapur, gimeracyl, and terrasil potassium without increasing the toxicity (especially the digestive tract and bone marrow toxicity) It is possible to obtain an antitumor effect that exceeds the effect of the triple agent formulation and the effect of the 1-OHP alone formulation. In addition, the anti-tumor effect is a combination therapy of tegapur and uracil formulations and d, l-folate, one of the standard therapies for treating colorectal cancer, and tegapur and uracil combinations, d, l-folate and l-. It is superior to the antitumor effect by the combination therapy of OHP. In addition, excellent anti-tumor effect enhancing or anti-tumor effects can be expected for 5-FU resistant tumors or multi-drug resistant tumors.

The present invention will be described in more detail with reference to the following Examples, which however are not intended to limit the present invention.

(Example)

Pharmacological Test Example  One

Preparation of Dosage Formulations

Tegapur, gimeracil, and terrasil potassium mixture (tegapur: gimerasil: orerasil potassium (molar ratio) = 1: 0.4: 1, hereinafter sometimes referred to as TS-1), tega 0.5% hydroxy of uracil compound (tegapur: uracil (molar ratio) = 1: 4, sometimes referred to as UFT) and d, l-calcium phosphate (hereinafter referred to as LV) It was dissolved or suspended in a propylmethylcellulose (HPMC) solution, and prepared so that the final dose of the preparation might be 10 ml / kg. For example, when the Tegapur dose was 8.3 mg / kg, oral administration was prepared so that the drug in the amount of 8.3 mg was dissolved or suspended in 10 ml of HPMC, and the dosage of the formulation was 10 ml / kg.

Administration of the formulation

A fragment of about 2 mm square of human colon cancer KM20C strain was implanted subcutaneously under the back of male nude rat F344 / NJcl-rnu. Rats were grouped at the stage where the average tumor volume (= 0.5 x long diameter [mm] x short diameter [mm] ² ) became about 200 mm ³ (day 0).

TS-1 formulation or UFT + LV formulation prepared as above was orally administered once a day for 14 consecutive days from the day after group classification (day 1). The l-OHP formulation was administered once in the tail vein at 10 mg / kg immediately prior to administration of the formulation on the day following grouping (day 1).

The ratio of the tumor volume at the time of group classification (day 0) and the 15th tumor volume (the 15th tumor volume / the 0th tumor volume) was made into the relative tumor volume.

Moreover, the tumor growth inhibition rate (%) was calculated | required from the average value of the relative tumor volume of a drug administration group, and the average value of the relative tumor volume of a control group.

[(1- (Relative Tumor Volume of Dosing Group) / (Relative Tumor Volume of Tumor-bearing Control Group) × 100 (%)]

On the 15th day, the relative tumor volume was used to analyze the presence or absence of an increase in effect by the combination-intersection test (IUT) procedure (see Statistical Science 1996, Vol. 11, No. 4, 283-319).

On the other hand, the ratio (weight change rate) of the rat body weight on the 15th day and the body weight difference on the 0th day with respect to the body weight on the 0th day was made into the index which shows the systemic toxicity by a drug.

[((At 15th rat weight-0th rat weight) / 0th rat weight) * 100 (%)]

The obtained results are shown in Table 1. In addition, although calcium phosphate was used in the experiment, the dose converted into phosphate is shown in a table | surface.

TABLE 1

drugs Tegapur Blend Dose (mg / kg / day) Oxaliplatin Dosage (mg / kg / day) Relative Tumor Volume (Mean) Tumor growth inhibition rate (%) % Change in weight none - - 5.81 - 1.3 Oxaliplatin (l-OHP) - 10 4.64 20.1 0.9 Tegapur + Kimerasil + Oteracil Potassium (TS-1) 12 + 3.5 + 11.7 - 2.83 51.4 －3.4 Tegapur + Kimerasil + Oteraceyl Potassium + Oxaliplatin (TS-1 + l-OHP) 12 + 3.5 + 11.7 10 2.13 *, ## 63.3 6.4 Tegapur + uracil + polyic acid (UFT + LV) 24 + 53.8 + 20.0 - 3.73 35.8 -3.1 Tegapur + uracil + folic acid + oxaliplatin (UTF + LV + l-OHP) 24 + 53.8 + 20.0 10 2.79 * 51.9 －4.5

*: Group in which effective synergy (P <0.05) was obtained in IUT order

＃＃: Effectively high effect for the UFT + LV administration group using the same amount of l-OHP (P

      <0. 01) obtained

As a result, a statistically effective synergistic effect was obtained by TS-1 and l-OHP co-administration compared to TS-1 monotherapy, and a statistically higher effect was obtained than when l-OHP was co-administered with UFT + LV. It is suggested that the combination of TS-1 and l-OHP is a very effective treatment since there is no increase in effective toxicity.

Pharmacological Test Example  2 (5-FU Introvert  Action)

A fragment of about 2 mm angle of 5-FU resistant strain (KM12C / 5-FU) of human colon cancer KM12C strain established by the applicant was implanted into the dorsal subcutaneous of male nude mouse BALB / c-nu / nu. Mice were grouped at the stage where the mean tumor volume (= 0.5 x long diameter [mm] x short diameter [mm] ² ) was about 200 mm ³ (day 0). TS-1 preparations prepared in the same manner as in Pharmacological Test Example 1 were orally administered to the mice at the doses shown in Table 2 below once a day for 9 consecutive days from the day after group classification (day 1). The 1-OHP preparation was administered once 8.3 mg / kg in the subvenous vein immediately before the TS-1 preparation on the day following grouping (day 1). The ratio of tumor volume on day 0 and day 10 was calculated as a relative tumor volume, and tumor growth inhibition rate and weight change rate were computed from the average value of the relative tumor volume of a drug administration group and a control group similarly to pharmacological test example 1.

TABLE 2

drugs Tegapur Blend Dose (mg / kg / day) Oxaliplatin Dosage (mg / kg / day) Relative Tumor Volume (Mean) Tumor growth inhibition rate (%) % Change in weight none - - 9.5 - -6.2 Oxaliplatin (l-OHP) - 8.3 7.97 16.1 -8.0 Tegapur + Kimerasil + Oteracil Potassium (TS-1) 8.3 + 2.4 + 8.1 - 6.39 32.7 －9.2 Tegapur + Kimerasil + Oteraceyl Potassium + Oxaliplatin (TS-1 + l-OHP) 8.3 + 2.4 + 8.1 8.3 4.89 * 48.5 －18.6

＊ Groups in which effective synergy (P <0.05) was obtained in IUT order

As a result, in the resistant strains, almost no effect was found in the TS-1 monosaccharide, but the combination of TS-1 and l-OHP showed an increase in the rate of tumor growth inhibition to approximately the same level (near 50%) as that of other 5-FU-sensitive strains. did. Also valid weight changes were not recognized. Therefore, it was suggested that TS-1 and l-OHP co-administration are effective treatments for 5-FU resistant cancer.

Pharmacological Test Example  3 ( Tea  Action on resistant strains)

A fragment of approximately 2 mm angle of human colon cancer HCT-15 strain expressing excessive P sugar protein and showing multidrug resistance was implanted subcutaneously in the back of male nude mouse BALB / c-nu / nu. Mice were grouped at the stage where the mean tumor volume (= 0.5 x long diameter [mm] x short diameter [mm] ² ) was about 200 mm ³ (day 0). TS-1 preparations prepared in the same manner as in Pharmacological Test Example 1 were orally administered to the mice at the doses shown in Table 3 below once a day for 14 consecutive days from the day after group classification (day 1). 1-OHP was administered 10.0 mg / kg in the single vein immediately before the TS-1 preparation on the day following group classification (day 1). Thereafter, the tumor growth inhibition rate was calculated in the same manner as in Pharmacological Test Example 1. Using the relative tumor volume on day 15, the difference between the relative tumor volume of the control group and the dosing group was analyzed by Dunnett's test, and the difference between the TS-1 or l-OHP monotherapy group and the combination group was interpreted by Student's t-test.

TABLE 3

drugs Tegapur Blend Dose (mg / kg / day) Oxaliplatin Dosage (mg / kg / day) Relative Tumor Volume (Mean) Tumor growth inhibition rate (%) none - - 4.53 - Oxaliplatin (l-OHP) - 10 4.33 4.3 Tegapur + Kimerasil + Oteracil Potassium (TS-1) 10 + 2.9 + 9.8 - 2.56 * 43.4 Tegapur + Kimerasil + Oteraceyl Potassium + Oxaliplatin (TS-1 + l-OHP) 10 + 2.9 + 9.8 10 1.54 **, #, $ 66.0

*: The group in which an effective (P <0.05) effect was obtained with respect to the cancer control group.

＊＊: The group in which an effective (P <0.01) effect was obtained with respect to the cancer control group.

Iv: group in which an effective (P <0.025) effect was obtained for TS-1.

VIII: The group which the effective (P <0.01) high effect was obtained with respect to the oxaliplatin agent.

As mentioned above, the antitumor effect of TS-1 was effectively improved when TS-1 and l-OHP were used also in the tumor which l-OHP hardly shows antitumor effect. Therefore, it was suggested that the improvement of antitumor effect was due to the antitumor effect enhancing activity of l-OHP against TS-1. Even if the tumor used was a multidrug resistant tumor, the combination of TS-1 and l-OHP was useful even when it was not sensitive to many anticancer drugs.

Pharmacological Test Example  4 (l- OHP Dose dependence)

A fragment of about 2 mm square of human colon cancer COL-1 strain was implanted subcutaneously in the back of male nude mouse BALB / c-nu / nu. Mice were grouped at the stage where the mean tumor volume (= 0.5 x long diameter [mm] x short diameter [mm] ² ) was about 125 mm ³ (day 0). TS-1 preparation prepared in the same manner as in Pharmacological Test Example 1 was orally administered 6.9 mg / kg in a Tegapur equivalent dose once daily for 14 consecutive days from the day following the group classification. 1-OHP was dissolved in 5% glucose solution at 2.8, 3.5, 4.2, or 5.0 mg / kg / day in the vein immediately before administration of the TS-1 preparation on days 1 and 8.

The antitumor effect was calculated as the relative tumor volume at the time of group classification (day 0) and at day 15 as the relative tumor volume, and the tumor growth inhibition rate was calculated from the average value of the relative tumor volume of the drug administration group and the control group. Using the relative tumor volume on the day of determination, the statistically effective difference of the relative tumor volume of the control group and TS-1 alone group was Student's t-test, and the dose correlation of the anti-tumor effect of l-OHP was Williams test. The statistically effective difference in relative tumor volume of the -OHP-only group was Dunnett's test.IUT sequence for the presence or absence of an increase in the effect of the combination of the TS-1 and l-OHP-only group and the TS-1 and l-OHP-only group. Interpreted as.

On the other hand, the mouse body weight on the 15th day and the weight change rate on the day 0 with respect to the body weight on the grouping day were used as an index indicating the systemic toxicity by the drug.

TABLE 4

drugs Tegapur Blend Dose (mg / kg) Oxaliplatin Dosage (mg / kg) Relative Tumor Volume (Mean) Tumor growth inhibition rate (%) % Change in weight Dead animals none - - 5.75 - －16.1 - Tegapur + Kimerasil + Oteracil Potassium (TS-1) 6.9 + 2.0 + 6.8 - 3.80 ^** 33.9 -20.5 0 Oxaliplatin (l-OHP) - 2.9 5.06 ^§ 11.9 -18.0 0 l-OHP - 3.5 4.54 ^§ 21.0 -20.6 0 l-OHP - 4.2 4.43 ^{§, **} 23.0 -19.0 0 l-OHP - 5.0 4.41 ^{§, **} 23.3 －16.8 0 TS-1 + OHP 6.9 + 2.0 + 6.8 2.9 3.70 ^# 35.7 －20.1 0 TS-1 + OHP 6.9 + 2.0 + 6.8 3.5 2.55 ^# 55.6 －19.3 0 TS-1 + OHP 6.9 + 2.0 + 6.8 4.2 2.65 ^# 53.9 -22.0 0 TS-1 + OHP 6.9 + 2.0 + 6.8 5.0 2.34 ^# 59.3 －23.4 One

*: The group in which an effective (P <0.05) effect was obtained for the control group.

＊＊: A group in which an effective (P <0.01) effect was obtained for the control group.

§: A group of valid (P <0.05) dose correlations obtained.

＃: group in which effective (P <0.05) synergy was obtained by combination in IUT order.

From the above results, it was confirmed that the dose dependency of l-OHP to the tegapur, gimeracil, and terrasil potassium mixtures.

Pharmacological Test Example  5 (effect comparison test)

Preliminary Exam ( Capecitabine  maximum Drug resistance  Review)

A fragment of about 2 mm square of human colon cancer COL-1 strain was implanted into the dorsal subcutaneous of male nude mouse BALB / c-nu / nu. Mice were grouped (day 0) at the stage where the average tumor volume (= 0.5 x long diameter [mm] x short diameter [mm] ² ) was about 190 mm ³ . Suspension of capecitabine in 0.5% HPMC solution was orally administered 240, 360, or 540 mg / kg once daily for 14 consecutive days from the day following the grouping. 1-OHP was dissolved in the 5% glucose solution at 4.2 mg / kg / day in the vein immediately before the administration of capecitabine on the first and eighth days. On the other hand, the ratio of the weight of the mouse on the 15th day to the weight of the grouping on the day 0, and the presence or absence of death were used as an index indicating systemic toxicity by the drug. As a result, it was estimated that the maximum tolerated amount of capecitabine which does not express toxic death in the combination therapy with l-OHP was 360 mg / kg / day.

This test (effect comparison test)

A fragment of about 2 mm square of human colon cancer COL-1 strain was implanted subcutaneously in the back of male nude mouse BALB / c-nu / nu. Mice were grouped (day 0) at the stage where the mean tumor volume (= 0.5 x long diameter [mm] x short diameter [mm] ² ) was about 170 mm ³ . TS-1 preparation prepared in the same manner as in pharmacological test 1 was orally administered with 6.9 mg / kg of the maximum drug-coated dose of Tegapur once daily for 14 consecutive days from the day following the group classification, and l-OHP was a 5% glucose solution. Dissolved on the first day and on the 8th day, 4.2 mg / kg / day of the maximum tolerated dose immediately before administration of the TS-1 preparation was administered into the vein. Suspension of capecitabine in 0.5% HPMC solution was orally administered 360 mg / kg, the maximum tolerated amount calculated by the preliminary test once a day for 14 consecutive days from the day following the group classification, and l-OHP was a 5% glucose solution. Dissolved on the first day and day 8, 4.2 mg / kg / day was administered into the vein immediately before the administration of the capecitabine agent.

The antitumor effect was calculated as the relative tumor volume at the time of group classification (day 0) and at day 15 as the relative tumor volume, and the tumor growth inhibition rate was calculated from the average value of the relative tumor volume of the drug administration group and the control group. Using the relative tumor volume on the day of determination, the statistically effective difference of the relative tumor volume between the control group and each drug-administered group was Dunnett's test, and the relative tumors of the TS-1 and l-OHP combination groups, and the capecitabine and l-OHP combination groups. The statistically effective difference in volume was interpreted by Student's t-test. On the other hand, the mouse body weight on the 15th day and the weight change rate on the day 0 with respect to the body weight on the grouping day were used as an index indicating the systemic toxicity by the drug.

TABLE 5

drugs Pyrimidine Fluoride Dose (mg / kg) Oxaliplatin Dosage (mg / kg) Oxaliplatin Dosage Day Relative Tumor Volume (Mean) Tumor growth inhibition rate (%) % Change in weight none - - 5.42 - －14.8 Tegapur + Kimerasil + Oteraceyl Potassium + Oxaliplatin (TS-1 + l-OHP) 6.9 + 2.0 + 6.8 4.2 1, 8 1.87 ^{***, ###} 65.5 -24.0 Capecitabine + Oxaliplatin 360 4.2 1, 8 2.94 ^*** 45.7 －26.4

***: group in which an effective (P <0.01) effect was obtained for the control group.

###: Effective (P <0.01) effect is obtained for the capecitabine + oxaliplatin group

     Jin-gun

From the results of the comparison of efficacy between the above maximum tolerated doses, the combination therapy of tegapur, gimeracil, and terrasil potassium compound and l-OHP clearly showed an anti-tumor effect exceeding the combination therapy of capecitabine and l-OHP. Indicated. In addition, systemic toxicity (weight loss) was about the same.

From the results of the above test example, the combination therapy of tegapur, gimeracyl, and terrasil potassium mixtures and l-OHP was not associated with a significant increase in side effects. Compared with the case, it was found to significantly increase antitumor activity. In addition, the antitumor effect in this case suggests that it is an effective treatment even when the conventional standard therapy, tegapur and lausyl compound and d, l-calcium phosphate are used in combination and capecitabine is used in combination. It became. In addition, conventionally, in the recurrence after the treatment centered on pyrimidine fluoride, the regimen to be administered centered on fluoride fluoride has been shown to have low usefulness. In the case of the oterasyl potassium compound, the combination of l-OHP was expected to continue the therapy without significantly increasing the side effects. In addition, when an anti-tumor effect of l-OHP hardly exhibited an anti-tumor effect, the effective anti-tumor effect was obtained when a tegapur, gimeracil, orteracyl potassium compound and l-OHP were administered in combination. It was suggested that the enhancement of the antitumor effect exhibited by the combination of OHP was due to the antitumor effect enhancing activity of l-OHP to tegafur, gimeracil and octeracyl potassium mixtures. The results of tests using multi-drug resistant tumors also suggested that the combination of tegapur, gimeracil, and terrasil potassium blends and l-OHP was useful even when many anticancer drugs were not susceptible (with resistance).

Prescription Example

Hereinafter, the prescription examples of the anti-tumor effect enhancer and anti-tumor agent of the present invention.

Prescription Example 1: Injection

l-OHP 100mg

50 ml of 5% glucose solution

50 ml per ampoule

An injection was prepared in the said compounding ratio by the conventional method.

Prescription 2: Granule

Tegapur 50mg

Kimeracil 14.5mg

Oteracil Potassium 49mg

l-OHP 55mg

Lactose 280mg

Cornstarch 298mg

Hydroxypropylmethylcellulose          10mg

756.5mg per package

The granule was prepared by the said compounding ratio by the said conventional method.

Formulation Example 3: Capsule

Tegapur 25mg

Gimeracil 7.25mg

Oteracil Potassium 24.5mg

l-OHP 40mg

Lactose 51mg

Crystalline cellulose 28mg

Magnesium stearate                     5mg

180.75mg per capsule

The capsule was prepared by the said compounding ratio by the said compounding ratio.

Prescription 4: Tablet

Tegapur 20mg

Gimeracil 5.8mg

Oteracil Potassium 19.6mg

l-OHP 39.6mg

Lactose 51mg

Crystalline Cellulose 15mg

Magnesium Stearate 3mg

Cornstarch 14mg

Hydroxypropylmethylcellulose          10mg

178.0mg per tablet

The tablet was prepared by the said compounding ratio by the conventional method.

Prescription 5: suppository

Tegapur 200mg

Kimeracil 58mg

Oteracil Potassium 196mg

l-OHP 396mg

Uthezol W-35 1150mg

2000mg each

A suppository was prepared by the said compounding ratio by the conventional method.

According to the antitumor effect enhancers, cancer therapies, antitumor agents, kits, and the like of the present invention, the known antitumor agents of tegapur, gimeracyl, and terrasil potassium without increasing the toxicity (especially the digestive tract and bone marrow toxicity) It is possible to obtain an antitumor effect that exceeds the effect of the triple agent formulation and the effect of the 1-OHP alone formulation. In addition, the anti-tumor effect is a combination therapy of tegapur and uracil formulations and d, l-folate, one of the standard therapies for treating colorectal cancer, and tegapur and uracil combinations, d, l-folate and l-. It is superior to the antitumor effect by the combination therapy of OHP. In addition, excellent anti-tumor effect enhancing or anti-tumor effects can be expected for 5-FU resistant tumors or multi-drug resistant tumors.

Claims (14)

A therapeutically effective amount of Tegapur, an anti-tumor effect, comprising an effective amount of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) as an active ingredient for enhancing antitumor effect To enhance the antitumor activity of antitumor agents containing an amount of gimeracil effective for enhancement and an amount of oterasyl potassium effective for suppressing side effects. Anti-tumor effect enhancers. The method of claim 1, The antitumor agent contains tegapur, gimeracil and potassium terasil in a molar ratio of tegapur: kimeracil: oterathyl potassium = 1: 0.4: 1 Anti-tumor effect enhancers. The method of claim 1, The active ingredient ratio of the antitumor agent is 0.1-5 mol of gimeracil and 0.1-5 mol of potassium terrasil with respect to 1 mol of tegafur, and cis-oxalate with respect to 1 mol of tegafur contained in the antitumor agent. (1R, 2R-diaminocyclohexane) used to make platinum (II) 0.1 to 5 mol Anti-tumor effect enhancers. The method of claim 3, wherein The active ingredient molar ratio of the anti-tumor agent is tegapur: kimeracil: oterathyl potassium = 1: 0.4: 1, and cis-oxalate (1R, 2R-) is used for 1 mole of tegafur contained in the anti-tumor agent. Diaminocyclohexane) platinum (II) is used to 0.1 to 5 moles Anti-tumor effect enhancers. Consists of a plurality of preparations each comprising, alone or in any combination, an active ingredient consisting of tegapur, gimeracyl, potassium terasil and cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II). Or in the form of a formulation consisting of one formulation comprising all active ingredients Antitumor agents. The method of claim 5, wherein It consists of the formulation which makes three components of tegapur, gimeracyl, and octeracyl potassium an active ingredient, and the formulation which uses cis-oxalate (1R, 2R- diaminocyclohexane) platinum (II) as an active ingredient. Formulation form Antitumor agents. The method according to claim 5 or 6, The ratio of active ingredient is 0.1-5 mol of gimeracyl, 0.1-5 mol of potassium terrasil, and cis-oxalate (1R, 2R- diaminocyclohexane) platinum (II) 0.1-5 with respect to 1 mol of tegapur. Driving Antitumor agents. The method of claim 7, wherein The molar ratio of the active ingredient is tegapur: gimeracyl: oteracyl potassium: cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) = 1: 0.4: 1: 0.1 to 5 Antitumor agents. The method of claim 5, wherein A therapeutically effective amount of tegapur, an effective amount of gimeracil to enhance anti-tumor effects, and an effective amount of oterasyl potassium to inhibit side effects, simultaneously with or within 4 hours before or after administration of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) is administered Antitumor agents. (a) an antitumor composition containing tegapur in an amount effective for treatment, an amount of gimeracil for enhancing antitumor effect and an amount of oterasyl potassium for suppressing side effects, and (b) an antitumor effect Consisting of a combination of pharmaceutical compositions for the treatment of cancer in mammals consisting of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) in an amount effective for enhancement Kit. The method of claim 10, (a) cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) is administered simultaneously or within 4 hours before or after administration of the anti-tumor composition Kit. A therapeutically effective amount of Tegapur, for enhancing antitumor effect, characterized by adding an effective amount of cis-oxalate (1R, 2R-diaminocyclohexane) platinum (II) to enhance antitumor effect. A method for preparing an anti-tumor effect enhancer which enhances the effect of an anti-tumor agent containing an effective amount of gimeracil and an effective amount of oterasyl potassium for suppressing side effects. Effective amount of tegapur, effective amount of gimeracil to enhance anti-tumor effect, effective amount of oteracil potassium to inhibit side effects, and effective amount of cis-oxalate to enhance anti-tumor effect (1R, A method for producing an anti-tumor agent, characterized by containing 2R-diaminocyclohexane) platinum (II). delete