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WO2019176985A1 - Antitumor agent, antitumor effect potentiator and antitumor kit - Google Patents

Antitumor agent, antitumor effect potentiator and antitumor kit Download PDF

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Publication number
WO2019176985A1
WO2019176985A1 PCT/JP2019/010170 JP2019010170W WO2019176985A1 WO 2019176985 A1 WO2019176985 A1 WO 2019176985A1 JP 2019010170 W JP2019010170 W JP 2019010170W WO 2019176985 A1 WO2019176985 A1 WO 2019176985A1
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cancer
antitumor
salt
tumor
alkylating agent
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French (fr)
Japanese (ja)
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山田　孝之
和徳 佐伯
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Fujifilm Corp
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Fujifilm Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an antitumor agent, an antitumor effect enhancer, and an antitumor kit.
  • Compound A (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (hereinafter sometimes referred to as “compound A”) has excellent antitumor activity, It is known to be useful as an antitumor agent (Patent Document 1). Compound A is also known to have strong antitumor activity even after oral administration to mice (Non-Patent Documents 1 and 2). Further, a salt of Compound A and a production method thereof are also known (Patent Documents 2 to 4).
  • antitumor drugs with enhanced antitumor effects by combining specific acylthiourea compounds with antitumor agents such as paclitaxel, gemcitabine, rapanitib, decafur, gimeracil, oteracil potassium, irinotecan) are known (Patent Document 5).
  • alkylating agents are known as representative agents of antitumor agents.
  • Representative alkylating agents include cyclophosphamide, ifosfamide, melphalan, busulfan, ranimustine, nimustine, temozolomide, and the like, which are used for the treatment of various malignant tumors.
  • high nephrotoxicity, hemorrhagic cystitis and resistant cancer are prone to be induced in clinical settings (Non-Patent Documents 3 to 5).
  • multi-drug combination therapy is performed to compensate for the difference in sensitivity of each anti-tumor agent to the tumor and enhance its efficacy, and various alkylating agents can be used in combination with various drugs. Approval or development of combination therapy for multiple tumors. However, even if the alkylating agent has an antitumor effect, the antitumor action enhancing effect is not always obtained by using it together with other drugs.
  • An object of the present invention is to provide an antitumor agent, an antitumor kit, and an antitumor effect potentiator that have an excellent antitumor effect as compared with gemcitabine, an alkylating agent, and a combination therapy thereof.
  • an antitumor agent comprising an alkylating agent and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof.
  • the alkylating agent is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. Antitumor agent.
  • the tumor is bladder cancer, renal pelvis / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, lung cancer, esophageal cancer, cervical cancer, glioma, neuroblastoma, stomach cancer, bone Sarcoma, germ cell tumor (testis tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, colon cancer, small intestine cancer, malignant lymphoma, breast cancer, pancreatic cancer, liver cancer, renal cancer, malignant melanoma, chronic The antitumor agent according to (1) or (2), which is myeloid leukemia or multiple myeloma.
  • the antitumor agent according to any one of (1) to (3), wherein the tumor is breast cancer or pancreatic cancer.
  • An antitumor effect potentiator comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof used in combination with an alkylating agent.
  • An antitumor kit comprising a preparation containing an alkylating agent and a preparation containing 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof.
  • An antitumor agent comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof used in combination with an alkylating agent.
  • the alkylating agent is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. Antitumor effect enhancer.
  • the alkylation is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. Anti-tumor kit. (7-1) The alkylation is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. Antitumor agent.
  • Effective therapeutic dose when 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof is used in combination therapy, and combined treatment with alkylating agent
  • a therapeutic method for a tumor which comprises administering to a subject in combination with a therapeutically effective dose when used in the above.
  • Effective therapeutic dose when 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof is used in combination treatment, and combination treatment with alkylating agent
  • a method of treating a tumor comprising administering to a subject a therapeutically effective dose when used in a method simultaneously, separately, sequentially or at intervals.
  • the daily dose of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof is 20 to 200 mg / m 2 (1 ) Or (2).
  • Compound A or a salt thereof exhibits a remarkable antitumor effect when used in combination with an alkylating agent. That is, the antitumor agent and antitumor kit of the present invention have an excellent tumor growth inhibitory effect as compared with gemcitabine alone, an alkylating agent alone, or a combination of gemcitabine and an alkylating agent.
  • the antitumor effect enhancer of the present invention can enhance the antitumor effect by co-administering in combination with an alkylating agent.
  • FIG. 1 is a graph showing the combined effect of Compound A and temozolomide on the cell viability of human pancreatic cancer-derived cell line SUIT-2.
  • the range represented by “to” includes values at both ends unless otherwise specified.
  • the “subject” is a mammal such as a human, a mouse, a monkey, a domestic animal or the like in need of the prevention or treatment, and preferably a human in need of the prevention or treatment.
  • Prevention means inhibition of onset, reduction of onset risk or delay of onset.
  • Treatment means improvement of a target disease or condition or suppression (maintenance or delay) of progression.
  • Treatment means prevention or treatment of various diseases.
  • Tuor means benign or malignant tumor.
  • Benign tumor means a tumor in which the tumor cells and their sequences are close to the normal cells from which they are derived and which are not invasive or metastatic.
  • Malignant tumor means a tumor that is different from the normal cells from which the morphology and sequence of the tumor cells are derived, and exhibits invasive or metastatic properties.
  • the present invention is an antitumor agent comprising an alkylating agent and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (Compound A) or a salt thereof.
  • the present invention is also an antitumor agent comprising a combination of an alkylating agent and Compound A or a salt thereof.
  • “combination” means a combination for using compounds in combination, and includes both forms in which different substances are used at the time of administration, and forms as a mixture (compound).
  • “combination” does not mean that the administration timing of the compound of the present invention and the alkylating agent is completely the same.
  • one administration schedule includes an embodiment in which the compound of the present invention and the alkylating agent are administered, the form in which these are administered simultaneously or separately means “combination”.
  • the alkylating agent may be administered after the compound of the invention has been administered first.
  • the compound of the present invention may be administered after the alkylating agent is administered first.
  • salt examples include pharmaceutically acceptable salts, and specific examples include mineral acid salts, organic carboxylate salts, and sulfonate salts.
  • Preferred salts include mineral acid salts and sulfonic acid salts.
  • Examples of mineral acid salts include hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, and sulfate, and hydrochloride, hydroiodide, nitrate, and sulfate are preferable. Hydrochloride is more preferable.
  • Examples of organic carboxylates include formate, acetate, citrate, oxalate, fumarate, maleate, succinate, malate, tartrate, aspartate, trichloroacetate and Examples include trifluoroacetate.
  • sulfonate examples include methanesulfonate, benzenesulfonate, p-toluenesulfonate, mesitylenesulfonate, and naphthalenesulfonate, and methanesulfonate is preferable.
  • the salt of Compound A may be an anhydride, hydrate or solvate.
  • the form may be an anhydride, hydrate or solvate.
  • the term “anhydride” as used herein refers to a case in which it is in a state that is neither a hydrate nor a solvate, unless otherwise specified. Originally, even if the substance does not form a hydrate or solvate, the salt of Compound A having no water of crystallization, water of hydration and an interactive solvent is included in the “anhydride” in the present invention. . An anhydride may be referred to as an “anhydrate”.
  • the number of hydrated water is not particularly limited, and may be a monohydrate, a dihydrate or the like.
  • solvates include methanol solvates, ethanol solvates, propanol solvates and 2-propanol solvates.
  • particularly preferable salts of the compound A are as follows.
  • compound A or a salt thereof may be used alone or in combination of two or more.
  • Compound A can be produced, for example, by the method described in Patent Document 1 and Journal of Organic Chemistry, 1999, Vol. 64, pages 7912-7920.
  • the salt of compound A or a hydrate or solvate thereof can be produced, for example, by the method described in Patent Document 4.
  • the compound A or a salt thereof according to the present invention can be used as an antitumor agent or as an active ingredient of a pharmaceutical composition.
  • alkylating agent examples include cyclophosphamide, ifosfamide, dacarbazine, temozolomide, nimustine, ranimustine, bendamustine, busulfan, procarbazine, melphalan, thiotepa, and carbocon.
  • the alkylating agent of the present invention is preferably cyclophosphamide, ifosfamide, dacarbazine, temozolomide, nimustine, ranimustine, busulfan, procarbazine, melphalan or thiotepa, more preferably cyclophosphamide or temozolomide.
  • alkylating agents can be produced by known methods. Moreover, these alkylating agents can also be obtained by purchasing a commercial item.
  • cyclophosphamide is commercially available as Endoxan (registered trademark) from Shionogi & Co., Ltd.
  • Ifosfamide is commercially available as Ifomide (registered trademark) from Shionogi & Co., Ltd.
  • dacarbazine is commercially available as dacarbazine (registered trademark) from Kyowa Hakko Kirin Co., Ltd.
  • Temozolomide is commercially available from MSD Corporation as Temodal®.
  • Nimustine is commercially available from Daiichi Sankyo Co., Ltd. as Nidran (registered trademark).
  • Ranimustine is commercially available as Cymerin (registered trademark) from Nipro ES Pharma Co., Ltd.
  • Busulfan is commercially available from Otsuka Pharmaceutical Co., Ltd. as Busulfex (registered trademark) or from Ohara Pharmaceutical Co., Ltd. as Mablin (registered trademark).
  • Procarbazine is commercially available from Chugai Pharmaceutical Co., Ltd. as procarbazine hydrochloride.
  • Melphalan is commercially available as Alquelan (registered trademark) from Aspen Japan.
  • the alkylating agent may form a pharmaceutically acceptable salt (hereinafter sometimes referred to as “the salt”) with an acid or a base.
  • the alkylating agent of the present invention includes these pharmaceutically acceptable salts. Only one alkylating agent may be used, or two or more alkylating agents may be contained.
  • the alkylating agent may be a composition containing them in addition to the alkylating agent or a salt thereof.
  • the salt include pharmaceutically acceptable salts, and specific examples include salts that are generally known in basic groups such as amino groups and acidic groups such as hydroxyl groups and carboxyl groups.
  • Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
  • mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid
  • formic acid acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid
  • Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And the salt.
  • alkali metals such as sodium and potassium
  • salts with alkaline earth metals such as calcium and magnesium
  • ammonium salts and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethy
  • Compound A is an antitumor agent having an excellent DNA synthesis inhibitory action.
  • Compound A is used in combination with an alkylating agent, it is expected to have an action of enhancing the antitumor effect of the alkylating agent without showing a marked increase in toxicity.
  • An antitumor agent comprising an alkylating agent and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof; and An antitumor agent comprising-(2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof: Is provided.
  • the antitumor agent of the present invention is usually used for formulation, excipients, binders, lubricants, disintegrants, colorants, flavoring agents, emulsifiers, surfactants, solubilizers, suspending agents.
  • Additives such as agents, tonicity agents, buffers, preservatives, antioxidants, stabilizers and absorption enhancers may be included.
  • the antitumor agent of the present invention containing an alkylating agent and compound A or a salt thereof is an alkylating agent and compound A or a salt thereof, even if it is a one-part preparation containing an alkylating agent and compound A or a salt thereof. It may be a two-part preparation containing a salt. Preferably, it is a two-drug preparation in which the alkylating agent and Compound A or a salt thereof are separate preparations.
  • each formulation can be administered to the subject simultaneously, separately, sequentially, or at intervals.
  • the administration means of the composition containing the alkylating agent and the administration means of the composition containing Compound A may be the same or different (for example, oral administration and injection).
  • the administration route of the antitumor agent of the present invention includes intravenous, intraarterial, rectal, intraperitoneal, intramuscular, intratumoral or intravesical injection, oral administration, transdermal administration and / or suppository. Is mentioned.
  • parenteral administration is preferable.
  • intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and / or intrathecal injection can be mentioned.
  • Examples of the administration method include administration by syringe or infusion.
  • the dosage or compounding amount of the alkylating agent and compound A or a salt thereof contained in the antitumor agent of the present invention is not particularly limited as long as the antitumor effect is enhanced.
  • the amount of the compound A of the present invention to be used varies depending on the individual combination with the alkylating agent, but is, for example, about 0.0001 to 10,000 times (weight ratio) of the alkylating agent, preferably about 0.001 to 1000 times (weight ratio).
  • the combination of Compound A and temozolomide is not particularly limited.
  • the dose of Compound A of the present invention is 20 to 200 mg / m 2 , preferably 40 to 200 mg / day per adult. m 2 , more preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2, and the dosage of temozolomide is 10 to 1000 mg / m 2 , preferably 20 to 200 mg / m 2 per day for an adult. More preferably, the dose is 50 to 150 mg / m 2, and the dose of the compound of the present invention is about 0.02 to 20 times (weight ratio), preferably about 0.53 to 3 times (weight ratio) of temozolomide. To be.
  • the dose of the compound A of the present invention is 20 to 200 mg / m 2 , preferably 40 to 200 mg per day for an adult. / M 2 , more preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2, and the dose of cyclophosphamide is 20 to 2000 mg / m 2 , preferably 30 to 1500 mg / m 2 , more preferably 50 to 1000 mg / m 2, and the dose of the compound of the present invention is about 0.01 to 10 times (weight ratio) of cyclophosphamide, preferably about 0.08. ⁇ 3 times (weight ratio).
  • the dose and frequency of administration of the alkylating agent may be, for example, 1 to 1000 mg / m per day by oral or parenteral (eg injection, infusion and administration to the rectal site) for adults. 2 can be administered in one to several divided doses. If the patient experiences excessive toxicity, a dose reduction is necessary. Dosage amount and regimen may be altered if one or more additional chemotherapeutic agents are used in addition to the combination therapy of the invention. The dosage regimen can be determined by the physician treating the particular patient.
  • 1 to 2000 mg / m 2 per day can be administered in 1 to several divided doses. However, it is not limited to these doses and administration methods.
  • the daily dose of Compound A or a salt thereof is 20 mg / m 2 or more, preferably 40 mg / m 2 or more, preferably 60 mg / m 2 or more, preferably 80 mg / m 2 or more.
  • the upper limit of the dose per day is 200 mg / m 2 , preferably 150 mg / m 2 , more preferably 120 mg / m 2 , and particularly preferably 100 mg / m 2 .
  • the daily dose is more preferably 40 to 200 mg / m 2 , further preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2 , and even more preferably 80 to 120 mg / m 2 .
  • the daily dose is preferably 20 to 120 mg / m 2 , more preferably 40 to 120 mg / m 2 , still more preferably 40 to 100 mg / m 2 , and more More preferably, it is 60 to 100 mg / m 2 .
  • a single dose may be 20 to 200 mg / m 2, and a course in which the drug is withdrawn in the 4th week after repeated administration once a week for 3 weeks may be repeated several times. it can.
  • the single dose is the same as the above-mentioned daily dose, preferably 40 to 200 mg / m 2 , more preferably 40 to 150 mg / m 2 , and still more preferably 80 ⁇ 150 mg / m 2 .
  • the dose per administration is preferably 20 to 120 mg / m 2 , more preferably 40 to 120 mg / m 2 , and still more preferably 40 to 100 mg / m 2 .
  • dosage forms of the antitumor agent of the present invention include tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, suppositories, eye drops, nasal drops, ear drops Although an agent, a patch, an ointment, and an injection are mentioned, an injection is preferable.
  • Each of these dosage forms can be produced by conventional formulation methods known to those skilled in the art.
  • the antitumor agent of the present invention is preferably an antineoplastic agent and can be used as an anticancer agent.
  • Antitumor agents of the present invention include, for example, bladder cancer, renal pelvis / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, lung cancer, esophageal cancer, cervical cancer, glioma, neuroblastoma, Gastric cancer, osteosarcoma, germ cell tumor (testis tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, colon cancer, small intestine cancer, malignant lymphoma, breast cancer, pancreatic cancer, liver cancer, renal cancer, malignant black It can be used effectively for the treatment of various types of tumors including tumors, chronic myelogenous leukemias, multiple myeloma or other organ tumors.
  • prostate cancer osteosarcoma, germ cell tumor, malignant bone / soft tissue tumor, multiple myeloma, malignant lymphoma, breast cancer, lung cancer, uterine cancer, ovarian cancer, pancreatic cancer, malignant melanoma, neuroblastoma, retinoblast Tumor, thyroid cancer, stomach cancer, liver cancer, colon cancer or chronic myelogenous leukemia are preferred, and particularly effective for the treatment of pancreatic cancer or breast cancer.
  • the present invention also relates to an antitumor effect potentiator comprising Compound A or a salt thereof for enhancing the antitumor effect of an alkylating agent for cancer patients. That is, according to the present invention, An antitumor effect potentiator comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof in combination with an alkylating agent is provided.
  • the antitumor effect potentiator of the present invention is usually an excipient, a binder, a lubricant, a disintegrant, a colorant, a flavoring agent, an emulsifier, a surfactant, a solubilizing agent, a suspension, Additives such as turbidity agents, tonicity agents, buffers, preservatives, antioxidants, stabilizers and absorption enhancers may be included.
  • the antitumor effect potentiator of the present invention can be administered to a subject simultaneously, separately or at intervals with the alkylating agent.
  • parenteral administration is preferable.
  • intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and intrathecal injection
  • administration method include administration by syringe or infusion.
  • the dose or amount of compound A or a salt thereof contained in the antitumor effect potentiator of the present invention is not particularly limited as long as it exhibits a potentiating effect on the antitumor effect.
  • the amount of the compound A of the present invention to be used varies depending on the individual combination with the alkylating agent, but is, for example, about 0.0001 to 10,000 times (weight ratio) of the alkylating agent, preferably about 0.001 to 1000 times (weight ratio).
  • 1 to 2000 mg / m 2 can be divided into 1 to several times per day. . However, it is not limited to these doses and administration methods.
  • the daily dose of Compound A or a salt thereof is 20 mg / m 2 or more, preferably 40 mg / m 2 or more, preferably 60 mg / m 2 or more, preferably 80 mg / m 2 or more.
  • the upper limit of the dose per day is 200 mg / m 2 , preferably 150 mg / m 2 , more preferably 120 mg / m 2 , and particularly preferably 100 mg / m 2 .
  • the dose per day is more preferably 40 to 200 mg / m 2 , further preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2 , and still more preferably 80 to 120 mg. / M 2 .
  • the daily dose is preferably 20 to 120 mg / m 2 , more preferably 40 to 120 mg / m 2 , still more preferably 40 to 100 mg / m 2 , and more More preferably, it is 60 to 100 mg / m 2 .
  • a single dose may be 20 to 200 mg / m 2, and a course in which the drug is withdrawn in the 4th week after repeated administration once a week for 3 weeks may be repeated several times. it can.
  • the single dose is the same as the above-mentioned daily dose, preferably 40 to 200 mg / m 2 , more preferably 40 to 150 mg / m 2 , and still more preferably 80 ⁇ 150 mg / m 2 .
  • the dose per administration is preferably 20 to 120 mg / m 2 , more preferably 40 to 120 mg / m 2 , and still more preferably 40 to 100 mg / m 2 .
  • the antitumor effect enhancer of the present invention is preferably an antimalignant effect enhancer and can be used as an anticancer effect enhancer.
  • Antitumor effect potentiators of the present invention include bladder cancer, renal pelvis / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, lung cancer, esophageal cancer, cervical cancer, glioma, neuroblastoma, Gastric cancer, osteosarcoma, germ cell tumor (testis tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, colon cancer, small intestine cancer, malignant lymphoma, breast cancer, pancreatic cancer, liver cancer, renal cancer, malignant black It can be used effectively for the treatment of various types of tumors including tumors, chronic myelogenous leukemias, multiple myeloma or other organ tumors.
  • prostate cancer osteosarcoma, germ cell tumor, malignant bone / soft tissue tumor, multiple myeloma, malignant lymphoma, breast cancer, lung cancer, uterine cancer, ovarian cancer, pancreatic cancer, malignant melanoma, neuroblastoma, retinoblast Tumor, thyroid cancer, stomach cancer, liver cancer, colon cancer or chronic myelogenous leukemia are preferred, and particularly effective for the treatment of pancreatic cancer or breast cancer.
  • an antitumor kit comprising a preparation containing an alkylating agent and a preparation containing 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof.
  • the antitumor kit of the present invention is a kit comprising a combination of (a) an alkylating agent and (b) compound A or a salt thereof. Further, in the above kit, (a) the alkylating agent and (b) compound A or a salt thereof can be in various known preparation forms, and are accommodated in various commonly used containers according to the preparation form. Is done.
  • the alkylating agent and (b) compound A or a salt thereof may be stored in separate containers, or may be mixed and stored in the same container. It is preferable that (a) the alkylating agent and (b) compound A or a salt thereof are respectively contained in separate containers.
  • the present invention provides an alkylating agent and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof, preferably for use in the treatment of tumors.
  • a method for use in the treatment of pancreatic cancer or breast cancer comprising the step of administering a therapeutically effective dose to a subject in need of such treatment (mammals including humans).
  • the present invention also provides a therapeutically effective dose when 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof is used in combination therapy, and an alkylating agent.
  • a method for treating a tumor characterized by being administered to a subject in combination with a therapeutically effective dose when used in combination therapy.
  • the present invention provides a therapeutically effective dose when 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof is used in combination therapy, and an alkylating agent.
  • a method of treating a tumor characterized in that a therapeutically effective dose when used in combination therapy is administered to a subject simultaneously, separately, sequentially or at intervals.
  • cytosine or a salt thereof can be used for the production of an antitumor agent in combination with an alkylating agent.
  • cytosine or a salt thereof can be used for an antitumor agent in combination with an alkylating agent.
  • D-arabinofuranosyl) cytosine or a salt thereof can be obtained.
  • Example 1 A methanesulfonate salt of 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (Compound A) was synthesized by the method described in International Publication No. 2013/146833 pamphlet. did.
  • SUIT-2 cells a human pancreatic cancer cell line
  • 10% serum Cat. # 10437-028 manufactured by Thermo Fisher Scientific Inc.
  • RPMI-1640 10% serum (Cat. # 10437-028 manufactured by Thermo Fisher Scientific Inc.) medium RPMI-1640.
  • All cell cultures were performed in a CO 2 incubator (37 ° C, 5% CO 2 setting, steam saturation).
  • the solution was diluted with 10% serum medium to 15000 cells / well / 100 ⁇ L and seeded in a 96-well plate.
  • the culture supernatant of each well was discarded, washed twice with 150 ⁇ L of serum-free medium, and 100 ⁇ L of serum-free medium was added and cultured for 3 days.
  • Methanesulfonic acid salt of compound A and gemcitabine were dissolved in DMSO to prepare 100 mmol / L DMSO solutions, respectively.
  • a DMSO solution having a concentration 1000 times the final treatment concentration was sequentially diluted with DMSO.
  • Temozolomide was dissolved in a serum-free medium to prepare a Temozolomide solution of 1200 ⁇ mol / L.
  • a DMSO diluted solution of Compound A and Gemcitabine was diluted with a Temozolomide solution (1200 ⁇ mol / L) to prepare treatment solutions each having a concentration 6 times the final treatment concentration.
  • Compound A and Gemcitabine were used in combination with Temozolomide with a maximum concentration of 10 ⁇ mol / L and a common ratio of 1/3 and 9 concentrations.
  • 20 ⁇ L of Compound A or Gemcitabine diluted with Temozolomide solution (1200 ⁇ mol / L) was added to each well.
  • a group in which only a solvent without a drug was added to a well in which cells were seeded positive control group
  • the cells were cultured for 3 days, and the cell viability was evaluated using CellTiter Glo (registered trademark) Reagent (cat. # G7570 manufactured by PROMEGA Co.) using the intracellular ATP amount as an index.
  • the concentration IC50 value that inhibits cell viability by 50% was calculated using XLFit software Ver.3 (registered trademark) (manufactured by CTC).
  • the cell viability of each well was determined with the amount of luminescent signal in the negative control group as 0% cell viability and the amount of luminescent signal in the positive control group as 100% cell viability.
  • the average value and standard deviation of the cell viability of each treatment group were calculated, and Table 1 was created.
  • the IC50 value when gemcitabine and temozolomide calculated from Table 1 were used together was 10,000 nmol / L (nM) or more, and the IC50 value when compound A and temozolomide were used together was 279.2 nmol / L.
  • Compound A significantly enhanced the antitumor effect of temozolomide. The effect was thought to be greater than the existing drug gemcitabine. A more detailed description will be given later.
  • CI Combination Index
  • the administration cycle is repeated for cancer patients by intravenous injection of compound A and oral administration of temozolomide for 5 consecutive days and withdrawn for 16 days or more.
  • the dose per administration of Compound A is 8 to 135 mg / m 2, and the dose of temozolomide is 20 to 200 mg / m 2 .
  • compound A is intravenously injected on day 1 and temozolomide is orally administered to cancer patients, and only temozolomide is orally administered from day 2 to day 5, Repeat the dosing cycle with a withdrawal of 16 days or more.
  • the dose per administration of Compound A is 8 to 135 mg / m 2, and the dose of temozolomide is 20 to 200 mg / m 2 .
  • the dosing cycle of administering compound A and cyclophosphamide to the cancer patient by intravenous injection and withdrawing the drug for 20 days is repeated. Repeat this for 4 to 6 cools.
  • the dose per administration of Compound A is 8 to 135 mg / m 2
  • the dose of cyclophosphamide is 50 to 1000 mg / m 2 .
  • the effect of treatment can be determined according to the following criteria.
  • the evaluation object was confirmed by diagnostic imaging using magnetic resonance imaging (MRI), and judged according to the following criteria.
  • MRI magnetic resonance imaging
  • CR Complete Response
  • PR Partial Response
  • SD Stable Disease
  • Tumor size does not change
  • PD Progressive Disease
  • the present invention is useful as an antitumor agent and an antitumor kit exhibiting a remarkable antitumor effect, and an antitumor effect enhancer.

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Abstract

The present invention addresses the problem of providing an antitumor agent and an antitumor kit having a superior antitumor effect in comparison to gemcitabine, an alkylating agent and a combination therapy thereof, and an antitumor effect potentiator. Provided is an antitumor agent that comprises an alkylating agent and 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine or a salt thereof.

Description

抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キットAntitumor agent, antitumor effect potentiator and antitumor kit

　本発明は、抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キットに関する。 The present invention relates to an antitumor agent, an antitumor effect enhancer, and an antitumor kit.

　１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシン（以下、「化合物Ａ」と称することがある。）は、優れた抗腫瘍活性を有し、抗腫瘍剤として有用であることが知られている（特許文献１）。また化合物Ａは、マウスへの経口投与でも強い抗腫瘍活性を有することが知られている（非特許文献１、２）。また化合物Ａの塩及びその製造方法についても知られている（特許文献２～４）。さらに、特定のアシルチオウレア化合物と、抗腫瘍剤（パクリタキセル、ゲムシタビン、ラパニチブ、デカフール・ギメラシル・オテラシルカリウム配合剤、イリノテカン等）とを組み合せることにより抗腫瘍効果が増強された抗腫瘍薬が知られている（特許文献５）。 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (hereinafter sometimes referred to as “compound A”) has excellent antitumor activity, It is known to be useful as an antitumor agent (Patent Document 1). Compound A is also known to have strong antitumor activity even after oral administration to mice (Non-Patent Documents 1 and 2). Further, a salt of Compound A and a production method thereof are also known (Patent Documents 2 to 4). Furthermore, antitumor drugs with enhanced antitumor effects by combining specific acylthiourea compounds with antitumor agents (such as paclitaxel, gemcitabine, rapanitib, decafur, gimeracil, oteracil potassium, irinotecan) are known (Patent Document 5).

　癌化学療法において、アルキル化剤は抗腫瘍剤の代表的薬剤として知られている。代表的なアルキル化剤として、シクロホスファミド、イホスファミド、メルファラン、ブスルファン、ラニムスチン、ニムスチン及びテモゾロミド等を挙げることができ、様々な悪性腫瘍に対する治療に用いられている。しかし、高い腎毒性、出血性膀胱炎及び耐性がんを誘発しやすいことが臨床の場で問題となっている（非特許文献３～５）。 In cancer chemotherapy, alkylating agents are known as representative agents of antitumor agents. Representative alkylating agents include cyclophosphamide, ifosfamide, melphalan, busulfan, ranimustine, nimustine, temozolomide, and the like, which are used for the treatment of various malignant tumors. However, high nephrotoxicity, hemorrhagic cystitis and resistant cancer are prone to be induced in clinical settings (Non-Patent Documents 3 to 5).

　臨床の場では、各抗腫瘍剤の腫瘍に対する感受性の違いを補い、薬効を増強すること等を目的として、多剤併用療法が行われており、アルキル化剤も種々の薬剤との組み合わせによる種々の腫瘍に対する併用療法が承認または開発されている。しかしながら、アルキル化剤が抗腫瘍効果を有するものであっても、必ずしも他の薬剤と併用することで抗腫瘍作用の増強効果が得られるとは限らない。 In clinical settings, multi-drug combination therapy is performed to compensate for the difference in sensitivity of each anti-tumor agent to the tumor and enhance its efficacy, and various alkylating agents can be used in combination with various drugs. Approval or development of combination therapy for multiple tumors. However, even if the alkylating agent has an antitumor effect, the antitumor action enhancing effect is not always obtained by using it together with other drugs.

国際公開第１９９７／０３８００１号パンフレットInternational Publication No. 1997/038001 Pamphlet 国際公開第２０１３／１４６８３３号パンフレットInternational Publication No. 2013/146833 Pamphlet 国際公開第２０１１／０７４４８４号パンフレットInternational Publication No. 2011/074484 Pamphlet 国際公開第２０１４／０２７６５８号パンフレットInternational Publication No. 2014/027658 Pamphlet 国際公開第２０１３／１０００１４号パンフレットInternational Publication No. 2013/100014 Pamphlet

キャンサー・レターズ（Cancer Letters）、１９９９年、第１４４巻、ｐ１７７－１８２Cancer Letters, 1999, vol. 144, pp. 177-182 オンコロジー・レポーツ（Oncology Reports）、２００２年、第９巻、ｐ１３１９－１３２２Oncology Reports, 2002, Vol. 9, pp. 1319-1322 薬局、２００７年、第５８巻、Ｎｏ．２、ｐ９２－９６Pharmacy, 2007, Vol. 2, p92-96 ザ・ジャーナル・オブ・ウロロジー（Journal of Urology）、１９９０年、第１４３巻、Issue 1、ｐ１－９The Journal of Urology, 1990, volume 143, Issue 1, p1-9 日本薬理学雑誌(Folia Pharmacologica Japonica)、２００６年、第１２７巻、ｐ３４２－３４７Journal of Japanese Pharmacology (Folia Pharmacologica Japonica), 2006, 127, p342-347

　近年では、抗腫瘍剤を単独で投与するのではなく、併用療法が広く行われている。しかしながら、いかなる抗腫瘍剤を組み合わせて使用した場合に、それらの抗腫瘍効果が増強されるのか、あるいは効果が相殺されるのかについてはまったく不明である。
　本発明の課題は、ゲムシタビン、アルキル化剤及びそれらの併用療法と比較して、抗腫瘍効果に優れた抗腫瘍剤及び抗腫瘍用キット、並びに抗腫瘍効果増強剤を提供することにある。 In recent years, anti-tumor agents are not administered alone, but combination therapy is widely performed. However, it is completely unclear whether any anti-tumor agent is used in combination to enhance or counteract their anti-tumor effect.
An object of the present invention is to provide an antitumor agent, an antitumor kit, and an antitumor effect potentiator that have an excellent antitumor effect as compared with gemcitabine, an alkylating agent, and a combination therapy thereof.

　そこで本発明者らは、種々の薬剤の併用を検討した結果、アルキル化剤と化合物Ａとを併用することにより、顕著な抗腫瘍効果を奏することを見出し、本発明を完成するに至った。
　すなわち、本発明は、下記を提供する。
（１）アルキル化剤と、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩とを含む抗腫瘍剤。
（２）上記アルキル化剤が、シクロホスファミド、イホスファミド、ダカルバジン、ニムスチン、テモゾロミド、ブスルファン、プロカルバジン、メルファラン、ラニムスチン及びチオテパからなる群から選ばれる少なくとも１つである、（１）に記載の抗腫瘍剤。
（３）上記腫瘍が、膀胱癌、腎盂・尿管腫瘍、前立腺癌、精巣癌、卵巣癌、頭頸部癌、肺癌、食道癌、子宮頸癌、神経膠腫、神経芽細胞腫、胃癌、骨肉腫、胚細胞腫瘍（精巣腫瘍、卵巣腫瘍、性腺外腫瘍）、悪性胸膜中皮腫、胆道癌、大腸癌、小腸癌、悪性リンパ腫、乳癌、膵臓癌、肝癌、腎癌、悪性黒色腫、慢性骨髄性白血病または多発性骨髄腫である、（１）または（２）に記載の抗腫瘍剤。
（４）上記腫瘍が、乳癌または膵臓癌である、（１）～（３）のいずれか一に記載の抗腫瘍剤。
（５）アルキル化剤と併用される、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を含む抗腫瘍効果増強剤。 
（６）アルキル化剤を含む製剤と、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を含む製剤とを含む抗腫瘍用キット。 
（７）アルキル化剤と併用される、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を含む抗腫瘍剤。
（５－１）上記アルキル化剤がシクロホスファミド、イホスファミド、ダカルバジン、ニムスチン、テモゾロミド、ブスルファン、プロカルバジン、メルファラン、ラニムスチン及びチオテパからなる群から選ばれる少なくとも１つである、（５）に記載の抗腫瘍効果増強剤。
（６－１）上記アルキル化がシクロホスファミド、イホスファミド、ダカルバジン、ニムスチン、テモゾロミド、ブスルファン、プロカルバジン、メルファラン、ラニムスチン及びチオテパからなる群から選ばれる少なくとも１つである、（６）に記載の抗腫瘍用キット。
（７－１）上記アルキル化がシクロホスファミド、イホスファミド、ダカルバジン、ニムスチン、テモゾロミド、ブスルファン、プロカルバジン、メルファラン、ラニムスチン及びチオテパからなる群から選ばれる少なくとも１つである、（７）に記載の抗腫瘍剤。
（８）アルキル化と、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩とを、腫瘍の処置に用いるための、好ましくは乳癌、または膵臓癌の処置に用いるための方法であって、治療有効用量をそのような処置が必要な対象（ヒトを含む哺乳動物）に投与する工程を含む方法。
（９）１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を併用治療に用いる場合の治療有効用量、及び、アルキル化剤を併用治療に用いる場合の治療有効用量とを組み合わせて、対象に投与することを特徴とする、腫瘍の治療方法。
（１０）１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を併用治療に用いる場合の治療有効用量、及び、アルキル化剤を併用治療に用いる場合の治療有効用量を、同時に、別々に、連続して、あるいは間隔をあけて、対象に投与することを特徴とする、腫瘍の治療方法。
（１１）１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩の、アルキル化剤と組み合わせてなる抗腫瘍剤の製造のための使用。
（１２）１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩の、アルキル化剤と組み合わせてなる抗腫瘍剤のための使用。
（１３）アルキル化剤と、一剤型の製剤形態、または別個の製剤形態として投与することにより腫瘍を治療するための、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩。
（１４）１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩の１日当たりの投与量が、２０～２００ｍｇ／ｍ２である、（１）または（２）に記載の抗腫瘍剤。
（１５）アルキル化剤がテモゾロミドであり、１日当たりの投与量が、１０～１０００ｍｇ／ｍ２である、（１４）に記載の抗腫瘍剤。
（１６）アルキル化剤がシクロホスファミドであり、１日当たりの投与量が、２０～２０００ｍｇ／ｍ２である、（１４）に記載の抗腫瘍剤。 Thus, as a result of studying the combined use of various drugs, the present inventors have found that the combined use of an alkylating agent and Compound A has a remarkable antitumor effect, and the present invention has been completed.
That is, the present invention provides the following.
(1) An antitumor agent comprising an alkylating agent and 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof.
(2) The alkylating agent is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. Antitumor agent.
(3) The tumor is bladder cancer, renal pelvis / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, lung cancer, esophageal cancer, cervical cancer, glioma, neuroblastoma, stomach cancer, bone Sarcoma, germ cell tumor (testis tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, colon cancer, small intestine cancer, malignant lymphoma, breast cancer, pancreatic cancer, liver cancer, renal cancer, malignant melanoma, chronic The antitumor agent according to (1) or (2), which is myeloid leukemia or multiple myeloma.
(4) The antitumor agent according to any one of (1) to (3), wherein the tumor is breast cancer or pancreatic cancer.
(5) An antitumor effect potentiator comprising 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof used in combination with an alkylating agent.
(6) An antitumor kit comprising a preparation containing an alkylating agent and a preparation containing 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof.
(7) An antitumor agent comprising 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof used in combination with an alkylating agent.
(5-1) The alkylating agent is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. Antitumor effect enhancer.
(6-1) The alkylation is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. Anti-tumor kit.
(7-1) The alkylation is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. Antitumor agent.
(8) An alkylation and 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof for use in the treatment of a tumor, preferably breast cancer, Alternatively, a method for use in the treatment of pancreatic cancer, comprising the step of administering a therapeutically effective dose to a subject (mammal including a human) in need of such treatment.
(9) Effective therapeutic dose when 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof is used in combination therapy, and combined treatment with alkylating agent A therapeutic method for a tumor, which comprises administering to a subject in combination with a therapeutically effective dose when used in the above.
(10) Effective therapeutic dose when 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof is used in combination treatment, and combination treatment with alkylating agent A method of treating a tumor, comprising administering to a subject a therapeutically effective dose when used in a method simultaneously, separately, sequentially or at intervals.
(11) Use of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof for the production of an antitumor agent in combination with an alkylating agent.
(12) Use of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof for an antitumor agent in combination with an alkylating agent.
(13) 1- (2-Deoxy-2-fluoro-4-thio-β-D for treating tumors by administering an alkylating agent and a one-dose or separate dosage form -Arabinofuranosyl) cytosine or a salt thereof.
(14) The daily dose of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof is 20 to 200 mg / m 2 (1 ) Or (2).
(15) The antitumor agent according to (14), wherein the alkylating agent is temozolomide and the daily dose is 10 to 1000 mg / m 2 .
(16) The antitumor agent according to (14), wherein the alkylating agent is cyclophosphamide, and the daily dose is 20 to 2000 mg / m 2 .

　化合物Ａまたはその塩は、アルキル化剤と併用することにより、顕著な抗腫瘍効果を奏する。すなわち、本発明の抗腫瘍剤及び抗腫瘍用キットは、ゲムシタビン単剤、アルキル化剤単剤またはゲムシタビンとアルキル化剤との併用と比較して、優れた腫瘍増殖抑制効果を有する。本発明の抗腫瘍効果増強剤は、アルキル化剤と組み合わせて併用投与することにより、抗腫瘍効果を増強することができる。 Compound A or a salt thereof exhibits a remarkable antitumor effect when used in combination with an alkylating agent. That is, the antitumor agent and antitumor kit of the present invention have an excellent tumor growth inhibitory effect as compared with gemcitabine alone, an alkylating agent alone, or a combination of gemcitabine and an alkylating agent. The antitumor effect enhancer of the present invention can enhance the antitumor effect by co-administering in combination with an alkylating agent.

図１は、ヒト膵臓癌由来細胞株ＳＵＩＴ－２の細胞生存率に対する化合物Ａ及びテモゾロミドとの併用効果を示すグラフである。FIG. 1 is a graph showing the combined effect of Compound A and temozolomide on the cell viability of human pancreatic cancer-derived cell line SUIT-2.

　また「～」で表す範囲は、特に記載した場合を除き、両端の値を含む。
　「対象」とは、その予防もしくは治療を必要とするヒト、マウス、サル、家畜等の哺乳動物であり、好ましくは、その予防もしくは治療を必要とするヒトである。
　「予防」とは、発症の阻害、発症リスクの低減または発症の遅延等を意味する。
　「治療」とは、対象となる疾患または状態の改善または進行の抑制（維持または遅延）等を意味する。
　「処置」とは、各種疾患に対する予防または治療等を意味する。
　「腫瘍」とは、良性腫瘍または悪性腫瘍を意味する。
　「良性腫瘍」とは、腫瘍細胞及びその配列がその由来する正常細胞に近い形態をとり、浸潤性または転移性のない腫瘍を意味する。
　「悪性腫瘍」とは、腫瘍細胞の形態やその配列がその由来する正常細胞と異なっており、浸潤性または転移性を示す腫瘍を意味する。 The range represented by “to” includes values at both ends unless otherwise specified.
The “subject” is a mammal such as a human, a mouse, a monkey, a domestic animal or the like in need of the prevention or treatment, and preferably a human in need of the prevention or treatment.
“Prevention” means inhibition of onset, reduction of onset risk or delay of onset.
“Treatment” means improvement of a target disease or condition or suppression (maintenance or delay) of progression.
“Treatment” means prevention or treatment of various diseases.
“Tumor” means benign or malignant tumor.
“Benign tumor” means a tumor in which the tumor cells and their sequences are close to the normal cells from which they are derived and which are not invasive or metastatic.
“Malignant tumor” means a tumor that is different from the normal cells from which the morphology and sequence of the tumor cells are derived, and exhibits invasive or metastatic properties.

　以下、本発明を詳細に説明する。
　本発明は、アルキル化剤と、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシン（化合物Ａ）またはその塩とを含む抗腫瘍剤である。また本発明は、アルキル化剤と、化合物Ａまたはその塩とを組み合わせてなる抗腫瘍剤である。 Hereinafter, the present invention will be described in detail.
The present invention is an antitumor agent comprising an alkylating agent and 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (Compound A) or a salt thereof. The present invention is also an antitumor agent comprising a combination of an alkylating agent and Compound A or a salt thereof.

　本発明において、「組み合わせ」とは、化合物を併用して用いるための組み合わせを意味し、別々の物質を投与時に併用する形態、及び混合物（配合剤）としての形態の両方を含む。本発明において、「併用」とは、本発明の化合物とアルキル化剤との投与時期が完全同一であることのみを意味するものではない。１つの投与スケジュールの中に本発明の化合物と、アルキル化剤とを投与する態様が含まれている限り、これらを同時にまたは別々に投与する形態は「併用」を意味する。別々に投与する場合、本発明の化合物を先に投与した後にアルキル化剤を投与してもよい。また、アルキル化剤を先に投与した後に本発明の化合物を投与してもよい。 In the present invention, “combination” means a combination for using compounds in combination, and includes both forms in which different substances are used at the time of administration, and forms as a mixture (compound). In the present invention, “combination” does not mean that the administration timing of the compound of the present invention and the alkylating agent is completely the same. As long as one administration schedule includes an embodiment in which the compound of the present invention and the alkylating agent are administered, the form in which these are administered simultaneously or separately means “combination”. When administered separately, the alkylating agent may be administered after the compound of the invention has been administered first. Alternatively, the compound of the present invention may be administered after the alkylating agent is administered first.

　まず、化合物Ａまたはその塩について説明する。
　塩としては、薬学的に許容される塩が挙げられ、具体的には、鉱酸塩、有機カルボン酸塩及びスルホン酸塩が挙げられる。好ましい塩としては、鉱酸塩及びスルホン酸塩が挙げられる。 First, Compound A or a salt thereof will be described.
Examples of the salt include pharmaceutically acceptable salts, and specific examples include mineral acid salts, organic carboxylate salts, and sulfonate salts. Preferred salts include mineral acid salts and sulfonic acid salts.

　鉱酸塩としては、例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、リン酸塩及び硫酸塩が挙げられ、塩酸塩、ヨウ化水素酸塩、硝酸塩または硫酸塩が好ましく、塩酸塩がより好ましい。有機カルボン酸塩としては、例えば、ギ酸塩、酢酸塩、クエン酸塩、シュウ酸塩、フマル酸塩、マレイン酸塩、コハク酸塩、リンゴ酸塩、酒石酸塩、アスパラギン酸塩、トリクロロ酢酸塩及びトリフルオロ酢酸塩が挙げられる。スルホン酸塩としては、例えば、メタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、メシチレンスルホン酸塩及びナフタレンスルホン酸塩が挙げられ、メタンスルホン酸塩が好ましい。 Examples of mineral acid salts include hydrochloride, hydrobromide, hydroiodide, nitrate, phosphate, and sulfate, and hydrochloride, hydroiodide, nitrate, and sulfate are preferable. Hydrochloride is more preferable. Examples of organic carboxylates include formate, acetate, citrate, oxalate, fumarate, maleate, succinate, malate, tartrate, aspartate, trichloroacetate and Examples include trifluoroacetate. Examples of the sulfonate include methanesulfonate, benzenesulfonate, p-toluenesulfonate, mesitylenesulfonate, and naphthalenesulfonate, and methanesulfonate is preferable.

　化合物Ａの塩は、無水物、水和物または溶媒和物であってもよい。本明細書で単に「塩」というとき、その形態は、無水物、水和物または溶媒和物であり得る。本明細書で「無水物」というときは、特に記載した場合を除き、水和物でも溶媒和物でもない状態にある場合をいう。元来、水和物または溶媒和物を形成しない物質であっても、結晶水、水和水及び相互作用する溶媒を持たない化合物Ａの塩は、本発明でいう「無水物」に含まれる。無水物は、「無水和物」ということもある。化合物Ａの塩が水和物であるとき、水和水の数は特に限られず、一水和物、二水和物等であり得る。溶媒和物の例としては、メタノール和物、エタノール和物、プロパノール和物及び２－プロパノール和物が挙げられる。 The salt of Compound A may be an anhydride, hydrate or solvate. When simply referred to herein as a “salt”, the form may be an anhydride, hydrate or solvate. The term “anhydride” as used herein refers to a case in which it is in a state that is neither a hydrate nor a solvate, unless otherwise specified. Originally, even if the substance does not form a hydrate or solvate, the salt of Compound A having no water of crystallization, water of hydration and an interactive solvent is included in the “anhydride” in the present invention. . An anhydride may be referred to as an “anhydrate”. When the salt of Compound A is a hydrate, the number of hydrated water is not particularly limited, and may be a monohydrate, a dihydrate or the like. Examples of solvates include methanol solvates, ethanol solvates, propanol solvates and 2-propanol solvates.

　特に好ましい化合物Ａの塩の具体的な例は、下記である。
１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンのメタンスルホン酸塩；
１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンの塩酸塩；
１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンの１／２硫酸塩；
１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンの硝酸塩；及び
１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンのヨウ化水素酸塩；ならびに上記の塩のいずれかの無水物。 Specific examples of particularly preferable salts of the compound A are as follows.
1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine methanesulfonate;
1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine hydrochloride;
1/2 sulfate of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine;
1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine nitrate; and 1- (2-deoxy-2-fluoro-4-thio-β-D-arabino Furanosyl) cytosine hydroiodide; as well as the anhydrides of any of the above salts.

　本発明において、化合物Ａまたはその塩は、一種のみを用いてもよく、または二種以上を含有してもよい。 In the present invention, compound A or a salt thereof may be used alone or in combination of two or more.

　次に、化合物Ａまたはその塩の製造法について説明する。化合物Ａは、例えば、特許文献１及びジャーナル・オブ・オーガニック・ケミストリー、１９９９年、第６４巻、７９１２～７９２０頁に記載の方法で製造することができる。化合物Ａの塩またはその水和物もしくは溶媒和物は、例えば、特許文献４に記載の方法で製造することができる。
　本発明にかかる化合物Ａまたはその塩は、抗腫瘍剤として、また医薬組成物の有効成分として用いることができる。 Next, the manufacturing method of the compound A or its salt is demonstrated. Compound A can be produced, for example, by the method described in Patent Document 1 and Journal of Organic Chemistry, 1999, Vol. 64, pages 7912-7920. The salt of compound A or a hydrate or solvate thereof can be produced, for example, by the method described in Patent Document 4.
The compound A or a salt thereof according to the present invention can be used as an antitumor agent or as an active ingredient of a pharmaceutical composition.

（アルキル化剤）
　本発明において、アルキル化剤は、例えば、シクロホスファミド、イホスファミド、ダカルバジン、テモゾロミド、ニムスチン、ラニムスチン、ベンダムスチン、ブスルファン、プロカルバジン、メルファラン、チオテパ、及びカルボコン等が挙げられる。
　本発明のアルキル化剤としては、シクロホスファミド、イホスファミド、ダカルバジン、テモゾロミド、ニムスチン、ラニムスチン、ブスルファン、プロカルバジン、メルファランまたチオテパが好ましく、シクロホスファミドまたはテモゾロミドがより好ましい。
　これらのアルキル化剤は、公知の方法で製造できる。
　また、これらのアルキル化剤は、市販品を購入することによって入手することもできる。例えば、シクロホスファミドは、塩野義製薬株式会社からEndoxan（登録商標）として市販されている。イホスファミドは塩野義製薬株式会社からIfomide（登録商標）として市販されている。ダカルバジンは、協和発酵キリン株式会社からDacarbazine（登録商標）として市販されている。テモゾロミドは、MSD株式会社からTemodal（登録商標）として市販されている。ニムスチンは、第一三共株式会社からNidran（登録商標）として市販されている。ラニムスチンは、ニプロESファーマ株式会社からサイメリン（登録商標）として市販されている。ブスルファンは、大塚製薬株式会社からBusulfex（登録商標）または大原薬品工業株式会社からMablin（登録商標）として市販されている。プロカルバジンは、中外製薬株式会社から塩酸プロカルバジンとして市販されている。メルファランは、アスペンジャパン株式会社からアルケラン（登録商標）として市販されている。 (Alkylating agent)
In the present invention, examples of the alkylating agent include cyclophosphamide, ifosfamide, dacarbazine, temozolomide, nimustine, ranimustine, bendamustine, busulfan, procarbazine, melphalan, thiotepa, and carbocon.
The alkylating agent of the present invention is preferably cyclophosphamide, ifosfamide, dacarbazine, temozolomide, nimustine, ranimustine, busulfan, procarbazine, melphalan or thiotepa, more preferably cyclophosphamide or temozolomide.
These alkylating agents can be produced by known methods.
Moreover, these alkylating agents can also be obtained by purchasing a commercial item. For example, cyclophosphamide is commercially available as Endoxan (registered trademark) from Shionogi & Co., Ltd. Ifosfamide is commercially available as Ifomide (registered trademark) from Shionogi & Co., Ltd. Dacarbazine is commercially available as Dacarbazine (registered trademark) from Kyowa Hakko Kirin Co., Ltd. Temozolomide is commercially available from MSD Corporation as Temodal®. Nimustine is commercially available from Daiichi Sankyo Co., Ltd. as Nidran (registered trademark). Ranimustine is commercially available as Cymerin (registered trademark) from Nipro ES Pharma Co., Ltd. Busulfan is commercially available from Otsuka Pharmaceutical Co., Ltd. as Busulfex (registered trademark) or from Ohara Pharmaceutical Co., Ltd. as Mablin (registered trademark). Procarbazine is commercially available from Chugai Pharmaceutical Co., Ltd. as procarbazine hydrochloride. Melphalan is commercially available as Alquelan (registered trademark) from Aspen Japan.

　本発明において、アルキル化剤は、酸または塩基と薬学的に許容される塩（以下、「その塩」ということがある）を形成する場合もある。本発明のアルキル化剤は、これらの薬学的に許容される塩をも包含する。アルキル化剤は、一種のみを用いてもよく、または二種以上を含有してもよい。アルキル化剤としては、アルキル化剤またはその塩以外に、それらを含む組成物でもよい。
　塩としては、薬学的に許容される塩が挙げられ、具体的には、通常知られているアミノ基等の塩基性基、ヒドロキシル基及びカルボキシル基等の酸性基における塩を挙げることができる。
　塩基性基における塩としては、例えば、塩酸、臭化水素酸、硝酸及び硫酸等の鉱酸との塩；ギ酸、酢酸、クエン酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、酒石酸、アスパラギン酸、トリクロロ酢酸及びトリフルオロ酢酸等の有機カルボン酸との塩；ならびにメタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メシチレンスルホン酸及びナフタレンスルホン酸等のスルホン酸との塩が挙げられる。
　酸性基における塩としては、例えば、ナトリウム及びカリウム等のアルカリ金属との塩；カルシウム及びマグネシウム等のアルカリ土類金属との塩；アンモニウム塩；ならびにトリメチルアミン、トリエチルアミン、トリブチルアミン、ピリジン、Ｎ、Ｎ－ジメチルアニリン、Ｎ－メチルピペリジン、Ｎ－メチルモルホリン、ジエチルアミン、ジシクロヘキシルアミン、プロカイン、ジベンジルアミン、Ｎ－ベンジル－β－フェネチルアミン、１－エフェナミン及びＮ、Ｎ'－ジベンジルエチレンジアミン等の含窒素有機塩基との塩が挙げられる。 In the present invention, the alkylating agent may form a pharmaceutically acceptable salt (hereinafter sometimes referred to as “the salt”) with an acid or a base. The alkylating agent of the present invention includes these pharmaceutically acceptable salts. Only one alkylating agent may be used, or two or more alkylating agents may be contained. The alkylating agent may be a composition containing them in addition to the alkylating agent or a salt thereof.
Examples of the salt include pharmaceutically acceptable salts, and specific examples include salts that are generally known in basic groups such as amino groups and acidic groups such as hydroxyl groups and carboxyl groups.
Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And the salt.

　化合物Ａは、優れたＤＮＡ合成阻害作用を有する、抗腫瘍剤である。化合物Ａをアルキル化剤と併用した場合に、顕著な毒性の増悪を示すことなく、アルキル化剤の抗腫瘍効果を増強する作用を有することが予想される。 Compound A is an antitumor agent having an excellent DNA synthesis inhibitory action. When Compound A is used in combination with an alkylating agent, it is expected to have an action of enhancing the antitumor effect of the alkylating agent without showing a marked increase in toxicity.

（抗腫瘍剤）
　本発明によれば、
　アルキル化剤と、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩とを含む抗腫瘍剤；並びに
　アルキル化剤と併用される、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を含む抗腫瘍剤：
が提供される。 (Anti-tumor agent)
According to the present invention,
An antitumor agent comprising an alkylating agent and 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof; and An antitumor agent comprising-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof:
Is provided.

　本発明の抗腫瘍剤は、通常、製剤化に使用される賦形剤、結合剤、滑沢剤、崩壊剤、着色剤、矯味矯臭剤、乳化剤、界面活性剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、防腐剤、抗酸化剤、安定化剤及び吸収促進剤等の添加剤を含んでいてもよい。 The antitumor agent of the present invention is usually used for formulation, excipients, binders, lubricants, disintegrants, colorants, flavoring agents, emulsifiers, surfactants, solubilizers, suspending agents. Additives such as agents, tonicity agents, buffers, preservatives, antioxidants, stabilizers and absorption enhancers may be included.

　アルキル化剤と化合物Ａまたはその塩とを含む本発明の抗腫瘍剤は、アルキル化剤と化合物Ａまたはその塩とを含む１剤型の製剤であっても、アルキル化剤と化合物Ａまたはその塩とを含む２剤型の製剤であってもよい。好ましくは、アルキル化剤と化合物Ａまたはその塩とを別個の製剤とする２剤型の製剤である。
　アルキル化剤と、化合物Ａまたはその塩とが別個の製剤として用いる場合、各製剤は、同時に、別々に、連続して、あるいは間隔をあけて対象に投与することができる。また、アルキル化剤を含む組成物の投与手段と、化合物Ａを含む組成物の投与手段は同一であってもよいし、相違していてもよい（例えば、経口投与と注射）。 The antitumor agent of the present invention containing an alkylating agent and compound A or a salt thereof is an alkylating agent and compound A or a salt thereof, even if it is a one-part preparation containing an alkylating agent and compound A or a salt thereof. It may be a two-part preparation containing a salt. Preferably, it is a two-drug preparation in which the alkylating agent and Compound A or a salt thereof are separate preparations.
When the alkylating agent and Compound A or a salt thereof are used as separate formulations, each formulation can be administered to the subject simultaneously, separately, sequentially, or at intervals. Moreover, the administration means of the composition containing the alkylating agent and the administration means of the composition containing Compound A may be the same or different (for example, oral administration and injection).

　本発明の抗腫瘍剤の投与経路としては、静脈内、動脈内、直腸内、腹腔内、筋肉内、腫瘍内または膀胱内注射する方法、経口投与、経皮投与及び／または坐剤等の方法が挙げられる。
　投与経路としては、非経口投与が好ましい。例えば、点滴等の静脈内注射（静注）、筋肉内注射、腹腔内注射、皮下注射、眼内注射及び／または髄腔内注射を挙げることができる。投与方法としては、シリンジまたは点滴による投与が挙げられる。 The administration route of the antitumor agent of the present invention includes intravenous, intraarterial, rectal, intraperitoneal, intramuscular, intratumoral or intravesical injection, oral administration, transdermal administration and / or suppository. Is mentioned.
As an administration route, parenteral administration is preferable. For example, intravenous injection (intravenous injection) such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and / or intrathecal injection can be mentioned. Examples of the administration method include administration by syringe or infusion.

　本発明の抗腫瘍剤に含まれるアルキル化剤と化合物Ａまたはその塩との投与量または配合量は、抗腫瘍効果の増強効果を奏する範囲であれば特に制限されない。
　使用する本発明の化合物Ａの量は、アルキル化剤との個々の組み合わせによって異なるが、例えば、アルキル化剤の約０．０００１～１００００倍（重量比）であり、好ましくは約０．００１～１０００倍（重量比）である。 The dosage or compounding amount of the alkylating agent and compound A or a salt thereof contained in the antitumor agent of the present invention is not particularly limited as long as the antitumor effect is enhanced.
The amount of the compound A of the present invention to be used varies depending on the individual combination with the alkylating agent, but is, for example, about 0.0001 to 10,000 times (weight ratio) of the alkylating agent, preferably about 0.001 to 1000 times (weight ratio).

　より具体的には、化合物Ａとテモゾロミドとを組み合わせる場合、特に限定されないが、例えば、本発明の化合物Ａの投与量を、成人１日あたり、２０～２００ｍｇ／ｍ２、好ましくは４０～２００ｍｇ／ｍ２、より好ましくは４０～１５０ｍｇ／ｍ２、さらに好ましくは８０～１５０ｍｇ／ｍ２とし、テモゾロミドの投与量を、成人１日あたり、１０～１０００ｍｇ／ｍ２、好ましくは２０～２００ｍｇ／ｍ２、さらに好ましくは５０～１５０ｍｇ／ｍ２とし、さらに、本発明の化合物の投与量を、テモゾロミドの約０．０２～２０倍（重量比）、好ましくは約０．５３～３倍（重量比）となるようにする。 More specifically, the combination of Compound A and temozolomide is not particularly limited. For example, the dose of Compound A of the present invention is 20 to 200 mg / m 2 , preferably 40 to 200 mg / day per adult. m 2 , more preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2, and the dosage of temozolomide is 10 to 1000 mg / m 2 , preferably 20 to 200 mg / m 2 per day for an adult. More preferably, the dose is 50 to 150 mg / m 2, and the dose of the compound of the present invention is about 0.02 to 20 times (weight ratio), preferably about 0.53 to 3 times (weight ratio) of temozolomide. To be.

　また、本発明の化合物とシクロホスファミドとを組み合わせる場合、特に限定されないが、例えば、本発明の化合物Ａの投与量を、成人１日あたり、２０～２００ｍｇ／ｍ２、好ましくは４０～２００ｍｇ／ｍ２、より好ましくは４０～１５０ｍｇ／ｍ２、さらに好ましくは８０～１５０ｍｇ／ｍ２とし、シクロホスファミドの投与量を、成人１日あたり、２０～２０００ｍｇ／ｍ２、好ましくは３０～１５００ｍｇ／ｍ２、さらに好ましくは５０～１０００ｍｇ／ｍ２とし、さらに、本発明の化合物の投与量を、シクロホスファミドの約０．０１～１０倍（重量比）、好ましくは約０．０８～３倍（重量比）となるようにする。 Further, when the compound of the present invention and cyclophosphamide are combined, there is no particular limitation. For example, the dose of the compound A of the present invention is 20 to 200 mg / m 2 , preferably 40 to 200 mg per day for an adult. / M 2 , more preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2, and the dose of cyclophosphamide is 20 to 2000 mg / m 2 , preferably 30 to 1500 mg / m 2 , more preferably 50 to 1000 mg / m 2, and the dose of the compound of the present invention is about 0.01 to 10 times (weight ratio) of cyclophosphamide, preferably about 0.08. ˜3 times (weight ratio).

　アルキル化剤の投与量及び投与回数は、例えば、成人に対しては、経口または非経口（例えば、注射、点滴及び直腸部位への投与）投与により、１日あたり例えば、１～１０００ ｍｇ／ｍ２を１回から数回に分割して投与することができる。患者が過度の毒性を経験した場合は、投与量の減少が必要となる。投与量及び投与計画は、本発明の併用療法に加えて、１またはそれ以上の追加の化学療法剤が使用される場合に変更してもよい。投与計画は、特定の患者を治療している医師により決定することができる。 The dose and frequency of administration of the alkylating agent may be, for example, 1 to 1000 mg / m per day by oral or parenteral (eg injection, infusion and administration to the rectal site) for adults. 2 can be administered in one to several divided doses. If the patient experiences excessive toxicity, a dose reduction is necessary. Dosage amount and regimen may be altered if one or more additional chemotherapeutic agents are used in addition to the combination therapy of the invention. The dosage regimen can be determined by the physician treating the particular patient.

　化合物Ａまたはその塩の投与量及び投与方法は、１日あたり１～２０００ ｍｇ／ｍ２を１回から数回に分割して投与することができる。しかし、これらの投与量及び投与方法に制限されるものではない。 Regarding the dose and administration method of Compound A or a salt thereof, 1 to 2000 mg / m 2 per day can be administered in 1 to several divided doses. However, it is not limited to these doses and administration methods.

　化合物Ａまたはその塩の１日当たりの投与量は、２０ｍｇ／ｍ２以上であり、好ましくは４０ｍｇ／ｍ２以上であり、好ましくは６０ｍｇ／ｍ２以上であり、好ましくは８０ｍｇ／ｍ２以上である。１日当たりの投与量の上限値は、２００ｍｇ／ｍ２であり、好ましくは１５０ｍｇ／ｍ２であり、さらに好ましくは１２０ｍｇ／ｍ２であり、特に好ましくは１００ｍｇ／ｍ２である。１日当たりの投与量は、より好ましくは４０～２００ｍｇ／ｍ２であり、さらに好ましくは４０～１５０ｍｇ／ｍ２であり、よりさらに好ましくは８０～１５０ｍｇ／ｍ２であり、さらに一層好ましくは８０～１２０ｍｇ／ｍ２である。
　また、別の態様として、１日当たりの投与量は、好ましくは２０～１２０ｍｇ／ｍ２であり、より好ましくは４０～１２０ｍｇ／ｍ２であり、さらに好ましくは４０～１００ｍｇ／ｍ２であり、よりさらに好ましくは６０～１００ｍｇ／ｍ２である。
　このような投与量の範囲とすることで、副作用を最小限として抗腫瘍剤としての治療効果を最大化することができる。 The daily dose of Compound A or a salt thereof is 20 mg / m 2 or more, preferably 40 mg / m 2 or more, preferably 60 mg / m 2 or more, preferably 80 mg / m 2 or more. . The upper limit of the dose per day is 200 mg / m 2 , preferably 150 mg / m 2 , more preferably 120 mg / m 2 , and particularly preferably 100 mg / m 2 . The daily dose is more preferably 40 to 200 mg / m 2 , further preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2 , and even more preferably 80 to 120 mg / m 2 .
In another aspect, the daily dose is preferably 20 to 120 mg / m 2 , more preferably 40 to 120 mg / m 2 , still more preferably 40 to 100 mg / m 2 , and more More preferably, it is 60 to 100 mg / m 2 .
By setting the dose within such a range, side effects can be minimized and the therapeutic effect as an antitumor agent can be maximized.

　化合物Ａまたはその塩の投与方法としては、１回の投与量が２０～２００ｍｇ／ｍ２とし、週１回の投与を３週間行った後に４週目は休薬するコースを複数回繰り返すことができる。この場合、１回の投与量は、上記の１日当たりの投与量と同様であるが、好ましくは４０～２００ｍｇ／ｍ２であり、より好ましくは４０～１５０ｍｇ／ｍ２であり、さらに好ましくは８０～１５０ｍｇ／ｍ２である。また、別の態様として、１回の投与量は、好ましくは２０～１２０ｍｇ／ｍ２であり、より好ましくは４０～１２０ｍｇ／ｍ２であり、さらに好ましくは４０～１００ｍｇ／ｍ２である。 As a method for administering Compound A or a salt thereof, a single dose may be 20 to 200 mg / m 2, and a course in which the drug is withdrawn in the 4th week after repeated administration once a week for 3 weeks may be repeated several times. it can. In this case, the single dose is the same as the above-mentioned daily dose, preferably 40 to 200 mg / m 2 , more preferably 40 to 150 mg / m 2 , and still more preferably 80 ~ 150 mg / m 2 . In another embodiment, the dose per administration is preferably 20 to 120 mg / m 2 , more preferably 40 to 120 mg / m 2 , and still more preferably 40 to 100 mg / m 2 .

　本発明の抗腫瘍剤の剤形の例としては、錠剤、カプセル剤、散剤、シロップ剤、顆粒剤、丸剤、懸濁剤、乳剤、液剤、坐剤、点眼剤、点鼻剤、点耳剤、貼付剤、軟膏剤及び注射剤が挙げられるが、注射剤が好ましい。これらの投与剤形は、各々当業者に公知慣用の製剤方法により製造できる。 Examples of dosage forms of the antitumor agent of the present invention include tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, suppositories, eye drops, nasal drops, ear drops Although an agent, a patch, an ointment, and an injection are mentioned, an injection is preferable. Each of these dosage forms can be produced by conventional formulation methods known to those skilled in the art.

　本発明の抗腫瘍剤は、好ましくは抗悪性腫瘍剤であり、抗がん剤として使用することができる。
　本発明の抗腫瘍剤は、例えば、膀胱癌、腎盂・尿管腫瘍、前立腺癌、精巣癌、卵巣癌、頭頸部癌、肺癌、食道癌、子宮頸癌、神経膠腫、神経芽細胞腫、胃癌、骨肉腫、胚細胞腫瘍（精巣腫瘍、卵巣腫瘍、性腺外腫瘍）、悪性胸膜中皮腫、胆道癌、大腸癌、小腸癌、悪性リンパ腫、乳癌、膵臓癌、肝癌、腎癌、悪性黒色腫、慢性骨髄性白血病、多発性骨髄腫またはその他の器官の腫瘍を包含する多様なタイプの腫瘍の処置に有効に使用できる。このうち、前立腺癌、骨肉腫、胚細胞腫瘍、悪性骨・軟部腫瘍、多発性骨髄腫、悪性リンパ腫、乳癌、肺癌、子宮癌、卵巣癌、膵臓癌、悪性黒色腫、神経芽腫、網膜芽腫、甲状腺癌、胃癌、肝臓癌、大腸癌または慢性骨髄性白血病が好ましく、特に膵臓癌または乳癌の処置に有効である。 The antitumor agent of the present invention is preferably an antineoplastic agent and can be used as an anticancer agent.
Antitumor agents of the present invention include, for example, bladder cancer, renal pelvis / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, lung cancer, esophageal cancer, cervical cancer, glioma, neuroblastoma, Gastric cancer, osteosarcoma, germ cell tumor (testis tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, colon cancer, small intestine cancer, malignant lymphoma, breast cancer, pancreatic cancer, liver cancer, renal cancer, malignant black It can be used effectively for the treatment of various types of tumors including tumors, chronic myelogenous leukemias, multiple myeloma or other organ tumors. Among these, prostate cancer, osteosarcoma, germ cell tumor, malignant bone / soft tissue tumor, multiple myeloma, malignant lymphoma, breast cancer, lung cancer, uterine cancer, ovarian cancer, pancreatic cancer, malignant melanoma, neuroblastoma, retinoblast Tumor, thyroid cancer, stomach cancer, liver cancer, colon cancer or chronic myelogenous leukemia are preferred, and particularly effective for the treatment of pancreatic cancer or breast cancer.

（抗腫瘍効果増強剤）
　本発明はまた、癌患者に対するアルキル化剤の抗腫瘍効果を増強するための化合物Ａまたはその塩を含む抗腫瘍効果増強剤に関する。
　すなわち、本発明によれば、
アルキル化剤と併用される、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を含む抗腫瘍効果増強剤を提供される。
　本発明の抗腫瘍効果増強剤は、通常、製剤化に使用される賦形剤、結合剤、滑沢剤、崩壊剤、着色剤、矯味矯臭剤、乳化剤、界面活性剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、防腐剤、抗酸化剤、安定化剤及び吸収促進剤等の添加剤を含んでいてもよい。 (Anti-tumor effect enhancer)
The present invention also relates to an antitumor effect potentiator comprising Compound A or a salt thereof for enhancing the antitumor effect of an alkylating agent for cancer patients.
That is, according to the present invention,
An antitumor effect potentiator comprising 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof in combination with an alkylating agent is provided.
The antitumor effect potentiator of the present invention is usually an excipient, a binder, a lubricant, a disintegrant, a colorant, a flavoring agent, an emulsifier, a surfactant, a solubilizing agent, a suspension, Additives such as turbidity agents, tonicity agents, buffers, preservatives, antioxidants, stabilizers and absorption enhancers may be included.

　本発明の抗腫瘍効果増強剤は、アルキル化剤と同時に、別々に、連続して、あるいは間隔をあけて対象に投与することができる。 The antitumor effect potentiator of the present invention can be administered to a subject simultaneously, separately or at intervals with the alkylating agent.

　本発明の抗腫瘍効果増強剤の投与経路としては、非経口投与が好ましい。例えば、点滴等の静脈内注射（静注）、筋肉内注射、腹腔内注射、皮下注射、眼内注射及び髄腔内注射を挙げることができる。投与方法としては、シリンジまたは点滴による投与が挙げられる。 As an administration route of the antitumor effect enhancer of the present invention, parenteral administration is preferable. For example, intravenous injection (intravenous injection) such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection, intraocular injection, and intrathecal injection can be mentioned. Examples of the administration method include administration by syringe or infusion.

　本発明の抗腫瘍効果増強剤に含まれる化合物Ａまたはその塩の投与量または配合量は、抗腫瘍効果の増強効果を奏する範囲であれば特に制限されない。
　使用する本発明の化合物Ａの量は、アルキル化剤との個々の組み合わせによって異なるが、例えば、アルキル化剤の約０．０００１～１００００倍（重量比）であり、好ましくは約０．００１～１０００倍（重量比）である。 The dose or amount of compound A or a salt thereof contained in the antitumor effect potentiator of the present invention is not particularly limited as long as it exhibits a potentiating effect on the antitumor effect.
The amount of the compound A of the present invention to be used varies depending on the individual combination with the alkylating agent, but is, for example, about 0.0001 to 10,000 times (weight ratio) of the alkylating agent, preferably about 0.001 to 1000 times (weight ratio).

　本発明の抗腫瘍効果増強剤に含まれる化合物Ａまたはその塩の投与量及び投与方法は、１日あたり、１～２０００ ｍｇ／ｍ２を１回から数回に分割して投与することができる。しかし、これらの投与量及び投与方法に制限されるものではない。 Regarding the dose and administration method of Compound A or a salt thereof contained in the antitumor effect potentiator of the present invention, 1 to 2000 mg / m 2 can be divided into 1 to several times per day. . However, it is not limited to these doses and administration methods.

　化合物Ａまたはその塩の１日当たりの投与量は、２０ｍｇ／ｍ２以上であり、好ましくは４０ｍｇ／ｍ２以上であり、好ましくは６０ｍｇ／ｍ２以上であり、好ましくは８０ｍｇ／ｍ２以上である。１日当たりの投与量の上限値は、２００ｍｇ／ｍ２であり、好ましくは１５０ｍｇ／ｍ２であり、さらに好ましくは１２０ｍｇ／ｍ２であり、特に好ましくは１００ｍｇ／ｍ２である。１日当たりの投与量は、より好ましくは４０～２００ｍｇ／ｍ２であり、さらに好ましくは４０～１５０ｍｇ／ｍ２であり、さらに好ましくは８０～１５０ｍｇ／ｍ２であり、さらに一層好ましくは８０～１２０ｍｇ／ｍ２である。
　また、別の態様として、１日当たりの投与量は、好ましくは２０～１２０ｍｇ／ｍ２であり、より好ましくは４０～１２０ｍｇ／ｍ２であり、さらに好ましくは４０～１００ｍｇ／ｍ２であり、よりさらに好ましくは６０～１００ｍｇ／ｍ２である。
　このような投与量の範囲とすることで、副作用を最小限として抗腫瘍剤としての治療効果を最大化することができる。 The daily dose of Compound A or a salt thereof is 20 mg / m 2 or more, preferably 40 mg / m 2 or more, preferably 60 mg / m 2 or more, preferably 80 mg / m 2 or more. . The upper limit of the dose per day is 200 mg / m 2 , preferably 150 mg / m 2 , more preferably 120 mg / m 2 , and particularly preferably 100 mg / m 2 . The dose per day is more preferably 40 to 200 mg / m 2 , further preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2 , and still more preferably 80 to 120 mg. / M 2 .
In another aspect, the daily dose is preferably 20 to 120 mg / m 2 , more preferably 40 to 120 mg / m 2 , still more preferably 40 to 100 mg / m 2 , and more More preferably, it is 60 to 100 mg / m 2 .
By setting the dose within such a range, side effects can be minimized and the therapeutic effect as an antitumor agent can be maximized.

　化合物Ａまたはその塩の投与方法としては、１回の投与量が２０～２００ｍｇ／ｍ２とし、週１回の投与を３週間行った後に４週目は休薬するコースを複数回繰り返すことができる。この場合、１回の投与量は、上記の１日当たりの投与量と同様であるが、好ましくは４０～２００ｍｇ／ｍ２であり、より好ましくは４０～１５０ｍｇ／ｍ２であり、さらに好ましくは８０～１５０ｍｇ／ｍ２である。また、別の態様として、１回の投与量は、好ましくは２０～１２０ｍｇ／ｍ２であり、より好ましくは４０～１２０ｍｇ／ｍ２であり、さらに好ましくは４０～１００ｍｇ／ｍ２である。 As a method for administering Compound A or a salt thereof, a single dose may be 20 to 200 mg / m 2, and a course in which the drug is withdrawn in the 4th week after repeated administration once a week for 3 weeks may be repeated several times. it can. In this case, the single dose is the same as the above-mentioned daily dose, preferably 40 to 200 mg / m 2 , more preferably 40 to 150 mg / m 2 , and still more preferably 80 ~ 150 mg / m 2 . In another embodiment, the dose per administration is preferably 20 to 120 mg / m 2 , more preferably 40 to 120 mg / m 2 , and still more preferably 40 to 100 mg / m 2 .

　本発明の抗腫瘍効果増強剤は、好ましくは抗悪性腫瘍効果増強剤であり、抗がん効果増強剤として使用することができる。
　本発明の抗腫瘍効果増強剤は、膀胱癌、腎盂・尿管腫瘍、前立腺癌、精巣癌、卵巣癌、頭頸部癌、肺癌、食道癌、子宮頸癌、神経膠腫、神経芽細胞腫、胃癌、骨肉腫、胚細胞腫瘍（精巣腫瘍、卵巣腫瘍、性腺外腫瘍）、悪性胸膜中皮腫、胆道癌、大腸癌、小腸癌、悪性リンパ腫、乳癌、膵臓癌、肝癌、腎癌、悪性黒色腫、慢性骨髄性白血病、多発性骨髄腫またはその他の器官の腫瘍を包含する多様なタイプの腫瘍の処置に有効に使用できる。このうち、前立腺癌、骨肉腫、胚細胞腫瘍、悪性骨・軟部腫瘍、多発性骨髄腫、悪性リンパ腫、乳癌、肺癌、子宮癌、卵巣癌、膵臓癌、悪性黒色腫、神経芽腫、網膜芽腫、甲状腺癌、胃癌、肝臓癌、大腸癌または慢性骨髄性白血病が好ましく、特に膵臓癌または乳癌の処置に有効である。 The antitumor effect enhancer of the present invention is preferably an antimalignant effect enhancer and can be used as an anticancer effect enhancer.
Antitumor effect potentiators of the present invention include bladder cancer, renal pelvis / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, lung cancer, esophageal cancer, cervical cancer, glioma, neuroblastoma, Gastric cancer, osteosarcoma, germ cell tumor (testis tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, colon cancer, small intestine cancer, malignant lymphoma, breast cancer, pancreatic cancer, liver cancer, renal cancer, malignant black It can be used effectively for the treatment of various types of tumors including tumors, chronic myelogenous leukemias, multiple myeloma or other organ tumors. Among these, prostate cancer, osteosarcoma, germ cell tumor, malignant bone / soft tissue tumor, multiple myeloma, malignant lymphoma, breast cancer, lung cancer, uterine cancer, ovarian cancer, pancreatic cancer, malignant melanoma, neuroblastoma, retinoblast Tumor, thyroid cancer, stomach cancer, liver cancer, colon cancer or chronic myelogenous leukemia are preferred, and particularly effective for the treatment of pancreatic cancer or breast cancer.

（抗腫瘍用キット）
　本発明によれば、
　アルキル化剤を含む製剤と、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を含む製剤とを含む抗腫瘍用キットが提供される。
　本発明の抗腫瘍用キットは、（ａ）アルキル化剤及び（ｂ）化合物Ａまたはその塩の組み合わせを含むキットである。
　また、上記キットでは、（ａ）アルキル化剤及び（ｂ）化合物Ａまたはその塩は各々公知の各種の製剤形態とすることができ、その製剤形態に応じて、通常用いられる各種の容器に収容される。
　さらに、上記キットでは、（ａ）アルキル化剤及び（ｂ）化合物Ａまたはその塩は各々別の容器に収容されてもよいし、混合されて同じ容器に収容されてもよい。（ａ）アルキル化剤及び（ｂ）化合物Ａまたはその塩が各々別の容器に収容されていることが好ましい。 (Anti-tumor kit)
According to the present invention,
Provided is an antitumor kit comprising a preparation containing an alkylating agent and a preparation containing 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof. .
The antitumor kit of the present invention is a kit comprising a combination of (a) an alkylating agent and (b) compound A or a salt thereof.
Further, in the above kit, (a) the alkylating agent and (b) compound A or a salt thereof can be in various known preparation forms, and are accommodated in various commonly used containers according to the preparation form. Is done.
Furthermore, in the above kit, (a) the alkylating agent and (b) compound A or a salt thereof may be stored in separate containers, or may be mixed and stored in the same container. It is preferable that (a) the alkylating agent and (b) compound A or a salt thereof are respectively contained in separate containers.

　本発明は、アルキル化剤と、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩とを、腫瘍の処置に用いるための、好ましくは膵臓癌または乳癌の処置に用いるための方法であって、治療有効用量をそのような処置が必要な対象（ヒトを含む哺乳動物）に投与する工程を含む方法を提供する。 The present invention provides an alkylating agent and 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof, preferably for use in the treatment of tumors. A method for use in the treatment of pancreatic cancer or breast cancer comprising the step of administering a therapeutically effective dose to a subject in need of such treatment (mammals including humans).

　また、本発明は１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を併用治療に用いる場合の治療有効用量、及び、アルキル化剤を併用治療に用いる場合の治療有効用量とを組み合わせて、対象に投与することを特徴とする、腫瘍の治療方法を提供する。 The present invention also provides a therapeutically effective dose when 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof is used in combination therapy, and an alkylating agent. Provided is a method for treating a tumor, characterized by being administered to a subject in combination with a therapeutically effective dose when used in combination therapy.

　さらに、本発明は１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を併用治療に用いる場合の治療有効用量、及び、アルキル化剤を併用治療に用いる場合の治療有効用量を、同時に、別々に、連続して、あるいは間隔をあけて、対象に投与することを特徴とする、腫瘍の治療方法を提供する。 Furthermore, the present invention provides a therapeutically effective dose when 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof is used in combination therapy, and an alkylating agent. Provided is a method of treating a tumor, characterized in that a therapeutically effective dose when used in combination therapy is administered to a subject simultaneously, separately, sequentially or at intervals.

　１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩の、アルキル化剤と組み合わせてなる抗腫瘍剤製造のために使用できる。 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof can be used for the production of an antitumor agent in combination with an alkylating agent.

　１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩の、アルキル化剤と組み合わせてなる抗腫瘍剤のための使用に使用できる。 1- (2-Deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof can be used for an antitumor agent in combination with an alkylating agent.

　本発明により、アルキル化剤と、一剤型の製剤形態、または別個の製剤形態として投与することにより腫瘍を治療するための、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を得ることができる。 In accordance with the present invention, 1- (2-deoxy-2-fluoro-4-thio-β-) for the treatment of tumors by administration with an alkylating agent and a single dosage form or as a separate dosage form. D-arabinofuranosyl) cytosine or a salt thereof can be obtained.

　以下に実施例及び試験例を示し、本発明をさらに詳しく説明するが、本発明はこれら実施例等に制限されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples and test examples, but the present invention is not limited to these examples.

（実施例１）
　１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシン（化合物Ａ）のメタンスルホン酸塩は、国際公開第２０１３／１４６８３３号パンフレットに記載の方法により合成した。    Example 1
A methanesulfonate salt of 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (Compound A) was synthesized by the method described in International Publication No. 2013/146833 pamphlet. did.

（試験例１）
　テモゾロミドの併用によるヒト膵臓癌由来細胞株SUIT-2に対する抗腫瘍活性の評価
　被験物質として、ゲムシタビン（以下、GemcitabineまたはGemともいう）、テモゾロミド（以下、Temozolomideともいう）及び化合物Ａのメタンスルホン酸塩を用いた。
　ゲムシタビンは、ゲムシタビン塩酸塩（Plantex社製）をジメチルスルホキシド（DMSO）に溶解させたものを用いた。Temozolomide（LKT Laboratories, Inc.  Cat.# T1849）は、無血清培地 RPMI-1640 (Thermo Fisher Scientific Inc.製Cat.# 11875-119)に溶解させたものを用いた。
　ヒト膵臓癌細胞株であるSUIT-2細胞を10%血清(Thermo Fisher Scientific Inc. 製 Cat.# 10437-028)培地RPMI-1640で継代培養を行った。本試験中、すべての細胞培養はCO2インキュベータ（37℃、5%CO2設定、水蒸気飽和）中で行った。15000 cells/well/100 μLとなるように10%血清培地で希釈し、96wellプレートに播種した。翌日、各wellの培養上清を捨て、150 μLの無血清培地で2回洗い、100 μLの無血清培地を添加して3日間培養した。
　化合物Ａのメタンスルホン酸塩及びGemcitabineをDMSOに溶解し、100 mmol/L DMSO溶液をそれぞれ調製した。順次DMSOで希釈し、最終処理濃度の1000倍濃度のDMSO溶液を調製した。Temozolomideを無血清培地に溶解し、Temozolomide溶液 1200 μmol/Lを調製した。化合物Ａ及びGemcitabineのDMSO希釈溶液を、Temozolomide溶液（1200 μmol/L）で希釈し、最終処理濃度の6倍濃度の処理液をそれぞれ調製した。化合物Ａ及びGemcitabineは最高濃度を10 μmol/Lとし、公比1/3で9濃度をTemozolomideと組み合わせて使用した。
　Temozolomide溶液（1200 μmol/L）で希釈した化合物ＡまたはGemcitabineを各wellに20 μLを添加した。この他、細胞を播種したwellに薬剤の入っていない溶媒のみを添加した群（陽性対照群）、培地のみを入れたwellに薬剤の入っていない溶媒のみを添加した群（陰性対照群）を設けた。全てn=3 wellとした。
　薬剤を添加後3日間培養し、細胞内のATP量を指標にCellTiter Glo（登録商標）Reagent（PROMEGA Co.製 Cat.# G7570）を用いて細胞生存率を評価した。細胞生存率を50%阻害する濃度IC50値はXLFitソフトウエア Ver.3（登録商標）(CTC社製)を用いて算出した。 (Test Example 1)
Evaluation of antitumor activity against human pancreatic cancer-derived cell line SUIT-2 in combination with temozolomide As test substances, gemcitabine (hereinafter also referred to as Gemcitabine or Gem), temozolomide (hereinafter also referred to as Temozolomide) and methanesulfonate of Compound A Was used.
As gemcitabine, gemcitabine hydrochloride (manufactured by Plantex) dissolved in dimethyl sulfoxide (DMSO) was used. Temozolomide (LKT Laboratories, Inc. Cat. # T1849) used was dissolved in a serum-free medium RPMI-1640 (Cat. # 11875-119 manufactured by Thermo Fisher Scientific Inc.).
SUIT-2 cells, a human pancreatic cancer cell line, were subcultured in 10% serum (Cat. # 10437-028 manufactured by Thermo Fisher Scientific Inc.) medium RPMI-1640. During this test, all cell cultures were performed in a CO 2 incubator (37 ° C, 5% CO 2 setting, steam saturation). The solution was diluted with 10% serum medium to 15000 cells / well / 100 μL and seeded in a 96-well plate. On the next day, the culture supernatant of each well was discarded, washed twice with 150 μL of serum-free medium, and 100 μL of serum-free medium was added and cultured for 3 days.
Methanesulfonic acid salt of compound A and gemcitabine were dissolved in DMSO to prepare 100 mmol / L DMSO solutions, respectively. A DMSO solution having a concentration 1000 times the final treatment concentration was sequentially diluted with DMSO. Temozolomide was dissolved in a serum-free medium to prepare a Temozolomide solution of 1200 μmol / L. A DMSO diluted solution of Compound A and Gemcitabine was diluted with a Temozolomide solution (1200 μmol / L) to prepare treatment solutions each having a concentration 6 times the final treatment concentration. Compound A and Gemcitabine were used in combination with Temozolomide with a maximum concentration of 10 μmol / L and a common ratio of 1/3 and 9 concentrations.
20 μL of Compound A or Gemcitabine diluted with Temozolomide solution (1200 μmol / L) was added to each well. In addition, a group in which only a solvent without a drug was added to a well in which cells were seeded (positive control group), a group in which only a solvent without a drug was added to a well in which only a medium was added (negative control group) Provided. All were n = 3 well.
After adding the drug, the cells were cultured for 3 days, and the cell viability was evaluated using CellTiter Glo (registered trademark) Reagent (cat. # G7570 manufactured by PROMEGA Co.) using the intracellular ATP amount as an index. The concentration IC50 value that inhibits cell viability by 50% was calculated using XLFit software Ver.3 (registered trademark) (manufactured by CTC).

　陰性対照群の発光シグナル量を細胞生存率0%、陽性対照群の発光シグナル量を細胞生存率100%として、各ウェルの細胞生存率を求めた。各処理群の細胞生存率の平均値及び標準偏差を算出し、表１を作成した。 The cell viability of each well was determined with the amount of luminescent signal in the negative control group as 0% cell viability and the amount of luminescent signal in the positive control group as 100% cell viability. The average value and standard deviation of the cell viability of each treatment group were calculated, and Table 1 was created.

Temozolomide 200 μmol/Lとの併用試験結果 Combined test results with Temozolomide 200 μmol / L

Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001

　さらに、上記表１から作成したグラフを図１に示す。 Furthermore, the graph created from the above Table 1 is shown in FIG.

　表１から算出したゲムシタビンとテモゾロミドを併用したときのIC50値は10,000 nmol/L（nM）以上であり、化合物Ａとテモゾロミドを併用したときのIC50値は279.2 nmol/Lであった。このように、化合物Ａは、テモゾロミドの抗腫瘍効果を顕著に増強した。その効果は、既存薬であるゲムシタビンよりも大きいと考えられた。より詳細な説明は後述する。 The IC50 value when gemcitabine and temozolomide calculated from Table 1 were used together was 10,000 nmol / L (nM) or more, and the IC50 value when compound A and temozolomide were used together was 279.2 nmol / L. Thus, Compound A significantly enhanced the antitumor effect of temozolomide. The effect was thought to be greater than the existing drug gemcitabine. A more detailed description will be given later.

　本発明の併用効果について、併用効果の定量的指標となる併用係数（Combination Index:CI）を用いて評価した結果を示す。CIは、キャンサー・リサーチ、2010年、70巻、440～446頁に従って、以下の式で算出できる。
　すなわち、併用する薬剤を薬剤１及び薬剤２とすると、ある薬剤濃度におけるCIは、
CI＝｛（薬剤1及び薬剤2併用時の細胞生存率）÷100｝／｛［（薬剤1の細胞生存率）÷100］×［（薬剤2の細胞生存率）÷100］｝
CI＝1：相加効果
CI＞1：拮抗効果
CI＜1：相乗効果
　テモゾロミドとゲムシタビンを併用したときのCIは0.74であり、テモゾロミドと化合物Ａを併用したときのCIは0.23であった。CI＜1であるから、化合物Ａとテモゾロミドとの併用による相乗効果が認められた。また、CI値が小さいほど相乗効果が高いと推察されることから、化合物Ａの相乗効果は、既存薬であるゲムシタビンよりもより顕著であると言える。 The results of evaluating the combined effect of the present invention using a combination index (Combination Index: CI) that is a quantitative index of the combined effect are shown. CI can be calculated by the following formula according to Cancer Research, 2010, 70, 440-446.
That is, when the drugs used in combination are drug 1 and drug 2, CI at a certain drug concentration is
CI = {(cell survival rate when drug 1 and drug 2 are used in combination) ÷ 100} / {[(cell survival rate of drug 1) ÷ 100] × [(cell survival rate of drug 2) ÷ 100]}
CI = 1: additive effect
CI> 1: Antagonistic effect
CI <1: Synergistic effect CI when temozolomide and gemcitabine were used in combination was 0.74, and CI when temozolomide and compound A were used in combination was 0.23. Since CI <1, a synergistic effect by the combined use of Compound A and temozolomide was observed. Moreover, since it is estimated that a synergistic effect is so high that CI value is small, it can be said that the synergistic effect of compound A is more remarkable than the existing drug gemcitabine.

（試験例２）
　癌患者における化合物Aとアルキル化剤との併用効果試験
＜液状医薬組成物の調製＞
　化合物Ａのメタンスルホン酸塩を適量の注射用水に溶かし、1 mol/L水酸化ナトリウム水溶液を用いてpHを調整する。化合物Ａの濃度が20 mg/mLとなるように適量の注射用水を加えて混合する。
　また1.5質量%の濃度になるようにグリセリン（メルク社製、分子量92）を添加する。この液状医薬製剤のpHは2.9であり、この液をメンブランフィルター（0.22 μm）を用いてろ過し、液状医薬製剤を得ることができる。 (Test Example 2)
Combination effect test of compound A and alkylating agent in cancer patients <Preparation of liquid pharmaceutical composition>
Dissolve the methanesulfonate salt of Compound A in an appropriate amount of water for injection, and adjust the pH using a 1 mol / L aqueous sodium hydroxide solution. An appropriate amount of water for injection is added and mixed so that the concentration of Compound A is 20 mg / mL.
Further, glycerin (Merck, molecular weight 92) is added to a concentration of 1.5% by mass. The pH of this liquid pharmaceutical preparation is 2.9, and this liquid can be filtered using a membrane filter (0.22 μm) to obtain a liquid pharmaceutical preparation.

＜投与及び治療効果の判定＞ <Determination of administration and treatment effect>

　本発明の化合物Ａとテモゾロミドを併用する場合、がん患者に対して、化合物Ａを静脈注射、テモゾロミドを経口投与により5日間連続で、投与し、16日以上休薬するという投薬サイクルを繰り返す。化合物Ａの1回の投与当たりの投与量は、8～135 mg/m2とし、テモゾロミドの投与量は20～200 mg/m2とする。
　別の様態としては、がん患者に対して、第1日目は化合物Ａを静脈注射、テモゾロミドを経口投与により投与し、第2日目～第5日目まではテモゾロミドのみを経口投与し、16日以上休薬するという投薬サイクルを繰り返す。化合物Ａの1回の投与当たりの投与量は、8～135 mg/m2とし、テモゾロミドの投与量は20～200 mg/m2とする。 When the compound A of the present invention and temozolomide are used in combination, the administration cycle is repeated for cancer patients by intravenous injection of compound A and oral administration of temozolomide for 5 consecutive days and withdrawn for 16 days or more. The dose per administration of Compound A is 8 to 135 mg / m 2, and the dose of temozolomide is 20 to 200 mg / m 2 .
In another embodiment, compound A is intravenously injected on day 1 and temozolomide is orally administered to cancer patients, and only temozolomide is orally administered from day 2 to day 5, Repeat the dosing cycle with a withdrawal of 16 days or more. The dose per administration of Compound A is 8 to 135 mg / m 2, and the dose of temozolomide is 20 to 200 mg / m 2 .

　また、本発明の化合物Ａとシクロホスファミドを併用する場合、がん患者に対して、化合物Ａとシクロホスファミドを静脈注射により投与し、20日間休薬するという投薬サイクルを繰り返す。これを1クールとし，4～6クール繰り返す。化合物Ａの1回の投与当たりの投与量は、8～135 mg/m2とし、シクロホスファミドの投与量は50～1000 mg/m2とする。 When the compound A of the present invention and cyclophosphamide are used in combination, the dosing cycle of administering compound A and cyclophosphamide to the cancer patient by intravenous injection and withdrawing the drug for 20 days is repeated. Repeat this for 4 to 6 cools. The dose per administration of Compound A is 8 to 135 mg / m 2, and the dose of cyclophosphamide is 50 to 1000 mg / m 2 .

　治療の効果は、以下の基準で判定することができる。
　MRI(核磁気共鳴画像法；magnetic resonance imaging）による画像診断により評価対象を確認し、以下の基準で判定した。
CR（Complete Response）：腫瘍が完全に消失した状態
PR（Partial Response）：腫瘍の大きさの和が30%以上減少した状態
SD（Stable Disease）：腫瘍の大きさが変化しない状態
PD（Progressive Disease）：腫瘍の大きさの和が20%以上増加かつ絶対値でも5 mm以上増加した状態、あるいは新病変が出現した状態 The effect of treatment can be determined according to the following criteria.
The evaluation object was confirmed by diagnostic imaging using magnetic resonance imaging (MRI), and judged according to the following criteria.
CR (Complete Response): The tumor has completely disappeared
PR (Partial Response): The sum of tumor size is reduced by 30% or more
SD (Stable Disease): Tumor size does not change
PD (Progressive Disease): A condition in which the sum of tumor sizes has increased by 20% or more and the absolute value has increased by 5 mm or more, or a new lesion has appeared

　本発明は、顕著な抗腫瘍効果を示す抗腫瘍剤及び抗腫瘍用キット、並びに抗腫瘍効果増強剤として有用である。 The present invention is useful as an antitumor agent and an antitumor kit exhibiting a remarkable antitumor effect, and an antitumor effect enhancer.

Claims (7)

　アルキル化剤と、
　１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩とを含む抗腫瘍剤。 An alkylating agent;
An antitumor agent comprising 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof. 　前記アルキル化剤が、シクロホスファミド、イホスファミド、ダカルバジン、ニムスチン、テモゾロミド、ブスルファン、プロカルバジン、メルファラン、ラニムスチン及びチオテパからなる群から選ばれる少なくとも１つである、請求項１に記載の抗腫瘍剤。 The antitumor agent according to claim 1, wherein the alkylating agent is at least one selected from the group consisting of cyclophosphamide, ifosfamide, dacarbazine, nimustine, temozolomide, busulfan, procarbazine, melphalan, ranimustine, and thiotepa. . 　前記腫瘍が、膀胱癌、腎盂・尿管腫瘍、前立腺癌、精巣癌、卵巣癌、頭頸部癌、肺癌、食道癌、子宮頸癌、神経膠腫、神経芽細胞腫、胃癌、骨肉腫、胚細胞腫瘍、悪性胸膜中皮腫、胆道癌、大腸癌、小腸癌、悪性リンパ腫、乳癌、膵臓癌、肝癌、腎癌、悪性黒色腫、慢性骨髄性白血病または多発性骨髄腫である、請求項１または２に記載の抗腫瘍剤。 The tumor is bladder cancer, renal pelvis / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, lung cancer, esophageal cancer, cervical cancer, glioma, neuroblastoma, gastric cancer, osteosarcoma, embryo The tumor is malignant pleural mesothelioma, biliary tract cancer, colon cancer, small intestine cancer, malignant lymphoma, breast cancer, pancreatic cancer, liver cancer, renal cancer, malignant melanoma, chronic myelogenous leukemia or multiple myeloma. Or the antitumor agent of 2. 　前記腫瘍が、乳癌または膵臓癌である、請求項１～３のいずれか一項に記載の抗腫瘍剤。 The antitumor agent according to any one of claims 1 to 3, wherein the tumor is breast cancer or pancreatic cancer. 　アルキル化剤と併用される、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を含む抗腫瘍効果増強剤。 An antitumor effect potentiator containing 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof used in combination with an alkylating agent. 　アルキル化剤を含む製剤と、
　１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を含む製剤とを含む抗腫瘍用キット。 A formulation comprising an alkylating agent;
An anti-tumor kit comprising 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof. 　アルキル化剤と併用される、１－（２－デオキシ－２－フルオロ－４－チオ－β－Ｄ－アラビノフラノシル）シトシンまたはその塩を含む抗腫瘍剤。 An antitumor agent comprising 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine or a salt thereof used in combination with an alkylating agent.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023008511A1 (en) 2021-07-29 2023-02-02 富士フイルム株式会社 Pharmaceutical composition and anti-tumor agent for tumors that have at least either impaired bap1 or pbrm1 function

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013531069A (en) * 2010-07-19 2013-08-01 バイパー サイエンシズ，インコーポレイティド Method for treating metastatic breast cancer using 4-iodo-3-nitrobenzamide and irinotecan
WO2018043530A1 (en) * 2016-08-31 2018-03-08 富士フイルム株式会社 Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013531069A (en) * 2010-07-19 2013-08-01 バイパー サイエンシズ，インコーポレイティド Method for treating metastatic breast cancer using 4-iodo-3-nitrobenzamide and irinotecan
WO2018043530A1 (en) * 2016-08-31 2018-03-08 富士フイルム株式会社 Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AKAMATSU, HIROAKI: "Action mechanism of cancer pharmacotherapeutic agents, Cytotoxic antineoplastic agent, Platinum preparation, alkylating agent, and anticancer antibiotics", JAPANESE JOURNAL OF CLINICAL MEDICINE, vol. 72, no. suppl. 2, 2014, pages 124 - 126 *
MIMA, S. ET AL.: "FF-10502, an Antimetabolite with Novel Activity on Dormant Cells, Is Superior to Gemcitabine for Targeting Pancreatic Cancer Cells", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 366, no. 1, July 2018 (2018-07-01), pages 125 - 135, XP55636878 *
MIURA, S. ET AL.: "The antitumor mechanism of 1-(2-deoxy-2-fluoro-4-thio- beta -D-arabinofuranosyl)cytosine: effects of its triphosphate on mammalian DNA polymerases", JAPANESE JOURNAL OF CANCER RESEARCH, vol. 92, no. 5, 2001, pages 562 - 567, XP055213494, doi:10.1111/j.1349-7006.2001.tb01130.x *
ZAJCHOWSKI, D. ET AL.: "Anti-tumor efficacy of the nucleoside analog 1-(2-deoxy-2-fluoro-4-thio- beta -D-arabinofuranosyl)cytosine (4'-thio-FAC) in human pancreatic and ovarian xenograft models", PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH ANNUAL MEETING, vol. 45, 2004, pages 714, XP055213460, Retrieved from the Internet <URL:http://cancerres.aacrjournals.org/content/64/7_Supplement/714.3> [retrieved on 20190423] *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023008511A1 (en) 2021-07-29 2023-02-02 富士フイルム株式会社 Pharmaceutical composition and anti-tumor agent for tumors that have at least either impaired bap1 or pbrm1 function
KR20240028451A (en) 2021-07-29 2024-03-05 후지필름 가부시키가이샤 Pharmaceutical composition and anti-tumor agent for tumors with decreased function of at least one of BAP1 and PBRM1

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