WO2019176984A1 - 抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット - Google Patents
抗腫瘍剤、抗腫瘍効果増強剤及び抗腫瘍用キット Download PDFInfo
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
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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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
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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
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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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
- A61K31/70—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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).
- an antitumor platinum complex is known as a typical antitumor agent.
- a preparation containing an antitumor platinum complex as an active ingredient is known as a platinum preparation (platinum preparation).
- Typical anti-tumor platinum complexes include cisplatin, carboplatin, oxaliplatin, nedaplatin and the like, and are used for treatment of various malignant tumors.
- high nephrotoxicity and easy induction of resistant cancer are problematic in clinical settings (Non-patent Document 3).
- anti-tumor platinum complexes are also used as other anti-tumor agents.
- anti-tumor platinum complexes are also used as other anti-tumor agents.
- combination therapy Specifically, taxanes such as paclitaxel and docetaxel, camptothecins such as irinotecan and nogitecan, gemcitabine, 5-fluorouracil and capecitabine, nucleic acid metabolism antagonists such as tegafur, gimeracil and oteracil calcium combination (S-1), etoposide And combination therapy with topoisomerase II inhibitors such as doxorubicin, etc.
- the response rate for pancreatic cancer patients with a combination of gemcitabine and cisplatin is 11.5%, and the median survival time is 7.5 months (Non-patent Document 4).
- the median survival time is 5.7 months and the response rate is 9% (Non-patent Document 5), and it cannot be said that the therapeutic effect is sufficiently high in any combination therapy with any anti-tumor platinum complex.
- An object of the present invention is to provide an antitumor agent, an antitumor kit, and an antitumor effect potentiator that are superior in antitumor effect as compared with gemcitabine, an antitumor platinum complex (platinum preparation) and a combination therapy thereof. There is to do.
- the present inventors have found that an antitumor platinum complex and Compound A are used together to provide a remarkable antitumor effect, leading to the completion of the present invention. It was. That is, the present invention provides the following.
- An antitumor agent comprising an antitumor platinum complex and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof.
- the tumor is a testicular tumor, bladder cancer, renal pelvis / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, non-small cell lung cancer, small cell lung cancer, esophageal cancer, cervical cancer, glial Tumor, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumor (testis tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, colon cancer, rectal cancer, small intestine cancer, malignant lymphoma, breast cancer,
- the antitumor agent according to (1) or (2) which is pancreatic cancer, liver cancer, renal cancer, melanoma, leukemia, or multiple myeloma.
- An antitumor effect potentiator comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof used in combination with an antitumor platinum complex.
- Antitumor use comprising a preparation containing an antitumor platinum complex and a preparation containing 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof kit.
- An antitumor agent comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof used in combination with an antitumor platinum complex.
- (6-1) The antitumor effect enhancer according to (6), wherein the antitumor platinum complex is at least one selected from the group consisting of cisplatin, oxaliplatin and carboplatin.
- 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 antitumor platinum complex
- a method for treating a tumor which comprises administering to a subject in combination with a therapeutically effective dose when used in combination therapy.
- 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 antitumor platinum complex
- a therapeutic method for a tumor which comprises administering to a subject a therapeutically effective dose when used in combination therapy simultaneously, separately, sequentially or at intervals.
- Compound A or a salt thereof exhibits a remarkable antitumor effect when used in combination with an antitumor platinum complex. That is, the antitumor agent and antitumor kit of the present invention have an excellent antitumor effect as compared with gemcitabine alone, an antitumor platinum complex alone, or a combination of gemcitabine and an antitumor platinum complex.
- the antitumor effect enhancer of the present invention can enhance the antitumor effect by being administered in combination with an antitumor platinum complex.
- FIG. 1 is a graph showing the combined effect of compound A and cisplatin on cell viability of human pancreatic cancer-derived cell line SUIT-2.
- FIG. 2 is a graph showing the combined effect of compound A and oxaliplatin on the cell viability of human pancreatic cancer-derived cell line SUIT-2.
- FIG. 3 is a graph showing the combined effect of Compound A and cisplatin on the cell viability of human ovarian cancer cell line ES-2.
- FIG. 4 is a graph showing the combined effect of Compound A and cisplatin on cell viability of human ovarian cancer cell line SK-OV-3.
- FIG. 1 is a graph showing the combined effect of compound A and cisplatin on cell viability of human pancreatic cancer-derived cell line SUIT-2.
- FIG. 2 is a graph showing the combined effect of compound A and oxaliplatin on the cell viability of human pancreatic cancer-derived cell line SUIT-2.
- FIG. 3 is
- FIG. 5 is a graph showing the combined effect of Compound A and carboplatin on the cell viability of the human ovarian cancer cell line SK-OV-3.
- FIG. 6 is a graph showing the combined effect of Compound A and carboplatin on the cell viability of human ovarian cancer cell line ES-2.
- FIG. 7 is a graph showing the combined effect of Compound A and cisplatin on the cell viability of the human cholangiocarcinoma-derived cell line HuCC-T1.
- FIG. 8 is a graph showing the combined effect of Compound A and cisplatin on cell viability of human cholangiocarcinoma-derived cell line TFK-1 under spheroid culture.
- FIG. 9 is a graph showing the combined effect of Compound A and cisplatin on the cell viability of the human cholangiocarcinoma-derived cell line HuCC-T1 under spheroid culture.
- FIG. 10 is a graph showing the combined effect of Compound A and cisplatin on cell viability of human breast cancer-derived cell line HCC1954 under spheroid culture.
- 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 relates to an antitumor agent comprising an antitumor platinum complex and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine (compound A) or a salt thereof. is there.
- the present invention also provides an antitumor agent comprising a combination of an antitumor platinum complex 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 antitumor platinum complex is completely the same.
- one administration schedule includes an embodiment in which the compound of the present invention and the antitumor platinum complex are administered, the form in which these are administered simultaneously or separately means “combination”.
- the antitumor platinum complex may be administered after the compound of the invention is administered first.
- the compound of the present invention may be administered after the antitumor platinum complex 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.
- examples of the anti-tumor platinum complex include cisplatin, carboplatin, oxaliplatin, nedaplatin, xeniplatin, enroplatin, ormaplatin, loboplatin, sebritplatin, lobaplatin, miboplatin, or spiroplatin. It is done.
- cisplatin, carboplatin, oxaliplatin or nedaplatin is preferable, and cisplatin, carboplatin or oxaliplatin is more preferable.
- antitumor platinum complexes can be produced by known methods. These anti-tumor platinum complexes can also be obtained by purchasing commercially available products.
- cisplatin is commercially available as Randa (registered trademark) from Nippon Kayaku Co., Ltd., Platosin (registered trademark) from Pfizer Inc., Cisplamerck (registered trademark) from Merck Co., Ltd. and Briplatin (registered trademark) from Bristol Myers Co., Ltd. Has been.
- Carboplatin is commercially available as Paraplatin® from Bristol-Myers, Inc. and Carbomerck® from Merck.
- Oxaliplatin is commercially available from Yakult Honsha as Elplat® or Eloxatin®.
- Nedaplatin is commercially available as Aqupla (registered trademark) from Nichi-Iko Co., Ltd.
- Miboplatin is commercially available from Chugai as miboplatin hydrochloride or Lobaplatin®
- the antitumor platinum complex may form a pharmaceutically acceptable salt (hereinafter sometimes referred to as “the salt”) with an acid or a base.
- the antitumor platinum complex of the present invention also includes these pharmaceutically acceptable salts.
- the antitumor platinum complex may be used alone or in combination of two or more.
- the composition containing them other than an antitumor platinum complex or its salt may be sufficient.
- 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 antitumor platinum complex, it is expected to have an action of enhancing the antitumor effect of the antitumor platinum complex without showing a marked increase in toxicity.
- An antitumor agent comprising an antitumor platinum complex and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof; and a combination with an antitumor platinum complex
- An antitumor agent comprising 1- (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 antitumor platinum complex and Compound A or a salt thereof is an antitumor platinum even if it is a one-part preparation containing an antitumor platinum complex and Compound A or a salt thereof. It may be a two-drug preparation containing the complex and Compound A or a salt thereof. Preferably, it is a two-drug preparation in which the antitumor platinum complex 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 antitumor platinum complex 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.
- 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 .
- Anti-tumor platinum complexes can be administered according to known clinical practices.
- the dosage and dosing schedule can be varied according to the specific disease symptoms and the overall symptoms of the patient. For example, for adults, 1 to 2000 mg / m 2 is usually divided into 1 to several times per day for adults by oral or parenteral administration (eg, injection, infusion, and administration to the rectal site).
- 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.
- the dose or amount of the antitumor platinum complex and compound A or a salt thereof contained in the antitumor agent of the present invention 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 antitumor platinum complex, but is, for example, about 0.0001 to 10,000 times (weight ratio) of the antitumor platinum complex, preferably about 0.001 to 1000 times (weight ratio).
- the combination of Compound A and cisplatin 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
- the dosage of cisplatin is 1 to 2000 mg / m 2 , preferably 10 to 2000 mg / m 2 per day for an adult.
- the dose of the compound of the present invention is about 0.0001 to 10,000 times (weight ratio) of cisplatin, preferably about 0 0.001 to 1000 times (weight ratio).
- the dosage of cisplatin is 1 to 100 mg / m 2 , preferably 5 to 50 mg / m 2 , more preferably 10 to 50 mg / m 2 , more preferably 1 day per adult. and 10 ⁇ 30mg / m 2, further doses of the compounds of the present invention, about 0.2 to 200 times of cisplatin (weight ratio), so preferably a 1.6 to 15 times (weight ratio) To do.
- the dose of Compound A of the present invention is 20 to 200 mg / m 2 , preferably 40 to 200 mg / m 2 per day for an adult. More preferably 40 to 150 mg / m 2 , more preferably 80 to 150 mg / m 2, and the dose of carboplatin is 10 to 2000 mg / m 2 , preferably 50 to 1000 mg / m 2 per day for an adult.
- the dose of the compound of the present invention is 100 to 500 mg / m 2, and the dose of the compound of the present invention is about 0.0001 to 10,000 times (weight ratio), preferably about 0.001 to 1000 times (weight ratio) of carboplatin, and more. Preferably about 0.01 to 20 times (weight ratio), more preferably about 0.16 to 1.5 times (weight ratio). That.
- the dose of the compound A of the present invention is 20 to 200 mg / m 2 , preferably 40 to 200 mg / m 2 per day for an adult. 2 , more preferably 40 to 150 mg / m 2 , still more preferably 80 to 150 mg / m 2, and the dosage of oxaliplatin is 10 to 2000 mg / m 2 , preferably 50 to 1000 mg / m 2 per day for an adult.
- the dose is 100 to 500 mg / m 2, and the dose of the compound of the present invention is about 0.0001 to 10000 times (weight ratio), preferably about 0.001 to 1000 times (weight ratio) of oxaliplatin. ).
- the dose of oxaliplatin is 10 to 500 mg / m 2 , preferably 50 to 500 mg / m 2 , more preferably 50 to 150 mg / m 2 per day for an adult.
- the dose of the compound of the invention is about 0.04 to 20 times (weight ratio), preferably about 0.53 to 3 times (weight ratio) of oxaliplatin.
- 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.
- the antitumor agent of the present invention is, for example, testicular tumor, bladder cancer, renal pelvic / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, non-small cell lung cancer, small cell 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, rectal cancer, small intestine cancer, malignant lymphoma It can be used effectively in the treatment of various types of tumors, including breast cancer, pancreatic cancer, liver cancer, renal cancer, melanoma, leukemia, multiple myeloma or other organ tumors.
- testicular tumor bladder cancer, renal pelvic / ureteral tumor, prostate cancer, ovarian cancer, head and neck cancer
- non-small cell lung cancer small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma
- Germ cell tumor testis tumor, ovarian tumor, extragonadal tumor
- malignant pleural mesothelioma biliary tract cancer, colon cancer
- rectal cancer malignant lymphoma, breast cancer, pancreatic cancer, bladder cancer, ovarian cancer, biliary tract cancer, Breast cancer or pancreatic cancer
- biliary tract cancer is more preferred, and is particularly effective for the treatment of bile duct cancer.
- the present invention also relates to an antitumor effect enhancer comprising Compound A or a salt thereof for enhancing the antitumor effect of an antitumor platinum complex for cancer patients. That is, according to the present invention, Provided is an antitumor effect enhancer comprising 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof in combination with an antitumor platinum complex.
- 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 with the antitumor platinum complex, separately, continuously or at intervals.
- 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 antitumor platinum complex, but is, for example, about 0.0001 to 10,000 times (weight ratio) of the antitumor platinum complex, 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 testicular tumor, bladder cancer, renal pelvic / ureteral tumor, prostate cancer, testicular cancer, ovarian cancer, head and neck cancer, non-small cell lung cancer, small cell 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, rectal cancer, small intestine cancer, malignant lymphoma It can be used effectively in the treatment of various types of tumors, including breast cancer, pancreatic cancer, liver cancer, renal cancer, melanoma, leukemia, multiple myeloma or other organ tumors.
- testicular tumor bladder cancer, renal pelvic / ureteral tumor, prostate cancer, ovarian cancer, head and neck cancer
- non-small cell lung cancer small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma
- Germ cell tumor testis tumor, ovarian tumor, extragonadal tumor
- malignant pleural mesothelioma biliary tract cancer, colon cancer
- rectal cancer malignant lymphoma, breast cancer, pancreatic cancer, bladder cancer, ovarian cancer, biliary tract cancer, Breast cancer or pancreatic cancer
- biliary tract cancer is more preferred, and is particularly effective for the treatment of bile duct cancer.
- an antitumor kit comprising a preparation containing an antitumor platinum complex and a preparation containing 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof. Is done.
- the antitumor kit of the present invention is a kit comprising a combination of (a) an antitumor platinum complex and (b) compound A or a salt thereof.
- (a) the antitumor platinum complex and (b) compound A or a salt thereof can be in various known preparation forms, and various containers that are usually used depending on the preparation form. Is housed in.
- the antitumor platinum complex 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 antitumor platinum complex and (b) compound A or a salt thereof are contained in separate containers.
- the present invention provides an antitumor platinum complex and 1- (2-deoxy-2-fluoro-4-thio- ⁇ -D-arabinofuranosyl) cytosine or a salt thereof for use in treating a tumor.
- a method for use in the treatment of bladder cancer, ovarian cancer, biliary tract cancer, breast cancer or pancreatic cancer comprising the step of administering a therapeutically effective dose to a subject (mammals including humans) in need of such treatment.
- a method of including is provided.
- 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 antitumor platinum
- a method for treating a tumor which comprises administering to a subject in combination with a therapeutically effective dose when the complex is used in combination therapy.
- the present invention relates to 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 antitumor platinum
- a method for treating a tumor characterized in that a therapeutically effective dose when a complex is used for combination therapy is administered to a subject simultaneously, separately, sequentially or at intervals.
- cytosine or a salt thereof can be used for producing an antitumor agent in combination with an antitumor platinum complex.
- cytosine or a salt thereof can be used for an antitumor agent in combination with an antitumor platinum complex.
- ⁇ -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.
- Test Example 1 Evaluation of anti-tumor activity against human pancreatic cancer cell line SUIT-2 by combined use of cisplatin and oxaliplatin And Oxaliplatin) and the methanesulfonate of Compound A were used.
- gemcitabine gemcitabine hydrochloride (manufactured by Plantex) dissolved in dimethyl sulfoxide (DMSO) was used.
- Cisplatin Cat. # 039-20091 manufactured by Wako Pure Chemical Industries, Ltd.
- oxaliplatin Cat. # O0372 manufactured by Tokyo Chemical Industry Co., Ltd.
- RPMI-1640 Cat. # 11875-119 manufactured by Thermo Fisher Scientific Inc.
- 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.
- Cisplatin and Oxaliplatin were dissolved in a serum-free medium to prepare Cisplatin solution 30 ⁇ mol / L and Oxaliplatin solution 60 ⁇ mol / L, respectively.
- a DMSO-diluted solution of Compound A and Gemcitabine was diluted with a Cisplatin solution (30 ⁇ mol / L) or an Oxaliplatin solution (60 ⁇ 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 Cisplatin or Oxaliplatin 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 Cisplatin solution (30 ⁇ mol / L) or Oxaliplatin solution (60 ⁇ 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 at which cell viability was inhibited by 50% (IC50 value) 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.
- Tables 1 and 2 were prepared by calculating the average value and standard deviation of the cell viability of each treatment group.
- the IC50 value when gemcitabine and cisplatin calculated from Table 1 were used in combination was 1138.3 nmol / L (nM), and the IC50 value when compound A and cisplatin were used in combination was 12.9 nmol / L.
- the IC50 value calculated from Table 2 when gemcitabine and oxaliplatin were used in combination was 10,000 nmol / L or more, and the IC50 value when compound A and oxaliplatin were used in combination was 73.4 nmol / L.
- Compound A significantly enhanced the antitumor effects of cisplatin and oxaliplatin. The effect was thought to be greater than the existing drug gemcitabine. A more detailed description will be given later.
- CI Combination Index
- the CI when oxaliplatin and gemcitabine were used in combination was 0.97, and the CI when oxaliplatin and compound A were used in combination was 0.44. Since CI ⁇ 1, a synergistic effect by the combined use of Compound A and cisplatin or oxaliplatin 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.
- ES-2 and SK-OV-3 cells were subcultured in 10% serum medium. During this test, all cell cultures were performed in a CO 2 incubator (37 ° C, 5% CO 2 setting, steam saturation). ES-2 cells were diluted with 10% serum medium to 10,000 cells / well / 100 ⁇ L and SK-OV-3 cells to 15,000 cells / well / 100 ⁇ L, and seeded in 96-well plates.
- a DMSO-diluted solution of Compound A and Gemcitabine was diluted with a Cisplatin solution (60 ⁇ mol / L) or an Oxaliplatin solution (600 ⁇ 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 Cisplatin or Oxaliplatin 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 Cisplatin solution (60 ⁇ mol / L) or Oxaliplatin solution (600 ⁇ 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
- 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
- All were n 3 well.
- 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 at which cell viability was inhibited 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 Tables 3 to 6 were prepared.
- the IC50 value when compound A and cisplatin were used together was 63.2 nmol / L.
- the IC50 value was 3797.2 nmol / L, and the IC50 value when compound A and cisplatin were used in combination was 82.2 nmol / L. It was.
- the antitumor activity against human cholangiocarcinoma-derived cell line HuCC-T1 in combination with cisplatin was evaluated in the same manner as in Test Example 1.
- As test substances gemcitabine, cisplatin and methanesulfonate of Compound A were used.
- gemcitabine gemcitabine hydrochloride (manufactured by Plantex) dissolved in DMSO was used.
- Cisplatin (Cat. # 039-20091 manufactured by Wako Pure Chemical Industries, Ltd.) dissolved in a serum-free medium RPMI-1640 (Cat. # 11875-119 manufactured by Thermo Fisher Scientific Inc.) was used.
- HuCC-T1 cells a human cholangiocarcinoma 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.
- Cisplatin was dissolved in a serum-free medium to prepare a Cisplatin solution 60 ⁇ mol / L.
- a DMSO diluted solution of compound A and gemcitabine was diluted with a Cisplatin solution (60 ⁇ 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 Cisplatin at a maximum ratio of 10 ⁇ mol / L and a common ratio of 1/3 with 9 concentrations.
- 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 8 was created.
- the IC50 value calculated from Table 8 when gemcitabine and cisplatin were used in combination was 10,000 nmol / L or more, and when compound A and cisplatin were used in combination, the IC50 value was 261.0 nmol / L.
- Compound A significantly enhanced the antitumor effect of cisplatin. The effect was thought to be greater than the existing drug gemcitabine.
- the CI when cisplatin and gemcitabine were used in combination was 0.90, and the CI when cisplatin and compound A were used in combination was 0.34. Since CI ⁇ 1, a synergistic effect by the combined use of Compound A and cisplatin 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.
- Cisplatin was dissolved in DMSO to prepare a 100 mmol / L DMSO solution. Dilute with DMSO to prepare a DMSO solution 5000 times the final treatment concentration. Further, a DMSO solution of Cisplatin was diluted with 10% serum medium to prepare a Cisplatin-containing medium having a concentration 10 times the final treatment concentration. A DMSO-diluted solution of Compound A and Gemcitabine was diluted with a medium containing Cisplatin to prepare treatment solutions each having a concentration 10 times the final treatment concentration. Compound A and gemcitabine were used in combination with Cisplatin (10 ⁇ mol / L) at a maximum ratio of 10 ⁇ mol / L and a common ratio of 1/3 with 9 concentrations.
- 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 9 was created.
- the IC50 value when gemcitabine and cisplatin (10 ⁇ mol / L) are combined in spheroid culture is 10000 nmol / L or more, and the IC50 value when compound A and cisplatin (5 ⁇ mol / L) are combined is 469.3 nmol / L L.
- Compound A significantly enhanced the antitumor effect of cisplatin. The effect was thought to be greater than the existing drug gemcitabine.
- the CI when cisplatin and gemcitabine were used in combination was 0.78, and the CI when cisplatin and compound A were used in combination was 0.13. Since CI ⁇ 1, a synergistic effect by the combined use of Compound A and cisplatin 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.
- Cisplatin was dissolved in DMSO to prepare a 100 mmol / L DMSO solution. Dilute with DMSO to prepare a DMSO solution 5000 times the final treatment concentration. Further, a DMSO solution of Cisplatin was diluted with 10% serum medium to prepare a Cisplatin-containing medium having a concentration 10 times the final treatment concentration. A DMSO-diluted solution of Compound A and Gemcitabine was diluted with a medium containing Cisplatin to prepare treatment solutions each having a concentration 10 times the final treatment concentration. Compound A and gemcitabine were used in combination with Cisplatin (10 ⁇ mol / L) at a maximum ratio of 10 ⁇ mol / L and a common ratio of 1/3 with 9 concentrations.
- 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 10 was created.
- the IC50 value when gemcitabine and cisplatin (10 ⁇ mol / L) are used together in spheroid culture is 10000 nmol / L or more, and the IC50 value when compound A and cisplatin (10 ⁇ mol / L) are used is 164.6 nmol / L L.
- Compound A significantly enhanced the antitumor effect of cisplatin. The effect was thought to be greater than the existing drug gemcitabine.
- the CI when cisplatin and gemcitabine were used in combination was 0.79, and the CI when cisplatin and compound A were used in combination was 0.42. Since CI ⁇ 1, a synergistic effect by the combined use of Compound A and cisplatin 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.
- DMSO dilute with DMSO to prepare a DMSO solution 5000 times the final treatment concentration. Further, a DMSO solution of Cisplatin was diluted with 10% serum medium to prepare a Cisplatin-containing medium having a concentration 10 times the final treatment concentration. A DMSO-diluted solution of Compound A and Gemcitabine was diluted with a medium containing Cisplatin to prepare treatment solutions each having a concentration 10 times the final treatment concentration. Compound A and Gemcitabine were used in combination with Cisplatin (10 ⁇ mol / L, 5 ⁇ mol / L) at a maximum ratio of 10 ⁇ mol / L and a common ratio of 1/3 with 9 concentrations.
- 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 11 was created.
- the IC50 value when gemcitabine and cisplatin (10 ⁇ mol / L) are used in combination in spheroid culture is 10000 ⁇ mol / L or more, and the IC50 value when compound A is combined with cisplatin (10 ⁇ mol / L) is 49.4 ⁇ mol / L. L.
- Compound A significantly enhanced the antitumor effect of cisplatin. The effect was thought to be greater than the existing drug gemcitabine.
- CI when cisplatin and gemcitabine were used in combination was 0.60
- CI when cisplatin and compound A were used in combination was 0.03. Since CI ⁇ 1, a synergistic effect by the combined use of Compound A and cisplatin 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.
- Test Example 7 Combined effect test in a tumor-bearing model mouse subcutaneously transplanted with a bile duct cancer cell line Gemcitabine and methanesulfonate of compound A are used as test substances.
- Gemcitabine was obtained by dissolving gemcitabine hydrochloride (manufactured by TEVA) in physiological saline, and cisplatin was obtained by dissolving cisplatin (Cat. # 039-20091, manufactured by Wako Pure Chemical Industries, Ltd.) in physiological saline. Is used.
- Human cholangiocarcinoma cell lines TFK-1 cells or HuCCT-1 cells are injected subcutaneously into the posterior flank of 5-6 week old female BALB / cA Jcl-nu mice. After tumor transplantation, the major axis (mm) and minor axis (mm) of the tumor are measured, and the tumor volume (TV) is calculated. Mice are assigned to each group so that the average TV of each group is equal, and the day when this grouping is performed is defined as day 1.
- the dose of cisplatin was set with reference to the interview form and CANCER GENOMICS & PROTEOMICS, 2012, Vol. 9, p77-92 (Non-patent document 6).
- the doses of gemcitabine and compound A were Non-patent document 6 and The journal of pharmacology and experimental therapeutics, 2018, 366, 125-135 (non-patent document 7) Set for reference.
- the test solution of cisplatin alone group is prepared so that the administration dose is 1 to 10 mg / kg / day.
- the test solution for compound A alone is prepared to be 30 to 240 mg / kg / day.
- Compound A is administered from mouse tail vein once a week from day 1 for a total of 3 times, and cisplatin is administered by intraperitoneal administration of mice once a week from day 1 for a total of 3 times.
- Compound A is administered at 30 to 240 mg / kg / day and cisplatin is administered at 1 to 10 mg / kg / day.
- gemcitabine is used as a control drug.
- Prepare the test solution of gemcitabine alone group at 30-240 mg / kg / day.
- Gemcitabine is administered from the tail vein of mice once a week from day 1 for a total of 3 times.
- gemcitabine is administered at 30 to 240 mg / kg / day and cisplatin is administered at 1 to 10 mg / kg / day.
- the MTD of each drug is used for dose setting of Compound A and gemcitabine.
- Cisplatin uses the maximum dose that can be tolerated in combination with each drug. Antitumor agents are extremely close in dose to the maximum drug efficacy and doses of toxicity, and in order to evaluate the maximum antitumor effect of the drug in an animal model, it is common to evaluate in the vicinity of MTD. MTD and maximum effect dose are almost synonymous.
- the TV in each drug administration group was measured, and the relative tumor volume (RTV) and T / C (%) relative to day 1 were calculated by the following formula to obtain the antitumor effect. evaluate. Evaluation of combination effect is judged as having combination effect when the mean RTV value in the combination treatment group is statistically significant (Welch's IUT, over all maximum p ⁇ 0.05) than the mean RTV value in each individual treatment group To do.
- TV (mm 3 ) (major axis x minor axis 2 ) / 2
- RTV (TV on tumor measurement day) / (TV on Day 1)
- T / C (%) [(average RTV value of test solution administration group) / (average RTV value of control group)] ⁇ 100
- the dosing cycle is repeated in which the compound A and cisplatin are administered intravenously once a week from the first week to the second week and not administered in the third week. Specifically, with 21 days as one cycle, Compound A and cisplatin are administered on the first day and the eighth day, and the cycle consisting of these 21 days is repeated.
- the dose per administration of Compound A is 8 to 135 mg / m 2 and the dose of cisplatin is 10 to 50 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.
Abstract
Description
例えば、ゲムシタビンとシスプラチンとの併用での膵臓癌患者に対する奏効率は11.5%、生存期間中央値は7.5ヶ月であり(非特許文献4)、ゲムシタビンとオキサリプラチンとの併用では、それぞれ生存期間中央値5.7ヶ月、奏功率9%であり(非特許文献5)、いずれの抗腫瘍性白金錯体との併用療法においても治療効果として十分に高いとは言えない。
本発明の課題は、ゲムシタビン、抗腫瘍性白金錯体(白金製剤)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。
すなわち、本発明は、下記を提供する。
(1)抗腫瘍性白金錯体と、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)上記抗腫瘍性白金錯体が、シスプラチン、オキサリプラチン及びカルボプラチン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、睾丸腫瘍、膀胱癌、腎盂・尿管腫瘍、前立腺癌、精巣癌、卵巣癌、頭頸部癌、非小細胞肺癌、小細胞肺癌、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、結腸癌、直腸癌、小腸癌、悪性リンパ腫、乳癌、膵臓癌、肝癌、腎癌、黒色腫、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、膀胱癌、卵巣癌、胆道癌、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)上記胆道癌が胆管癌である、(4)に記載の抗腫瘍剤。
(6)抗腫瘍性白金錯体と併用される、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。
(7)抗腫瘍性白金錯体を含む製剤と、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。
(8)抗腫瘍性白金錯体と併用される、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。
(6-1)上記抗腫瘍性白金錯体がシスプラチン、オキサリプラチン及びカルボプラチンからなる群から選ばれる少なくとも1つである、(6)に記載の抗腫瘍効果増強剤。
(7-1)上記抗腫瘍性白金錯体がシスプラチン、オキサリプラチン及びカルボプラチンからなる群から選ばれる少なくとも1つである、(7)に記載の抗腫瘍用キット。
(8-1)上記抗腫瘍性白金錯体がシスプラチン、オキサリプラチン及びカルボプラチンからなる群から選ばれる少なくとも1つである、(8)に記載の抗腫瘍剤。
(9)抗腫瘍性白金錯体と、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、膀胱癌、卵巣癌、胆道癌、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。
(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、抗腫瘍性白金錯体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。
(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を併用治療に用いる場合の治療有効用量、及び、抗腫瘍性白金錯体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。
(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、抗腫瘍性白金錯体と組み合わせてなる抗腫瘍剤の製造のための使用。
(13)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、抗腫瘍性白金錯体と組み合わせてなる抗腫瘍剤のための使用。
(14)抗腫瘍性白金錯体と、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。
(15)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。
(16)抗腫瘍性白金錯体がシスプラチンであり、1日当たりの投与量が、1~100mg/m2である、(15)に記載の抗腫瘍剤。
(17)抗腫瘍性白金錯体がカルボプラチンであり、1日当たりの投与量が、50~1000mg/m2である、(15)に記載の抗腫瘍剤。
(18)抗腫瘍性白金錯体がオキサリプラチンであり、1日当たりの投与量が、10~500mg/m2である、(15)に記載の抗腫瘍剤。
「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。
本発明は、抗腫瘍性白金錯体と、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、抗腫瘍性白金錯体と、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。
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。
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。
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。
本発明において、抗腫瘍性白金錯体(抗腫瘍作用を有する白金錯体)は、例えば、シスプラチン、カルボプラチン、オキサリプラチン、ネダプラチン、ゼニプラチン、エンロプラチン、オルマプラチン、ロボプラチン、セブリプラチン、ロバプラチン、ミボプラチンまたはスピロプラチン等が挙げられる。
本発明の抗腫瘍性白金錯体としては、シスプラチン、カルボプラチン、オキサリプラチンまたはネダプラチンが好ましく、シスプラチン、カルボプラチンまたはオキサリプラチンがより好ましい。
これらの抗腫瘍性白金錯体は、公知の方法で製造できる。
また、これらの抗腫瘍性白金錯体は、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、シスプラチンは、日本化薬株式会社からRanda(登録商標)、ファイザー株式会社からPlatosin(登録商標)、メルク株式会社からCisplamerck(登録商標)及びブリストル・マイヤーズ株式会社からBriplatin(登録商標)として市販されている。カルボプラチンは、ブリストル・マイヤーズ株式会社からParaplatin(登録商標)及びメルク株式会社からCarbomerck(登録商標)として市販されている。オキサリプラチンは、ヤクルト本社からElplat(登録商標)またはEloxatin(登録商標)として市販されている。ネダプラチンは日医工株式会社からAqupla(登録商標)として市販されている。ミボプラチンは、中外製薬からミボプラチン塩酸塩またはLobaplatin(登録商標)として市販されている。
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、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。
本発明によれば、
抗腫瘍性白金錯体と、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
抗腫瘍性白金錯体と併用される、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。
抗腫瘍性白金錯体と、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、抗腫瘍性白金錯体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)。
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。
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。
使用する本発明の化合物Aの量は、抗腫瘍性白金錯体との個々の組み合わせによって異なるが、例えば、抗腫瘍性白金錯体の約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。
また、別の態様としては、例えば、シスプラチンの投与量を、成人1日あたり、1~100mg/m2、好ましくは5~50mg/m2、より好ましくは10~50mg/m2、さらに好ましくは10~30mg/m2とし、さらに、本発明の化合物の投与量を、シスプラチンの約0.2~200倍(重量比)、好ましくは約1.6~15倍(重量比)となるようにする。
また、別の態様としては、オキサリプラチンの投与量を、成人1日あたり、10~500mg/m2、好ましくは50~500mg/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、オキサリプラチンの約0.04~20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。
本発明の抗腫瘍剤は、例えば、睾丸腫瘍、膀胱癌、腎盂・尿管腫瘍、前立腺癌、精巣癌、卵巣癌、頭頸部癌、非小細胞肺癌、小細胞肺癌、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、結腸癌、直腸癌、小腸癌、悪性リンパ腫、乳癌、膵臓癌、肝癌、腎癌、黒色腫、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、睾丸腫瘍、膀胱癌、腎盂・尿管腫瘍、前立腺癌、卵巣癌、頭頸部癌、非小細胞肺癌、小細胞肺癌、食道癌、子宮頸癌、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、結腸癌、直腸癌、悪性リンパ腫、乳癌、膵臓癌が好ましく、膀胱癌、卵巣癌、胆道癌、乳癌または膵臓癌がより好ましく、胆道癌がさらに好ましく、特に胆管癌の処置に有効である。
本発明はまた、癌患者に対する抗腫瘍性白金錯体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、
抗腫瘍性白金錯体と併用される、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。
使用する本発明の化合物Aの量は、抗腫瘍性白金錯体との個々の組み合わせによって異なるが、例えば、抗腫瘍性白金錯体の約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。
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。
本発明の抗腫瘍効果増強剤は、睾丸腫瘍、膀胱癌、腎盂・尿管腫瘍、前立腺癌、精巣癌、卵巣癌、頭頸部癌、非小細胞肺癌、小細胞肺癌、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、結腸癌、直腸癌、小腸癌、悪性リンパ腫、乳癌、膵臓癌、肝癌、腎癌、黒色腫、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、睾丸腫瘍、膀胱癌、腎盂・尿管腫瘍、前立腺癌、卵巣癌、頭頸部癌、非小細胞肺癌、小細胞肺癌、食道癌、子宮頸癌、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、結腸癌、直腸癌、悪性リンパ腫、乳癌、膵臓癌が好ましく、膀胱癌、卵巣癌、胆道癌、乳癌または膵臓癌がより好ましく、胆道癌がさらに好ましく、特に胆管癌の処置に有効である。
本発明によれば、
抗腫瘍性白金錯体を含む製剤と、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)抗腫瘍性白金錯体及び(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)抗腫瘍性白金錯体及び(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)抗腫瘍性白金錯体及び(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)抗腫瘍性白金錯体及び(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。
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。
シスプラチン及びオキサリプラチン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)、シスプラチン(以下、Cisplatinともいう)、オキサリプラチン(以下、Oxaliplatin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。シスプラチン(和光純薬工業社製Cat.# 039-20091)及びオキサリプラチン(東京化成工業社製Cat.# O0372)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。Cisplatin及びOxaliplatinを無血清培地に溶解し、Cisplatin溶液 30 μmol/L及びOxaliplatin溶液60 μmol/Lをそれぞれ調製した。化合物A及びGemcitabineのDMSO希釈溶液を、Cisplatin溶液(30 μmol/L)またはOxaliplatin溶液(60 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CisplatinまたはOxaliplatinと組み合わせて使用した。
Cisplatin溶液(30 μmol/L)またはOxaliplatin溶液(60 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。
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
シスプラチンとゲムシタビンを併用したときのCIは0.96であり、シスプラチンと化合物Aを併用したときのCIは0.36であった。オキサリプラチンとゲムシタビンを併用したときのCIは0.97であり、オキサリプラチンと化合物Aを併用したときのCIは0.44であった。CI<1であるから、化合物Aとシスプラチンまたはオキサリプラチン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。
シスプラチン及びカルボプラチンとの併用によるヒト卵巣癌細胞株ES-2及びSK-OV-3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、シスプラチン、カルボプラチン及び化合物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DMSOに溶解させたものを用いた。シスプラチン(和光純薬工業社製Cat.# 039-20091)及びカルボプラチン(東京化成工業社製Cat.# C2043)は、1%血清(Thermo Fisher Scientific Inc. 製 Cat.# 10437-028)培地 McCoy's 5a (Thermo Fisher Scientific Inc.製Cat.# 16600-082)に溶解させたものを用いた。
ヒト卵巣癌細胞株であるES-2及びSK-OV-3細胞を10%血清培地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。ES-2細胞を10,000 cells/well/100 μL、SK-OV-3細胞を15,000 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1%血清培地で2回洗い、100 μLの1%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。Cisplatin及びCarboplatinを1%血清培地に溶解し、Cisplatin溶液 60 μmol/L及びCarboplatin溶液600 μmol/Lをそれぞれ調製した。化合物A及びGemcitabineのDMSO希釈溶液を、Cisplatin溶液(60 μmol/L)またはOxaliplatin溶液(600 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CisplatinまたはOxaliplatinと組み合わせて使用した。
Cisplatin溶液(60 μmol/L)またはOxaliplatin溶液(600 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。
ES-2細胞
SK-OV-3細胞
SK-OV-3細胞
それぞれの評価において化合物Aは、シスプラチンまたはカルボプラチンとの併用による相乗効果が認められ、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結果を得た。
シスプラチンとの併用によるヒト胆管癌由来細胞株HuCC-T1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、シスプラチン及び化合物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DMSOに溶解させたものを用いた。シスプラチン(和光純薬工業社製Cat.# 039-20091)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。
ヒト胆管癌細胞株であるHuCC-T1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。Cisplatinを無血清培地に溶解し、Cisplatin溶液 60 μmol/Lを調製した。化合物A及びGemcitabineのDMSO希釈溶液を、Cisplatin溶液(60 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Cisplatinと組み合わせて使用した。
Cisplatin溶液(60 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。
スフェロイド培養下におけるシスプラチンの併用による胆管癌細胞株TFK-1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、シスプラチン及び化合物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。シスプラチン(和光純薬工業社製Cat.# 039-20091)は、DMSOに溶解させたものを用いた。
ヒト胆管癌細胞株であるTFK-1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。5000 cells/well/100 μLとなるように10%血清培地で希釈し、Ultra-Low 付着性96wellプレート(Corning製Cat.# 7007)に播種した。4日間培養し、スフェロイドを形成させた。
化合物Aのメタンスルホン酸塩及びGemcitabineをDMSOに溶解し、10 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。CisplatinをDMSOに溶解し、100 mmol/L DMSO溶液を調製した。DMSOで希釈し、最終処理濃度の5000倍濃度のDMSO溶液を調製した。さらにCisplatinのDMSO溶液を10%血清培地で希釈し、最終処理濃度の10倍濃度のCisplatin含有培地を調製した。化合物A及びGemcitabineのDMSO希釈溶液を、Cisplatin含有培地で希釈し、最終処理濃度の10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Cisplatin(10 μmol/L)と組み合わせて使用した。
Cisplatin含有培地で希釈した化合物AまたはGemcitabineを各wellに10 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。
スフェロイド培養下におけるシスプラチンの併用による胆管癌細胞株HuCC-T1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、シスプラチン及び化合物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。シスプラチン(和光純薬工業社製Cat.# 039-20091)は、DMSOに溶解させたものを用いた。
胆管癌細胞株であるHuCC-T1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。5000 cells/well/100 μLとなるように10%血清培地で希釈し、Ultra-Low 付着性96wellプレート(Corning製Cat.# 7007)に播種した。4日間培養し、スフェロイドを形成させた。
化合物Aのメタンスルホン酸塩及びGemcitabineをDMSOに溶解し、10 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。CisplatinをDMSOに溶解し、100 mmol/L DMSO溶液を調製した。DMSOで希釈し、最終処理濃度の5000倍濃度のDMSO溶液を調製した。さらにCisplatinのDMSO溶液を10%血清培地で希釈し、最終処理濃度の10倍濃度のCisplatin含有培地を調製した。化合物A及びGemcitabineのDMSO希釈溶液を、Cisplatin含有培地で希釈し、最終処理濃度の10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Cisplatin(10 μmol/L)と組み合わせて使用した。
Cisplatin含有培地で希釈した化合物AまたはGemcitabineを各wellに10 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。
スフェロイド培養下におけるシスプラチンの併用による乳癌由来細胞株HCC1954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、シスプラチン及び化合物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。シスプラチン(和光純薬工業社製Cat.# 039-20091)は、DMSOに溶解させたものを用いた。
ヒト乳癌細胞株であるHCC1954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。5000 cells/well/100 μLとなるように10%血清培地で希釈し、Ultra-Low 付着性96wellプレート(Corning製Cat.# 7007)に播種した。4日間培養し、スフェロイドを形成させた。
化合物Aのメタンスルホン酸塩及びGemcitabineをDMSOに溶解し、10 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。CisplatinをDMSOに溶解し、100 mmol/L DMSO溶液を調製した。DMSOで希釈し、最終処理濃度の5000倍濃度のDMSO溶液を調製した。さらにCisplatinのDMSO溶液を10%血清培地で希釈し、最終処理濃度の10倍濃度のCisplatin含有培地を調製した。化合物A及びGemcitabineのDMSO希釈溶液を、Cisplatin含有培地で希釈し、最終処理濃度の10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Cisplatin(10 μmol/L、5 μmol/L)と組み合わせて使用した。
Cisplatin含有培地で希釈した化合物AまたはGemcitabineを各wellに10 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。
胆管癌細胞株の皮下移植担がんモデルマウスにおける併用効果試験
被験物質として、ゲムシタビン、及び化合物Aのメタンスルホン酸塩を用いる。
ゲムシタビンは、ゲムシタビン塩酸塩(TEVA社製)を生理食塩水に溶解させたものを用い、シスプラチンは、シスプラチン(和光純薬工業社製Cat.# 039-20091)を生理食塩水に溶解させたものを用いる。
ヒト胆管癌細胞株であるTFK-1細胞またはHuCCT-1細胞を生後5~6週齢の雌性BALB/cA Jcl-nuマウスの後部横腹に皮下注射する。腫瘍移植後に腫瘍の長径(mm)及び短径(mm)を測定し、腫瘍体積(tumor volume:TV)を算出する。各群の平均TVが均等になるように各群にマウスを割り付け、この群分けを実施した日をday 1とする。
シスプラチンの投与量はインタビューフォーム及びキャンサー・ゲノミクス・アンド・プロテオミクス(CANCER GENOMICS&PROTEOMICS)、2012年、9巻、p77~92頁(非特許文献6)を参考に設定し、ゲムシタビン及び化合物Aの投与量は非特許文献6及びザ・ジャーナル・オブ・ファーマコロジー・アンド・エクスペリメンタル・セラピューティクス(The journal of pharmacology and experimental therapeutics)、2018年、366巻、125~135頁(非特許文献7)を参考に設定する。シスプラチン単独群の被験液は、投与用量として1~10 mg/kg/dayとなるよう調製する。また化合物A単独群の被験液は、30~240 mg/kg/dayとなるよう調製する。化合物Aはday 1から1週間に1度、計3回マウス尾静脈より投与し、シスプラチンはday 1から1週間に1度、計3回マウス腹腔内投与により投与する。併用投与群では、化合物Aを30~240 mg/kg/dayとシスプラチンを1~10 mg/kg/dayで投与する。
比較実験として、対照薬としてゲムシタビンを用いる。ゲムシタビン単独群の被験液は、30~240 mg/kg/dayとなるよう調製する。ゲムシタビンはday 1から1週間に1度、計3回マウス尾静脈より投与し、併用投与群では、ゲムシタビンを30~240 mg/kg/dayとシスプラチンを1~10 mg/kg/dayで投与する。
本試験では、化合物A及びゲムシタビンの用量設定は、各薬剤のMTDを用いる。シスプラチンは、各薬剤との併用において耐用可能な最大用量を用いる。抗腫瘍剤は最大薬効を示す用量と毒性発現用量が極めて近く、その薬剤が持つ最大抗腫瘍効果を動物モデルで評価するためにはMTD近傍において評価することが一般的であり、本試験例においては、MTDと最大効果発揮用量はほぼ同義である。
TV(mm3)=(長径×短径2)/2
RTV=(腫瘍測定日におけるTV)/(Day 1におけるTV)
T/C(%)=[(被験液投与群の平均RTV値)/(対照群の平均RTV値)]×100
癌患者における化合物Aと抗腫瘍性白金錯体との併用効果試験
<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。
がん患者に対して、第1週目~第2週目までは週1回、化合物Aとシスプラチンを静脈注射により投与し、第3週目は投薬しないという投薬サイクルを繰り返す。具体的には、21日間を1サイクルとして、第1日目、第8日目に化合物Aとシスプラチンを投与し、この21日間からなる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、シスプラチンの投与量は10~50 mg/m2とする。
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
Claims (8)
- 抗腫瘍性白金錯体と、
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。 - 前記抗腫瘍性白金錯体が、シスプラチン、オキサリプラチン及びカルボプラチン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。
- 前記腫瘍が、睾丸腫瘍、膀胱癌、腎盂・尿管腫瘍、前立腺癌、精巣癌、卵巣癌、頭頸部癌、非小細胞肺癌、小細胞肺癌、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、結腸癌、直腸癌、小腸癌、悪性リンパ腫、乳癌、膵臓癌、肝癌、腎癌、黒色腫、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。
- 前記腫瘍が、膀胱癌、卵巣癌、胆道癌、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。
- 前記胆道癌が胆管癌である、請求項4に記載の抗腫瘍剤。
- 抗腫瘍性白金錯体と併用される、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。
- 抗腫瘍性白金錯体を含む製剤と、
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。 - 抗腫瘍性白金錯体と併用される、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。
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CA3093794A CA3093794C (en) | 2018-03-13 | 2019-03-13 | Antitumor enhancer agent comprising 1-(2-deoxy-2-fluoro-4-thio-b-d-arabinofuranosyl)cytosine and an antitumor platinum complex |
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US11141421B2 (en) | 2018-01-29 | 2021-10-12 | Fujifilm Corporation | Antitumor agent for biliary tract cancer and method for treating biliary tract cancer |
US11369625B2 (en) | 2016-08-31 | 2022-06-28 | Fujifilm Corporation | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit |
WO2023008511A1 (ja) | 2021-07-29 | 2023-02-02 | 富士フイルム株式会社 | Bap1およびpbrm1の少なくとも1つの機能低下を有する腫瘍に対する医薬組成物および抗腫瘍剤 |
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US11369625B2 (en) | 2016-08-31 | 2022-06-28 | Fujifilm Corporation | Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit |
US11141421B2 (en) | 2018-01-29 | 2021-10-12 | Fujifilm Corporation | Antitumor agent for biliary tract cancer and method for treating biliary tract cancer |
WO2023008511A1 (ja) | 2021-07-29 | 2023-02-02 | 富士フイルム株式会社 | Bap1およびpbrm1の少なくとも1つの機能低下を有する腫瘍に対する医薬組成物および抗腫瘍剤 |
KR20240028451A (ko) | 2021-07-29 | 2024-03-05 | 후지필름 가부시키가이샤 | Bap1 및 pbrm1 중 적어도 하나의 기능 저하를 갖는 종양에 대한 의약 조성물 및 항종양제 |
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