WO2014118946A1 - Procédé de traitement du cancer par l'utilisation combinée de médicaments - Google Patents

Procédé de traitement du cancer par l'utilisation combinée de médicaments Download PDF

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WO2014118946A1
WO2014118946A1 PCT/JP2013/052231 JP2013052231W WO2014118946A1 WO 2014118946 A1 WO2014118946 A1 WO 2014118946A1 JP 2013052231 W JP2013052231 W JP 2013052231W WO 2014118946 A1 WO2014118946 A1 WO 2014118946A1
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day
paclitaxel
administration
cancer
antitumor agents
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PCT/JP2013/052231
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Japanese (ja)
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幸規 荒井
伸明 網野
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アステラス製薬株式会社
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Priority to PCT/JP2013/052231 priority Critical patent/WO2014118946A1/fr
Priority to US14/021,157 priority patent/US20140066385A1/en
Publication of WO2014118946A1 publication Critical patent/WO2014118946A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to pharmaceuticals, in particular N 2 -[(2E) -3- (4-chlorophenyl) -2-propenoyl] -N- [2-oxo-2- (4- ⁇ [6- (trifluoromethyl) pyrimidine -4-yl] oxy ⁇ piperidin-1-yl) ethyl] -3-pyridin-2-yl-L-alaninamide or a salt thereof as an active ingredient for cancer treatment for use in combination with a taxane antitumor agent Relates to the composition.
  • taxane antitumor agents are used as effective drugs in several carcinomas.
  • Taxane antitumor agents are known to inhibit the division of cancer cells by inhibiting the depolymerization of microtubules necessary for cell division.
  • Paclitaxel is used for the treatment of ovarian cancer, non-small cell lung cancer, breast cancer, gastric cancer, etc.
  • Docetaxel is used for the treatment of breast cancer, non-small cell lung cancer, gastric cancer, head and neck cancer, ovarian cancer, esophageal cancer, endometrial cancer, etc. .
  • multi-drug combination therapy combining a taxane anti-tumor agent with another anti-tumor agent having a different mechanism of action is performed.
  • paclitaxel and carboplatin Cancer, 1996, 77: 2458-63.
  • docetaxel and cisplatin Eur. J. Surg. Oncol. 2006 32 (3) 297-302 .
  • the maximum tolerated dose is set from the viewpoint of side effects, and the dose is limited.
  • paclitaxel “injects 210 mg / m 2 once a day for 3 hours by intravenous infusion. The administration is repeated for at least 3 weeks, and the administration is repeated as a course.
  • paclitaxel has been specified in addition to the dose, as described in the following. .
  • taxotere injection registered trademark: trade name of docetaxel
  • the maximum single dose is 70 mg / m 2 ” and the dose is indicated.
  • a peptide derivative having good nitric oxide (NO) synthase (NOS) inhibitory activity is disclosed in WO 02/055541 (Patent Document 1).
  • Non-Patent Document 2 It is also effective in monkey renal ischemia / reperfusion injury and ischemia / reperfusion injury in rat liver transplantation (Non-Patent Documents 3 and 4), and fiber induced by increased TGF ⁇ 1 or activation of stellate cells It is effective in the treatment of cirrhosis (Patent Document 2, Non-Patent Document 5), and also effective in inflammatory keratosis, keratosis, or inflammatory skin disease (Patent Document 3) ) Has already been reported.
  • INOS is expressed in various types of cells such as epithelial cells, smooth muscle cells, macrophages, etc., and its expression is induced at the transcriptional level by cytokines induced by infection, inflammation, etc., and produces NO.
  • iNOS plays a central role as a mediator in infection and biological defense.
  • Non-Patent Document 6 Physiological studies on cancer have been conducted from both aspects of production suppression, and there is no certain opinion as to whether NO production promotion or NO production inhibition is good for application to cancer treatment.
  • Non-Patent Documents 9 and 10 describe that in human ovarian cancer cells and cervical cancer cells, low concentrations of NO tend to suppress apoptosis by cisplatin and paclitaxel, and high concentrations of NO promote apoptosis. ing. These documents also describe that the combination of iNOS inhibitor 1400W and survivin RNAi promotes apoptosis by not only paclitaxel but also cisplatin, and it can be said that the cytoprotective effect of NO is not a paclitaxel selective action.
  • Taxane antitumor agents are useful for the treatment of various tumors, but their dosage and usage are limited in terms of side effects, and treatment methods that increase the efficacy of various tumors without increasing the dose are now available. It is still sought after. In addition, although effective at the beginning of treatment, there is a problem of acquired resistance in which the antitumor effect decreases as treatment is continued.
  • the present invention has been completed by discovering that significant antitumor action enhancement is achieved and the mechanism of the enhancement action. That is, the present invention (1) A composition for treating cancer comprising FK330 or a salt thereof as an active ingredient, wherein the composition is used in combination with one or more antitumor agents selected from taxane antitumor agents .
  • composition according to (1) wherein the composition is used in combination with paclitaxel or docetaxel.
  • the composition according to (2) wherein the composition is used in combination with paclitaxel.
  • the composition according to (2) wherein the composition is used in combination with docetaxel.
  • the composition according to (1) to (4) which is a composition for oral administration containing 60 to 1200 mg / day of FK330 or a salt thereof.
  • antitumor agents selected from platinum antitumor agents, anthracycline antitumor agents, cyclophosphamide, fluorouracil, trastuzumab and capecitabine.
  • (1) to (6) characterized by being used in combination administration on at least one day in one administration cycle of one or more antitumor agents selected from taxane antitumor agents Composition.
  • the composition according to (8) which is used so as to be administered in combination on at least one day of administration of one or more antitumor agents selected from taxane antitumor agents.
  • the composition according to (8) which is used so as to be administered in combination on all days during one administration cycle of one or more antitumor agents selected from taxane antitumor agents.
  • the present invention also relates to the following inventions.
  • One or more antitumor agents selected from taxane antitumor agents are administered simultaneously, separately, successively or at intervals, (1) to (6) The composition for cancer treatment as described.
  • the cancer therapeutic composition according to (13), wherein the cancer in which the taxane antitumor agent is used is non-small cell lung cancer, prostate cancer, breast cancer, or stomach cancer.
  • the cancer therapeutic composition according to (13), wherein the cancer in which the taxane antitumor agent is used is non-small cell lung cancer.
  • the cancer therapeutic composition according to (13), wherein the cancer in which the taxane antitumor agent is used is prostate cancer or castration resistant prostate cancer.
  • the present invention also relates to the following inventions.
  • (17) A combination of a therapeutically effective dose when used in combination treatment with one or more antitumor agents selected from taxane antitumor agents and a therapeutically effective dose when used in combination treatment with FK330 or a salt thereof,
  • a method for treating cancer characterized by comprising (18) A therapeutically effective dose when used in combination treatment with one or more antitumor agents selected from taxane antitumor agents, and a therapeutically effective dose when used in combination treatment with FK330 or a salt thereof are simultaneously separated.
  • a method for treating cancer comprising administering to a subject continuously or at intervals.
  • the “subject” is a human or other animal that needs the prevention or treatment, and as a certain aspect, it is a human that needs the prevention or treatment.
  • the present invention relates to the following inventions.
  • FK330 or a salt thereof for producing a composition for treating cancer characterized by being used in combination with one or more antitumor agents selected from taxane antitumor agents use.
  • FK330 or a salt thereof for cancer treatment characterized by being used in combination with one or more antitumor agents selected from taxane antitumor agents.
  • a cancer therapeutic agent containing FK330 or a salt thereof as an active ingredient which is administered in combination with one or more antitumor agents selected from taxane antitumor agents.
  • the present invention relates to the following inventions.
  • composition according to (29) which is a composition for oral administration containing 60 to 200 mg / day of FK330 or a salt thereof. (31) Furthermore, it is used to be used in combination with one or more antitumor agents selected from platinum antitumor agents, anthracycline antitumor agents, cyclophosphamide, fluorouracil, trastuzumab and capecitabine.
  • the composition according to (25) to (30). (32) It is characterized by being administered simultaneously with one or more antitumor agents selected from taxane antitumor agents, separately, sequentially or at intervals. The composition as described.
  • a composition for treating prostate cancer or ovarian cancer comprising FK330 or a salt thereof as an active ingredient, for treating a subject treated with one or more antitumor agents selected from taxane antitumor agents .
  • FK330 for producing a composition for treating prostate cancer or ovarian cancer wherein the composition is used for combined administration with one or more antitumor agents selected from taxane antitumor agents Use of its salt.
  • FK330 or a salt thereof for treating prostate cancer or ovarian cancer characterized by being used in combination with one or more antitumor agents selected from taxane antitumor agents.
  • a combination of a therapeutically effective dose when used in combination treatment with one or more antitumor agents selected from taxane antitumor agents and a therapeutically effective dose when used in combination treatment with FK330 or a salt thereof A method for treating prostate cancer or ovarian cancer, characterized by comprising (39) A therapeutically effective dose when used in combination treatment with one or more antitumor agents selected from taxane antitumor agents, and a therapeutically effective dose when used in combination treatment with FK330 or a salt thereof are simultaneously separated.
  • a method for treating prostate cancer or ovarian cancer comprising administering to a subject continuously or at intervals.
  • composition for cancer treatment containing FK330 or a salt thereof of the present invention as an active ingredient and the taxane antitumor agent achieves enhancement of the cancer treatment effect of the taxane antitumor agent.
  • the composition for cancer treatment can be used in combination with one or more antitumor agents selected from taxane antitumor agents for the treatment of various cancers for which existing taxane antitumor agents are known to be applied.
  • Applicable cancers include solid cancers and lymphomas in which taxane antitumor agents are used.
  • Another aspect of cancer that is indicated is prostate cancer or ovarian cancer in which a taxane antitumor agent is used.
  • FIG. 1 is a graph showing the antitumor effect in Example 1 when FK330 and doxorubicin are administered alone or in combination. Dox indicates doxorubicin.
  • FIG. 2 is a graph showing the antitumor effect of FK330 and gemcitabine administered alone or in combination in Example 1. Gem indicates gemcitabine.
  • FIG. 3 is a graph showing the antitumor effect in Example 1 when FK330 and irinotecan are administered alone or in combination. Iri indicates irinotecan.
  • FIG. 4 is a graph showing the antitumor effect in Example 1 when FK330 and carboplatin are administered alone or in combination. CBDCA indicates carboplatin.
  • FIG. 5 is a graph showing the antitumor effect in Example 1 when FK330 and paclitaxel are administered alone or in combination.
  • PTX indicates paclitaxel.
  • FIG. 6 is a graph showing the antitumor effect in Example 1 when FK330 and docetaxel are administered alone or in combination.
  • Doce indicates docetaxel.
  • FIG. 7 is a graph showing the results of Example 2 in which the antitumor effect enhancing effect of FK330 upon multiple cycles of paclitaxel in mice bearing human non-small cell lung cancer (Calu-6) was examined.
  • PTX indicates paclitaxel.
  • FIG. 8 is a graph showing the results of Example 3 in which the dose dependence of the antitumor effect enhancing effect of paclitaxel of FK330 in mice bearing human non-small cell lung cancer (Calu-6) was examined.
  • PTX indicates paclitaxel.
  • FIG. 9 is a graph showing the results of Example 4 in which the administration timing of FK330 in mice bearing human non-small cell lung cancer (Calu-6) was examined.
  • PTX indicates paclitaxel.
  • FIG. 10 is a graph showing the results of Example 5 in which the antitumor effect enhancement effect of paclitaxel by FK330 in human gastric cancer (AZ-521) tumor-bearing mice was examined.
  • PTX indicates paclitaxel.
  • FIG. 11 is a graph showing the results of Example 5 in which the antitumor effect enhancement effect of paclitaxel by FK330 in human gastric cancer (MKN-28) tumor-bearing mice was examined.
  • PTX indicates paclitaxel.
  • FIG. 12 is a graph showing the results of Example 5 in which the antitumor effect enhancement effect of paclitaxel by FK330 in human gastric cancer (NCI-N87) tumor-bearing mice was examined.
  • PTX indicates paclitaxel.
  • FIG. 13 is a graph showing the results of Example 6 in which the antitumor effect potentiating action of paclitaxel by FK330 in human breast cancer cell (MDA-MB-231) -bearing mice was examined.
  • FIG. 14 is a graph showing the results of Example 7 in which the inhibitory action of SNAP, which is a NO donor, on the taxane-induced tubulin polymerization action was examined.
  • A) and B) show a representative example of the inhibitory action of SNAP on paclitaxel-induced tubulin polymerization and the aggregated values for 60 minutes after the start of tubulin polymerization, respectively.
  • PTX represents paclitaxel
  • SNAP represents S-nitroso-N-acetyl-D, L-penicillamine.
  • FIG. 15 is a graph showing the results of Example 7 in which the inhibitory action of SNAP, which is a NO donor, on the taxane-induced tubulin polymerization action was examined.
  • A) and B) show a representative example of the inhibitory action of SNAP on docetaxel-induced tubulin polymerization and the aggregate value for 60 minutes after the start of tubulin polymerization, respectively.
  • DTX represents docetaxel
  • SNAP represents S-nitroso-N-acetyl-D, L-penicillamine.
  • FIG. 16 is a graph showing the results of Example 8 in which the effects of paclitaxel alone and FK330 in combination on tumor tissue iNOS protein expression in human lung cancer cell line Calu-6 tumor-bearing mice were examined.
  • FIG. 17 is a graph showing the results of Example 8 in which the effect on macrophage (F4 / 80) infiltration in tumor tissues when paclitaxel alone and FK330 were combined in human lung cancer cell line Calu-6 tumor-bearing mice was shown.
  • PTX indicates paclitaxel.
  • FIG. 18 shows the results of Example 8 in which the effect on the expression of nitrotyrosine (the main final product of NO) in tumor tissue when paclitaxel alone and FK330 were used in human lung cancer cell line Calu-6 tumor-bearing mice was shown. It is a graph.
  • PTX indicates paclitaxel.
  • FIG. 17 is a graph showing the results of Example 8 in which the effect on macrophage (F4 / 80) infiltration in tumor tissues when paclitaxel alone and FK330 were combined in human lung cancer cell line Calu-6 tumor-bearing mice was shown.
  • PTX indicates paclitaxel.
  • FIG. 18 shows the results of Example 8 in which the effect
  • FIG. 19 is a graph showing the results of Example 9 in which the antitumor effect enhancing effect of paclitaxel by FK330 in mice bearing human hormone resistant prostate cancer cells (PC-3) was examined.
  • PTX indicates paclitaxel.
  • FIG. 20 is a graph showing the results of Example 10 in which the antitumor effect-enhancing effect of docetaxel by FK330 in mice bearing human hormone-resistant prostate cancer cells (PC-3) was examined.
  • DTX indicates docetaxel.
  • FIG. 21 is a graph showing the results of Example 11 in which the antitumor effect enhancing effect of docetaxel by FK330 in mice bearing human breast cancer cells (MDA-MB-468) was examined.
  • DTX indicates docetaxel.
  • FIG. 22 is a graph showing the results of Example 12 in which the antitumor effect enhancing effect of paclitaxel by FK330 in mice bearing human ovarian cancer cells (MCAS) was examined.
  • PTX indicates paclitaxel.
  • composition for cancer treatment is a pharmaceutical composition for use in combination with a taxane antitumor agent.
  • Another embodiment is a pharmaceutical composition for enhancing the antitumor action of a taxane antitumor agent. is there.
  • “Cancer” in the “cancer treatment composition” of the present invention includes cancers in which taxane antitumor agents are used, that is, all solid cancers and lymphomas in which taxane antitumor agents are used.
  • Some embodiments include breast cancer, endometrial cancer, ovarian cancer, prostate cancer, lung cancer, stomach (gastric gland) cancer, non-small cell lung cancer, pancreatic cancer, squamous cell carcinoma of the head and neck, esophageal cancer, bladder cancer, melanoma, colon cancer, Examples include renal cell carcinoma, non-Hodgkin lymphoma, urothelial cancer, and the like.
  • breast cancer includes, for example, HER2-positive metastatic breast cancer, HER2-negative metastatic breast cancer, HER2-positive breast cancer, or metastatic breast cancer, and another embodiment includes HER2-negative metastatic breast cancer, Another embodiment includes HER2-positive metastatic breast cancer.
  • non-small cell lung cancer includes, for example, locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.
  • Another embodiment is non-squamous cell carcinoma in non-small cell lung cancer.
  • Another embodiment includes non-squamous cell carcinoma in metastatic non-small cell lung cancer, and yet another embodiment includes squamous cell carcinoma in metastatic non-small cell lung cancer.
  • gastric cancer metastatic gastric cancer, metastatic gastroesophageal junction cancer and the like can be mentioned.
  • prostate cancer includes hormone refractory prostate cancer. Certain embodiments of hormone resistant prostate cancer include castration resistant prostate cancer. Certain embodiments of castration resistant prostate cancer include metastatic castration resistant prostate cancer. Another embodiment includes hormone-resistant prostate cancer, another embodiment includes castration resistant prostate cancer, and another embodiment includes metastatic castration resistant prostate cancer.
  • FK330 or a salt thereof used in the present invention is the compound of Example 41 of WO 02/055541, and can be easily obtained by the production method disclosed in the patent.
  • FK330 is an (S) optical isomer based on the presence of an asymmetric carbon atom, but may contain an (R) optical isomer.
  • the salt of FK330 is a pharmaceutically acceptable salt of FK330, specifically, inorganic such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • Acid formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfone Acid addition salts such as acids, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, organic acids such as glutamic acid, and the like. These acid addition salts can be produced by subjecting them to a conventional salt formation reaction.
  • FK330 or a salt thereof of the present invention can be used as various hydrates, solvates, and crystalline polymorphic substances.
  • FK330 or a salt thereof also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • FK330 or a salt thereof used in the present invention is a free anhydride.
  • Another embodiment is free form dihydrate.
  • the FK330 free body obtained by the method described in Example 41 of WO 02/055541 pamphlet is recrystallized in an alcohol / water solvent system such as ethanol / water or isopropanol / water to obtain The obtained crystals can be dried under reduced pressure to obtain a free anhydride.
  • crystallization can be obtained by performing humidity control operation with respect to the obtained free body anhydride.
  • a pharmaceutical composition containing FK330 or a salt thereof as an active ingredient is prepared by a commonly used method using excipients usually used in the art, that is, pharmaceutical excipients or pharmaceutical carriers.
  • Administration may be in any form of oral administration by tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration by injections such as intraarticular, intravenous, intramuscular and the like. As a certain aspect, it is oral administration by a tablet, a pill, a capsule, a granule, a powder, a liquid agent etc.
  • a solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients are mixed with at least one inert excipient.
  • the composition may contain an inert additive such as a lubricant, a disintegrant, a stabilizer and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or it contains ethanol.
  • the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
  • the injection for parenteral administration contains a sterile aqueous or non-aqueous solution, suspension or emulsion.
  • aqueous solvent include distilled water for injection or physiological saline.
  • Non-aqueous solvents include alcohols such as ethanol.
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • the pharmaceutical composition of the present invention is 0.01 to 100% by weight, and in one embodiment, 0.01 to 50% by weight of the active ingredient. Or more FK330 or its salt is contained.
  • the daily dose of FK330 (dihydrate) is about 60-1200 mg / day, and this should be administered once or divided into 2 to 3 times.
  • the daily dose is 60 to 200 mg.
  • Still another embodiment is 120 to 250 mg, 120 to 220 mg, 150 to 250 mg, or 180 to 200 mg.
  • it is 100 to 180 mg, or 180 to 300 mg.
  • it is 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg.
  • it is 180 mg, 190 mg, or 200 mg.
  • the dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
  • taxane antitumor agents examples include pharmaceutical compositions containing a taxane ring or a compound having a similar structure as an active ingredient, and in another embodiment, a compound having a taxane ring is effective. Examples include pharmaceutical compositions as ingredients. Another embodiment of the taxane antitumor agent is a pharmaceutical composition containing a compound having a microtubule depolymerization inhibitory action as an active ingredient. As the excipient and dosage form applied to the pharmaceutical composition, those described above can be used.
  • taxane antitumor agents that can be used in combination with FK330 include paclitaxel, docetaxel, cabazitaxel, abraxane, tesetaxel, ortataxel, etc.
  • paclitaxel paclitaxel
  • docetaxel docetaxel
  • abraxane abraxane
  • paclitaxel paclitaxel
  • abraxane abraxane
  • paclitaxel or abraxane abraxane
  • Still another embodiment includes paclitaxel, and another embodiment includes docetaxel.
  • the main existing taxane antitumor agents that can be used in combination with the FK330 of the present invention are shown in the table below together with main indication cancer types or indication candidate cancers.
  • the applicable cancer types of these antitumor agents are not limited to these.
  • Paclitaxel, docetaxel, cabazitaxel, or Abraxane can be purchased and used commercially, or can be easily obtained by methods obvious to those skilled in the art or modifications thereof.
  • Cabazitaxel can also be easily obtained by the production method disclosed in WO 96/30355 or a modification thereof.
  • Tesetaxel can be easily obtained by a method obvious to those skilled in the art, a production method disclosed in WO 01/27115, or a modification thereof.
  • Ortataxel can be easily obtained by methods obvious to those skilled in the art, or by the production method disclosed in US Pat. No. 5,705,508 or a modification thereof.
  • the above-described antitumor agents have already been used clinically, and their administration route, administration cycle, and dosage are apparent to those skilled in the art.
  • the appropriate dosage and administration differs depending on the cancer type, symptoms, and drugs used in combination, and these detailed information can be obtained from various databases provided by the FDA, such as "Orange Book” (http: //www.fda. gov / cder / orange / default.htm) and the website for providing information on pharmaceutical and pharmaceutical devices in Japan (http://www.info.pmda.go.jp/). Information on each antitumor agent in these databases is incorporated in the present application.
  • the package insert of Taxol Injection (registered trademark: trade name of paclitaxel) on the website for providing information on pharmaceuticals and drugs in Japan includes “[Effectiveness or effects] Lung cancer, breast cancer, gastric cancer; [Dosage and administration]: 1. In general, for adults, instillate 210 mg / m 2 as paclitaxel once a day for 3 hours, and take a rest for at least 3 weeks. The administration is repeated as a cool. The dosage is appropriately reduced depending on the age and symptoms.
  • the package insert of Taxotere Note (registered trademark: trade name of docetaxel) on the website for providing information on pharmaceuticals and drugs in Japan includes “1. Breast cancer, non-small cell lung cancer, gastric cancer, Head and neck cancer; indication or dosage for each effect; 1. In general, once a day for adults, 60 mg / m 2 as docetaxel is infused intravenously at intervals of 3 to 4 weeks over 1 hour. It is increased or decreased as appropriate symptoms, however, the highest dose once is described as "the 70 mg / m 2.
  • the therapeutically effective dose when used in the combination therapy in the present invention is the same dose as that usually administered alone or a lower dose (for example, the highest dose when administered alone), depending on the administration route usually administered. 0.10 to 0.99 times).
  • the administration cycle can be appropriately adjusted so as to be suitable for combined use with FK330.
  • Specific administration frequency, dosage, administration cycle, and the like are appropriately determined according to individual cases in consideration of patient symptoms, age, sex, and the like.
  • the administration form when FK330 and a taxane antitumor agent are administered in combination is not particularly limited as long as an appropriate administration route, administration frequency, and dosage are adopted.
  • FK330 and a taxane antitumor agent are used.
  • Composition containing a tumor agent that is, administration as a single formulation
  • Simultaneous administration of two formulations obtained by separately formulating FK330 and a taxane antitumor agent by the same administration route (3) Administration of two types of preparations obtained by separately formulating FK330 and a taxane antitumor agent with a time difference in the same administration route (for example, administration in the order of FK330 and taxane antitumor agent) Or (4) administration in reverse order), (4) simultaneous administration of two preparations obtained by separately formulating FK330 and a taxane antitumor agent, and (5) FK330 and a taxane antitumor
  • Two types of formulations obtained by formulating tumor agents separately Administration at an interval via the different routes of administration e.g.
  • the composition for cancer treatment of the present invention is formulated separately from the taxane antitumor agent, and the taxane antitumor agent is administered intravenously, intravenously, or orally, and the cancer therapeutic composition of the present invention.
  • the product is administered orally or parenterally.
  • the taxane antitumor agent is administered by intravenous injection or intravenous infusion, and the cancer treatment composition of the present invention is administered orally.
  • a preferred mode of administration of the cancer therapeutic composition of the present invention is a method in which the cancer therapeutic composition of the present invention is orally or parenterally administered on at least one day in one cycle of administration of the taxane antitumor agent.
  • cycle means a treatment cycle or treatment course with a certain regimen. For example, in paclitaxel and docetaxel, 3 to 4 weeks from the start of administration until the next administration after the drug withdrawal period. About the unit dosage period.
  • the composition for cancer treatment of the present invention containing FK330 or a salt thereof is orally administered on at least one day of the administration date of the taxane antitumor agent, the entire day of administration of the taxane antitumor agent Orally administered to the patient, orally administered on at least one day of the taxane antitumor drug holiday, orally administered on all days of the taxane antitumor drug holiday, administration date of the taxane antitumor agent Orally administered on at least one day and on at least one day of drug holiday, orally administered on all days in one cycle of administration of a taxane antitumor agent, or intermittently during one cycle of administration of a taxane antitumor agent
  • composition for cancer treatment of the present invention may be administered from several days before to the day before the administration of the taxane antitumor agent, and this embodiment is included in the administration of a drug holiday of the taxane antitumor agent. If there is a concern about the drug interaction between FK330 and the taxane antitumor agent, the administration time can be divided and / or administered at a necessary interval in order to avoid the interaction.
  • composition for cancer treatment for treating a subject treated with one or more antitumor agents selected from taxane antitumor agents, comprising FK330 or a salt thereof as an active ingredient of the present invention or “ In "a composition for treating prostate cancer or ovarian cancer for treating a subject treated with one or more antitumor agents selected from taxane antitumor agents, comprising FK330 or a salt thereof as an active ingredient”
  • the “subject” may be administered other antitumor agents as long as the subject is treated with one or more antitumor agents selected from taxane antitumor agents.
  • Other antitumor agents include those described below.
  • the “subject” refers to one or more anti-tumor agents selected from taxane anti-tumor agents, simultaneously with the cancer treatment composition containing FK330 or a salt thereof as an active ingredient, separately, sequentially, or at intervals. It may be administered after empty.
  • the present invention may be in the form of “a kit comprising a combination of (a) FK330 or a salt thereof and (b) one or more antitumor agents selected from taxane antitumor agents”.
  • This includes a preparation containing the active ingredient (a) (first preparation) and a preparation containing the active ingredient (b) (second preparation) in combination so that they can be used in combination therapy of these active ingredients.
  • the kit of the present invention may be a packaged product that may contain an additional formulation or a display member that facilitates administration according to each administration time, such as a placebo.
  • the two types of preparations can be administered with the same or different administration routes under the administration conditions such as formulation formulation, administration route, administration frequency, etc.
  • suitable for each formulation taking into consideration the bioavailability, stability, etc. of each formulation. They are administered simultaneously, separately, sequentially or at intervals.
  • “simultaneously” means that the first formulation and the second formulation are administered together by the same administration route, and “separately” means that the first formulation and the second formulation are the same or different administration routes. It means that they are administered separately at the same or different dosing frequency or dosing interval.
  • “Sequentially” means that the first formulation and the second formulation are administered by the same or different routes of administration, in the order of the first formulation, followed by the second formulation, or in the reverse order.
  • “At an interval” means that the first preparation and the second preparation are administered by the same or different routes of administration, followed by the first preparation at a certain interval in the order of the second preparation or in the reverse order. Means that.
  • the present invention provides: “(a) A package insert indicating that a composition containing FK330 or a salt thereof as an active ingredient is used in combination with one or more antitumor agents selected from (c) ataxane antitumor agents”
  • a pharmaceutical composition for treating cancer “or”
  • composition (a) containing an active ingredient in a therapeutically effective dose when used in combination therapy, and one or more antitumor agents selected from taxane antitumor agents, It means a medicine for cancer treatment packaged including both of the package insert (c) relating to the composition of (a).
  • cancer treatment composition containing FK330 or a salt thereof of the present invention as an active ingredient is used in combination with a taxane antitumor agent
  • another antitumor agent used for chemotherapy is optionally used in combination.
  • other antitumor agents used for chemotherapy that can be used in combination are antitumor agents that are conventionally known to be used in combination with taxane antitumor agents, such as platinum antitumor agents, anthra
  • antitumor agents selected from cyclin antitumor agents, cyclophosphamide, fluorouracil, trastuzumab and capecitabine are included, and in one embodiment, cisplatin or carboplatin, and in another embodiment, doxorubicin .
  • the therapeutic effect of cancer is enhanced by the combined treatment of a composition for cancer treatment containing FK330 or a salt thereof of the present invention as an active ingredient and a taxane antitumor agent. It was found. The effect was confirmed by significantly reducing the mean tumor volume compared to the single agent administration of the composition for cancer treatment or the taxane antitumor agent containing FK330 or a salt thereof as an active ingredient. . Moreover, FK330 or a salt thereof of the present invention does not have a serious side effect as reported in many antitumor agents, and is useful from the viewpoint of safety.
  • the composition for cancer treatment of the present invention enhances the antitumor action selectively and in a dose-dependent manner. That is, in the case of FK330 or a salt thereof alone, no significant antitumor effect was observed, and even when FK330 or a salt thereof was used in combination with an antitumor agent other than a taxane, a markedly significant antitumor effect was confirmed. However, when combined with a taxane antitumor agent, a good antitumor effect was confirmed. In particular, FK330 has been shown to improve the attenuation of the antitumor effect of taxane drugs by multiple cycles of treatment and to favorably suppress tumor growth (see FIG. 7). This suggests that FK330 suppresses the tolerance of taxane antitumor agents.
  • NO directly suppresses the microtubule depolymerization inhibitory action of the taxane antitumor agent, and the taxane antitumor agent accompanies the expression of iNOS protein in cancer tissue. It induces NO production and FK330 has been shown to suppress its iNOS activity.
  • the present inventors have also shown that NO suppresses the cancer cell growth inhibitory action via apoptosis by the taxane antitumor agent, and the attenuation effect of the chemotherapeutic agent by NO is selectively observed in the taxane antitumor agent. It is also found that.
  • the present inventors have clarified the following as a mechanism for enhancing the antitumor action of the taxane antitumor agent by FK330. That is, the taxane antitumor agent enhances the expression of iNOS protein in the tumor tissue, and as a result, enhances NO production. The produced NO directly reduces the antitumor effect of the taxane antitumor agent by directly suppressing the inhibitory action of the taxane on microtubule depolymerization.
  • FK330 clarifies that inhibition of NO production enhanced by the taxane antitumor agent can suppress the attenuation of the effect of the taxane antitumor agent and enhance the antitumor action. From the above, it can be said that FK330 or a salt thereof can enhance the action of all taxane antitumor agents targeting the microtubule depolymerization inhibitory action.
  • Example 1 Free substance dihydrate was used as test substance FK330. Hereinafter, the dose of FK330 is indicated by the weight of the dihydrate.
  • Docetaxel hydrate injection (Taxotere TM intravenous drip infusion) was purchased from Sanofi-Aventis Co., Ltd. and used as docetaxel.
  • Paclitaxel injection (paclitaxel injection “Sawai”) was purchased from Sawai Pharmaceutical Co., Ltd. and used as paclitaxel.
  • Irinotecan hydrochloride Topictecin (trademark) Note) was purchased from Daiichi Sankyo Co., Ltd.
  • Gemcitabine hydrochloride for injection (Gemzar (trademark) for injection) was purchased from Eli Lilly Japan and used as gemcitabine.
  • Doxorubicin hydrochloride for injection (Adriacin (trademark) injection 10) was purchased from Kyowa Hakko Kogyo Co., Ltd. and used as doxorubicin.
  • Carboplatin injection solution (Paraplatin (trademark) injection solution) was purchased from Bristol-Myers Co., Ltd. and used as carboplatin. 2) Preparation and administration of test substance FK330 was suspended in a 0.5% aqueous methylcellulose solution (0.5% MC) (20 mg / mL).
  • Docetaxel was adjusted to 4 mg / kg with the attached dissolution solution and then diluted to 1 mg / mL with physiological saline (Otsuka Pharmaceutical). Paclitaxel, irinotecan, gemcitabine, doxorubicin and carboplatin were prepared at the time of injection in physiological saline for injection to 1 mg / mL, 3 mg / mL, 16 mg / mL, 1 mg / mL and 6 mg / mL, respectively. 3) Cells Human lung cancer-derived Calu 6 (HTB-56) was obtained from the American Type Culture Collection (VA, USA). The cells were cultured under the conditions of 37 ° C.
  • VA American Type Culture Collection
  • Control group untreated FK330 single administration group: FK330 100 mg / kg administered twice a day (bid) (200 mg / kg / day, administered daily from the start to the end of the experiment)
  • Docetaxel alone administration group docetaxel 10mg / kg / day (Day 1, 5 and 9)
  • Paclitaxel alone administration group Paclitaxel 10mg / kg / day (from day 1 to 7)
  • Irinotecan single administration group Irinotecan 30mg / kg / day (Day 1 to 7)
  • Doxorubicin alone administration group doxorubicin 10mg / kg / day (Day 1 and 8)
  • Carboplatin alone administration group Carboplatin 60mg / kg / day (Day 1 and 2)
  • Combination group FK330 100 mg / kg bid + docetaxel 10 mg / kg / day (Day
  • Each chemotherapeutic agent was administered intravenously (10 mL / kg) via the tail vein 2 to 4 hours after administration of FK330. Tumor diameter was measured every 3-4 days using body weight and digital calipers. The tumor volume was calculated from an elliptic volume calculation formula (major axis x [minor axis] 2 x 0.52).
  • FK330 did not affect the antitumor effect of gemcitabine and carboplatin, and some enhancement of the antitumor effect was due to doxorubicin (tumor volume reduction rate of 34.5% compared to doxorubicin alone group on Day29) and irinotecan (irinotecan alone on Day29)
  • doxorubicin tumor volume reduction rate of 34.5% compared to doxorubicin alone group on Day29
  • irinotecan irinotecan alone on Day29
  • the tumor volume reduction rate for the group was 34.1%), but this was not a significant effect.
  • Example 2 Test substance The dose of FK330 was expressed as the weight including hydrate.
  • Paclitaxel injection (paclitaxel injection “Sawai”) was purchased from Sawai Pharmaceutical Co., Ltd. and used as paclitaxel.
  • Preparation and administration of test substance FK330 was suspended in a 0.5% aqueous methylcellulose solution (0.5% MC) (20 mg / mL).
  • Paclitaxel was prepared at the time of use at 1 mg / mL with physiological saline for injection (Otsuka Pharmaceutical).
  • Control group untreated FK330 single administration group: FK330 100mg / kg bid (200mg / kg / day, continuous administration from the start of the experiment to the end of the experiment)
  • Paclitaxel alone administration group Paclitaxel 10mg / kg / day (7 days of continuous administration in 1 cycle, 6 days of continuous administration after 2 cycles)
  • Combination group FK330 100 mg / kg bid (200 mg / kg / day, continuous administration from the start of the experiment to the end of the experiment) + paclitaxel 10 mg / kg / day (7 days of continuous administration in 1 cycle, 6 days of continuous administration after 2 cycles)
  • FK330 was administered by oral gavage (5 mL / kg) twice a day at intervals of 6 to 8 hours.
  • Paclitaxel was administered as an intravenous bolus (10 mL / kg) from the tail vein 2 to 4 hours after administration of FK330. Tumor diameter was measured every 3-4 days using body weight and digital calipers. The tumor volume was calculated from an elliptic volume calculation formula (major axis x [minor axis] 2 x 0.52).
  • Example 3 Preparation of the test substance and cell preparation were performed in the same manner as in Example 2.
  • Control group untreated Paclitaxel alone administration group: Paclitaxel 10mg / kg / day (Consecutive administration from Day 0 for 6 days in 1 cycle, continuous administration from Day 27 to 6 days in 2 cycles)
  • Paclitaxel was administered as an intravenous bolus (10 mL / kg) from the tail vein 2 to 4 hours after administration of FK330. Tumor diameter was measured every 3-4 days using body weight and digital calipers. The tumor volume was calculated from an elliptic volume calculation formula (major axis x [minor axis] 2 x 0.52).
  • FIG. 8 shows the results of examining the dose dependence of the antitumor effect enhancing effect of paclitaxel of FK330.
  • Tumor volume at the end of the study (Day59) paclitaxel alone group in 1640.1 ⁇ 902.8 mm 3, FK330 in 30 mg / kg bid combination group, 955.9 ⁇ 231.0 mm 3, FK330 60mg / kg bid The combination group 706.2 ⁇ 256.1 mm 3, In the FK330 100 mg / kg bid combination group, it was 297.9 ⁇ 101.4 mm 3 , and FK330 enhanced the antitumor effect of paclitaxel in a dose-dependent manner (tumor volume reduction rate compared to paclitaxel alone group: 41.7% at FK330 30 mg / kg bid, FK330 (56.9% at 60mg / kg bid, 81.8% at FK330 100mg /
  • Example 4 Preparation of the test substance and cell preparation were performed in the same manner as in Example 2.
  • Control group untreated Paclitaxel alone administration group: Paclitaxel 10mg / kg / day (Day 0 to Day 5 and Day 27 to Day 31)
  • Sequential administration FK330 100 mg / kg bid (200 mg / kg / day) + paclitaxel 10 mg / kg / day (Day 0 to Day 5 and Day 27 to Day 31)
  • Continuous administration FK330 100 mg / kg bid (200 mg / kg / day) + paclitaxel 10 mg / kg / day (Day 0 to Day 5 and Day 27 to Day 31)
  • FK330 was administered by oral gavage (5 mL / kg) twice a day at intervals of 6 to 8 hours.
  • FK330 is on the day of paclitaxel administration (Day 0 to Day 5 and Day 27 to Day 31), in continuous administration on the drug holiday after the day of paclitaxel administration (Day 6 to Day 26 and Day 32 to Day 55), continuous administration is from the start of the experiment to the end of the experiment It was administered on all days until the day.
  • Paclitaxel was administered intravenously (10 mL / kg) from the tail vein 2 to 4 hours after administration of FK330. Tumor diameter was measured every 3 to 4 days using body weight and digital calipers. The tumor volume was calculated from an elliptic volume calculation formula (major axis x [minor axis] 2 x 0.52).
  • Example 5 The test substance was prepared in the same manner as in Example 2.
  • Cells Human gastric cancer-derived NCI-N87 (CRL-5822) is from the American Type Culture Collection (VA, USA)
  • MKN-28 (JCRB0253) is from the Pharmaceutical Research Laboratory (HSRRB)
  • AZ-521 (RCB2087) is from RIKEN
  • NCI-N87 and MKN-28 cells use RPMI1640 medium supplemented with 10% heat-inactivated fetal bovine serum (FBS)
  • AZ-521 contains DMEM medium containing 10% heat-inactivated FBS was cultured under the conditions of 37 ° C. and 5% CO 2 .
  • Cells collected using trypsin were suspended in PBS at 6 ⁇ 10 7 cells / mL and mixed with an equal amount of Matrigel TM Basement Membrane Matrix (Becton Dickinson Co., Bedford, MA, USA).
  • Tumor volume (major axis x [minor axis] 2 x 0.52) from 386.6 to 766.6 mm 3 in AZ-521 tumor-bearing mice, tumor volume from 186.0 to 319.2 mm 3 in MKN-28 tumor-bearing mice, NCI-N87 tumor bearing In mice, nude mice whose tumor volume was 192.1 to 364.2 were divided into groups using SAS so that variation in tumor volume between groups and within groups was reduced. 3) Drug administration and measurement With Day 0 as the first day of administration, observation was performed until Day 46 for AZ-521-bearing mice, until Day 84 for MKN-28-bearing mice, and until Day 56 for NCI-N87-bearing mice.
  • FK330 was administered by oral gavage at 5 mL / kg, and paclitaxel was administered by tail vein at 10 mL / kg.
  • Paclitaxel was administered in multiple cycles under the following conditions.
  • Control group untreated FK330 single administration group: FK330 100mg / kg bid (200mg / kg / day, continuous administration from the start of the experiment to the end of the experiment)
  • Paclitaxel alone administration group Paclitaxel 10mg / kg / day AZ-521 tumor-bearing mice: Paclitaxel was administered continuously for 6 days from Day 0 to Day 5, followed by a 22-day drug holiday (1 cycle), and paclitaxel was administered continuously for 5 days from Day 28 to Day 32 (2 cycles).
  • MKN-28 tumor-bearing mice Paclitaxel was administered continuously for 6 days from Day 0 to Day 5, and after a 22-day withdrawal period, it was administered continuously for 5 days from Day 28 to Day 32, followed by a 23-day withdrawal period (2 cycles). Furthermore, continuous administration for 5 days from Day 56 to Day 60 was performed (3 cycles).
  • NCI-N87 tumor-bearing mice Paclitaxel was administered continuously for 6 days from Day 0 to Day 5, and then administered continuously for 5 days from Day 32 to Day 36 after a 26-day drug holiday (2 cycles).
  • Combination group FK330 100 mg / kg bid (200 mg / kg / day, continuous administration from the start of the experiment to the end of the experiment) + paclitaxel 10 mg / kg / day
  • FK330 was administered by oral gavage (5 mL / kg) twice a day at intervals of 6 to 8 hours.
  • Paclitaxel was administered intravenously (10 mL / kg) from the tail vein 2 to 4 hours after administration of FK330. Tumor diameter was measured every 3 to 4 days using body weight and digital calipers. The tumor volume was calculated from an elliptic volume calculation formula (major axis x [minor axis] 2 x 0.52). 4)
  • SEM standard error
  • FIGS. 10 to 12 show the results of examining the combined use effect of FK330 with paclitaxel in mice bearing human gastric cancer (AZ-521, MKN-28, NCI-N87).
  • 10 shows the combined effect of FK330 and paclitaxel in AZ-521 tumor-bearing mice
  • FIG. 11 shows the combined effect in MKN-28-bearing mice
  • FIG. 12 shows the combined effect in NCI-N87-bearing mice.
  • FK330 enhanced the antitumor effect of paclitaxel.
  • the tumor volume of the paclitaxel alone group on the last day of the experiment was 3285.4 ⁇ 359.4 mm 3
  • the paclitaxel and FK330 combination group was 795.0 ⁇ 223.3 mm 3
  • the tumor volume was 75.8 compared to the paclitaxel alone group % (P ⁇ 0.01) decrease.
  • Example 6 Test substance The dose of FK330 was converted to the weight of a single substance (non-hydrate).
  • Paclitaxel was purchased from LC Laboratories (Woburn, MA, USA) and used as paclitaxel.
  • Preparation and administration of test substance FK330 was suspended in a 0.5% methylcellulose aqueous solution (0.5% MC) (20 mg / mL) and orally administered.
  • a 10 mg / mL stock solution in ethanol / cremophor solution (mixed 1: 1), then dilute to 1 mg / mL with saline for injection (Otsuka Pharmaceutical) just before administration. It was administered via the tail vein.
  • HTB-26 Human breast cancer-derived MDA-MB-231 was obtained from the American Type Culture Collection (VA, USA). The cells were cultured under conditions of 37 ° C. and 5% CO 2 using DMEM medium supplemented with 10% heat-inactivated fetal bovine serum (FBS). Cells collected using trypsin were suspended in PBS at 6 ⁇ 10 7 cells / mL and mixed with an equal amount of Matrigel TM Basement Membrane Matrix (Becton Dickinson, Bedford, MA, USA).
  • FBS heat-inactivated fetal bovine serum
  • Control group untreated FK330 single administration group: FK330 100 mg / kg bid (200 mg / kg / day, continuous administration from the start of the experiment to the end of the experiment)
  • Paclitaxel alone administration group Paclitaxel 10 mg / kg / day (continuous administration for 4 days in each cycle)
  • Combination group FK330 100 mg / kg bid (200 mg / kg / day, continuous administration from the start of the experiment to the end of the experiment) + paclitaxel 10 mg / kg / day (continuous administration for each cycle for 4 days)
  • FK330 was administered by oral gavage (5 mL / kg) twice a day at intervals of 6 to 8 hours.
  • Paclitaxel was administered as an intravenous bolus (10 mL / kg) from the tail vein 1 to 4 hours after administration of FK330. Tumor diameter was measured twice a week using body weight and digital calipers. The tumor volume was calculated from the ellipse volume calculation formula (major axis x [minor axis] 2 x 0.5).
  • FIG. 13 shows the results of examining the combined effect of FK330 with paclitaxel in human breast cancer-bearing mice.
  • Example 7 Test substance S-nitroso-N-acetyl-D, L-penicillamine (SNAP), which is a NO donor, was purchased from Cayman Chemical (Ann Arbor, MI, USA). The tubulin polymerization measurement kit was purchased from Cytoskeleton (Denver, CO, USA) and used. As paclitaxel, paclitaxel enclosed in the measurement kit was used as paclitaxel. Docetaxel was purchased from Sigma-Aldrich (St. Louis, MO, USA) and used as docetaxel. 2) Test method The tubulin polymerization reaction measurement by the fluorescence method was performed according to the instruction manual of the kit.
  • SNAP S-nitroso-N-acetyl-D, L-penicillamine
  • porcine brain-derived tubulin final concentration 2 mg / mL
  • SNAP final concentration 200 or 500 ⁇ mol / L
  • paclitaxel final concentration 3 ⁇ mol / L
  • docetaxel final concentration 1 ⁇ mol / L
  • GPT final concentration 1 mmol / L
  • the fluorescence intensity was measured every minute with a microplate reader (SpectraMax, Molecular Devices, Sunnyvale, CA, USA). The value of the fluorescence intensity was 60 minutes after the start of the reaction corresponding to the equilibrium stationary phase, expressed as a percentage of the SNAP and taxane-untreated group, and the average value obtained three times was used as the value.
  • FIGS. 15A and 15B Results A representative example of the inhibitory action of SNAP on paclitaxel-induced tubulin polymerization and the aggregated value for 60 minutes after the start of tubulin polymerization are shown in A) and B) of FIG. A representative example of this and the total value 60 minutes after the start of tubulin polymerization are shown in FIGS. 15A and 15B, respectively.
  • Paclitaxel or docetaxel significantly promoted tubulin polymerization by 152.7% (P ⁇ 0.05) and 184.1% (P ⁇ 0.001), respectively, compared to each taxane untreated.
  • NO donor SNAP significantly inhibited tubulin polymerization reactions promoted by paclitaxel and docetaxel.
  • SNAP also significantly suppressed the spontaneously induced tubulin polymerization reaction.
  • Example 8 Test substance The dose of FK330 was converted to the weight of a single substance (non-hydrate).
  • Paclitaxel injection (paclitaxel injection “Sawai”) was purchased from Sawai Pharmaceutical Co., Ltd. and used as paclitaxel.
  • Rat anti-mouse F4 / 80 antigen monoclonal antibody, rabbit anti-iNOS polyclonal antibody, and rabbit anti-nitrotyrosine antibody are AbD Serotec (Oxford, UK), Santa Cruz Biotechnology (Santa Cruz, CA, US), and Millipore, respectively. (Billerica, MA, USA) was used.
  • test substance FK330 was suspended in a 0.5% methylcellulose aqueous solution (0.5% MC) (20 mg / mL) and orally administered.
  • Paclitaxel was prepared at the time of use at 1 mg / mL in physiological saline for injection (Otsuka Pharmaceutical).
  • Cells Human lung cancer-derived Calu-6 was obtained from the American Type Culture Collection (VA, USA). The cells were cultured under the conditions of 37 ° C. and 5% CO 2 using RPMI1640 medium supplemented with 10% heat-inactivated fetal bovine serum (FBS).
  • Control group untreated FK330 single administration group: FK330 100 mg / kg bid (200 mg / kg / day, Day 1 to Day 6) Paclitaxel alone administration group: Paclitaxel 10 mg / kg / day (Day 1 to Day 5) Combination group: FK330 100 mg / kg bid (200 mg / kg / day, Day 1 to Day 6) + paclitaxel 10 mg / kg / day (Day 1 to Day 5) FK330 was administered by oral gavage (5 mL / kg) twice a day at intervals of 6 to 8 hours. Paclitaxel was administered as an intravenous bolus (10 mL / kg) from the tail vein 1 to 4 hours after administration of FK330.
  • Tissue fixation and frozen block preparation On Day 6, tumor tissues were collected from mice. Infiltration was fixed with 4% paraformaldehyde-phosphate buffer (Wako Pure Chemical Industries, Ltd.) at 4 ° C. for 12 hours. Tissue fixation, 10%, 15% and 20% sucrose / phosphate buffer were used, and sucrose substitution was performed stepwise at 4 ° C. according to a conventional method. After the replacement, the cancer tissue was embedded in an OCT compound (Toronto Research Chemicals, Toronto, Canada), a frozen block was prepared with dry ice / acetone, and stored at ⁇ 80 ° C.
  • OCT compound Toronto Research Chemicals, Toronto, Canada
  • Mouse macrophage staining Primary antibody treatment: incubated with rat anti-mouse F4 / 80 antigen monoclonal antibody (1: 200 dilution) for 60 minutes at room temperature. Secondary antibody treatment: Incubated with biotinylated anti-rat IgG antibody (1: 100 dilution, vector laboratories) for 30 minutes at room temperature. Detection system: Sections were incubated for 30 minutes at room temperature using VECTASTAIN ABC kit (Vector Laboratories). Color development: treated with 3,3′-diaminobenzidine tetrahydrochloride (DAB, Dako) reagent for 1 minute at room temperature.
  • DAB 3,3′-diaminobenzidine tetrahydrochloride
  • iNOS staining Primary antibody treatment: Incubated with rabbit anti-iNOS polyclonal antibody (1: 500 dilution) overnight at 4 ° C. Detection system: Sections were incubated for 30 minutes at room temperature using EnVision (DAKO;). Color development: treated with DAB reagent for 1 minute at room temperature. Nitrotyrosine staining: Primary antibody treatment: Incubated with rabbit anti-nitrotyrosine antibody (1: 500 dilution) overnight at 4 ° C. Detection system: Sections were incubated for 30 minutes at room temperature using EnVision (DAKO;). Color development: treated with DAB reagent for 1 minute at room temperature.
  • Stained images (200x for F4 / 80 and iNOS images, 400x for nitrotyrosine-stained images) are loaded into a computer via a microscope, and image analysis system equipped with WinROOF (version 5.7) (Mitani Corporation) Analyzed. The value was expressed as a ratio (%) of positive area per total area. Five visual fields were measured for each section, and the average value was taken as the value.
  • Example 9 Test substance The dose of FK330 was converted to the weight of a single substance (non-hydrate).
  • Paclitaxel was purchased from LC Laboratories (Woburn, MA, USA) and used as paclitaxel.
  • Preparation and administration of test substance FK330 was suspended in a 0.5% aqueous methylcellulose solution (0.5% MC) (20 mg / mL) and orally administered.
  • aqueous methylcellulose solution (0.5% MC) (20 mg / mL) and orally administered.
  • Cells Human hormone resistant prostate cancer-derived PC-3 (CRL-1435) was obtained from the American Type Culture Collection (VA, USA). The cells were cultured under conditions of 37 ° C. and 5% CO 2 using DMEM medium supplemented with 10% heat-inactivated fetal bovine serum (FBS). Cells collected using trypsin were suspended in PBS at 6 ⁇ 10 7 cells / mL and mixed with an equal amount of Matrigel TM Basement Membrane Matrix (Becton Dickinson, Bedford, MA, USA).
  • FBS heat-inactivated fetal bovine serum
  • FK330 was administered by oral gavage at 5 mL / kg, and paclitaxel was administered by tail vein at 10 mL / kg. Paclitaxel was administered continuously for 5 days from Day 0 to Day 4, followed by a 25-day rest (1 cycle). In the second cycle of paclitaxel, it was administered continuously from Day 30 for 4 days.
  • Control group untreated FK330 single administration group: FK330 100 mg / kg bid (200 mg / kg / day, continuous administration from the start of the experiment to the end of the experiment)
  • Paclitaxel alone administration group Paclitaxel 10 mg / kg / day was administered continuously for 5 days from Day 0 to Day 4, followed by a 25-day rest period (1 cycle), and paclitaxel was administered continuously for 4 days from Day 30 to Day 33 ( 2 cycles).
  • Combination group FK330 100 mg / kg bid (200 mg / kg / day, continuous administration from the start of the experiment to the end of the experiment) + paclitaxel 10 mg / kg / day (first cycle for 5 consecutive days, second cycle for 4 consecutive days) ).
  • FK330 was administered by oral gavage (5 mL / kg) twice a day at intervals of 6 to 8 hours.
  • Paclitaxel was administered as an intravenous bolus (10 mL / kg) from the tail vein 1 to 4 hours after administration of FK330.
  • Tumor diameter was measured twice a week using body weight and digital calipers. The tumor volume was calculated from the ellipse volume calculation formula (major axis x [minor axis] 2 x 0.5).
  • FIG. 19 shows the results of examining the combined effect of FK330 with paclitaxel in human hormone-resistant prostate cancer.
  • Example 10 Test substance The dose of FK330 was converted to the weight of a single substance (non-hydrate). Docetaxel (docetaxel hydrate injection (Taxotere TM intravenous drip infusion)) was purchased from Sanofi-Aventis Co., Ltd. and used as docetaxel. 2) Preparation and administration of test substance FK330 was suspended in a 0.5% aqueous methylcellulose solution (0.5% MC) (20 mg / mL) and orally administered. Docetaxel (40 mg / mL) was adjusted to 20 mg / mL with 95% ethanol and then diluted to 1 mg / mL with physiological saline for injection (Otsuka Pharmaceutical) immediately before administration and administered into the tail vein.
  • Docetaxel docetaxel hydrate injection (Taxotere TM intravenous drip infusion)
  • MC aqueous methylcellulose solution
  • Docetaxel 40 mg / mL was adjusted to 20 mg /
  • Cells Human hormone resistant prostate cancer-derived PC-3 (CRL-1435) was obtained from the American Type Culture Collection (VA, USA). The cells were cultured under conditions of 37 ° C. and 5% CO 2 using DMEM medium supplemented with 10% heat-inactivated fetal bovine serum (FBS). Cells collected using trypsin were suspended in PBS at 6 ⁇ 10 7 cells / mL and mixed with an equal amount of Matrigel TM Basement Membrane Matrix (Becton Dickinson, Bedford, MA, USA).
  • FBS heat-inactivated fetal bovine serum
  • FK330 was administered by oral gavage at 5 mL / kg, and docetaxel was administered by tail vein at 10 mL / kg. Docetaxel was administered for 2 days continuously on Day 0 and Day 1 and then was withdrawn for 25 days (1 cycle). In the second cycle of docetaxel, administration was continued for 2 days from Day 27.
  • Control group untreated FK330 single administration group: FK330 100 mg / kg bid (200 mg / kg / day, continuous administration from the start of the experiment to the end of the experiment)
  • Docetaxel alone administration group Docetaxel 10 mg / kg / day was administered continuously for 2 days, Day 0 and Day 1, followed by a 25-day rest period (1 cycle), and docetaxel was administered continuously for 2 days from Day 27 (2 cycles)
  • Combination group FK330 100 mg / kg bid (200 mg / kg / day, continuous administration from the start of the experiment to the end of the experiment) + docetaxel 10 mg / kg / day (continuous administration for 2 days in each cycle)
  • FK330 was administered by oral gavage (5 mL / kg) twice a day at intervals of 6 to 8 hours.
  • Docetaxel was administered as an intravenous bolus (10 mL / kg) from the tail vein 1 to 4 hours after administration of FK330. Tumor diameter was measured twice a week using body weight and digital calipers. The tumor volume was calculated from the ellipse volume calculation formula (major axis x [minor axis] 2 x 0.5).
  • FIG. 20 shows the results of examining the combined use effect of FK330 with docetaxel in human hormone-resistant prostate cancer.
  • Example 11 Test substance The dose of FK330 was converted to the weight of a single substance (non-hydrate). Docetaxel (docetaxel hydrate injection (Taxotere TM intravenous drip infusion)) was purchased from Sanofi-Aventis Co., Ltd. and used as docetaxel. 2) Preparation and administration of test substance FK330 was suspended in a 0.5% aqueous methylcellulose solution (0.5% MC) (20 mg / mL) and orally administered. Docetaxel (40 mg / mL) was adjusted to 20 mg / mL with 95% ethanol, then diluted to 1.5 mg / mL with physiological saline for injection (Otsuka Pharmaceutical) and administered into the tail vein immediately before administration.
  • Docetaxel (docetaxel hydrate injection (Taxotere TM intravenous drip infusion)) was purchased from Sanofi-Aventis Co., Ltd. and used as docetaxel. 2) Preparation and administration of test
  • HTB-132 Human breast cancer-derived MDA-MB-468 was obtained from the American Type Culture Collection (VA, USA). The cells were cultured under the conditions of 37 ° C. and 5% CO 2 using RPMI1640 medium supplemented with 10% heat-inactivated fetal bovine serum (FBS). Cells collected using trypsin were suspended in PBS at 6 ⁇ 10 7 cells / mL and mixed with an equal amount of Matrigel TM Basement Membrane Matrix (Becton Dickinson, Bedford, MA, USA).
  • FBS heat-inactivated fetal bovine serum
  • FK330 was administered by oral gavage at 5 mL / kg, and docetaxel was administered by tail vein at 10 mL / kg. Docetaxel was administered for 36 days after Day 0 administration (1 cycle) and administered again on Day 37 (2 cycles).
  • Docetaxel single administration group After docetaxel 15 mg / kg / day was administered on Day 0, a 36-day withdrawal period was placed (1 cycle), and docetaxel was administered again on Day 37 (2 cycles).
  • Combination group FK330 100 mg / kg bid + docetaxel 15 mg / kg / day.
  • FK330 was administered by oral gavage (5 mL / kg) twice a day at intervals of 6 to 8 hours.
  • Docetaxel was administered as a bolus (10 mL / kg) from the tail vein 1 to 4 hours after administration of FK330.
  • Tumor diameter was measured twice a week using body weight and digital calipers. The tumor volume was calculated from the ellipse volume calculation formula (major axis x [minor axis] 2 x 0.5).
  • FIG. 21 shows the results of examining the combined use effect of FK330 with docetaxel in a human breast cancer-bearing model.
  • Example 12 Test substance The dose of FK330 was converted to the weight of a single substance (non-hydrate).
  • Paclitaxel was purchased from LC Laboratories (Woburn, MA, USA) and used as paclitaxel.
  • Preparation and administration of test substance FK330 was suspended in a 0.5% aqueous methylcellulose solution (0.5% MC) (20 mg / mL) and orally administered. After preparing a 10 mg / mL stock solution in ethanol / Cremophor solution (mixed 1: 1), paclitaxel is diluted to 1 mg / mL with physiological saline for injection (Otsuka Pharmaceutical) immediately before administration. And administered via the tail vein.
  • physiological saline for injection Otsuka Pharmaceutical
  • JCRB0240 Cells Human ovarian cancer-derived MCAS (JCRB0240) was obtained from the Pharmaceutical Research Institute (HSRRB). The cells were cultured under conditions of 37 ° C. and 5% CO 2 using EMEM medium supplemented with 20% heat-inactivated fetal bovine serum (FBS). Cells collected using trypsin were suspended in PBS at 6 ⁇ 10 7 cells / mL and mixed with an equal amount of Matrigel TM Basement Membrane Matrix (Becton Dickinson, Bedford, MA, USA).
  • FBS heat-inactivated fetal bovine serum
  • FK330 was administered by oral gavage at 5 mL / kg, and paclitaxel was administered by tail vein at 10 mL / kg. Paclitaxel was administered continuously for 5 days from Day 0 to Day 4, followed by 24 days of withdrawal (1 cycle). The second cycle of paclitaxel was administered from Day 29 for 5 consecutive days. Administration of paclitaxel in the third cycle after 29 days of withdrawal was continued for 5 consecutive days from Day 63.
  • Control group untreated FK330 single administration group: FK330 100 mg / kg bid (200 mg / kg / day, continuous administration from the start of the experiment to the end of the experiment)
  • Paclitaxel alone administration group Paclitaxel 10 mg / kg / day was administered continuously for 5 days from Day 0 to Day 4, and a 24-day drug holiday was placed (1 cycle). Next, paclitaxel was continuously administered for 5 days from Day 29, followed by a 29-day drug holiday (2 cycles), and paclitaxel was continuously administered for 5 days from Day 63 (3 cycles).
  • Combination group FK330 100 mg / kg bid (200 mg / kg / day, continuous administration from the start of the experiment to the end of the experiment) + paclitaxel 10 mg / kg / day (continuous administration for each cycle for 5 days)
  • FK330 was administered by oral gavage (5 mL / kg) twice a day at intervals of 6 to 8 hours.
  • Paclitaxel was administered as a bolus (10 mL / kg) from the tail vein 1 to 4 hours after administration of FK330.
  • Tumor diameter was measured twice a week using body weight and digital calipers. The tumor volume was calculated from the ellipse volume calculation formula (major axis x [minor axis] 2 x 0.5).
  • FIG. 22 shows the results of examining the combined use effect of FK330 with paclitaxel in human ovarian cancer.
  • FK330 markedly enhanced the antitumor effect of paclitaxel, and the tumor volume reduction rate compared to the paclitaxel alone group at Day 63 was 61.5% (no significant difference), and paclitaxel alone at Day 91 The tumor volume reduction rate for the group was 86.0% (P ⁇ 0.05).
  • composition for cancer treatment containing FK330 or a salt thereof as an active ingredient is used in combination with a taxane antitumor agent, wherein the composition is used in combination with the taxane antitumor agent of the present invention.
  • a taxane antitumor agent Is particularly useful for the treatment of various cancers known to be applied to existing taxane antitumor agents.
  • Applicable cancers are solid cancers and lymphomas in which taxane antitumor agents are used, and in some embodiments, breast cancer, endometrial cancer, ovarian cancer, prostate cancer, lung cancer, stomach (gastric gland) cancer, non-cancerous Small cell lung cancer, pancreatic cancer, squamous cell carcinoma of the head and neck, esophageal cancer, bladder cancer, melanoma, colon cancer, renal cell cancer, non-Hodgkin lymphoma, etc.
  • Other embodiments include prostate cancer or ovarian cancer.

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Abstract

[Problème] Comment satisfaire à une demande en méthode thérapeutique permettant d'améliorer les effets médicinaux d'agents antitumoraux à base de taxane sur diverses tumeurs ? [Solution] Le présent inventeur a effectué des études sur un procédé permettant d'améliorer les effets antitumoraux d'agents antitumoraux à base de taxane, études à la suite desquelles l'inventeur a confirmé qu'une composition destinée au traitement du cancer, ladite composition contenant comme principe actif le N2-[(2E)-3-(4-chlorophényl)-2-propénoyl]-N- [2-oxo-2-(4-{[6-(trifluorométhyl)pyrimidin-4-yl]oxy}pipéridin-1-yl)éthyl]-3-pyridin-2-yl-L-alanineamide (FK330) ou un sel de celui-ci, améliore les effets antitumoraux d'agents antitumoraux à base de taxane pour ainsi achever la présente invention. Ainsi, la présente invention concerne une composition destinée à traiter le cancer, qui contient comme principe actif le FK330 ou un sel de celui-ci et qui est destinée à être administrée en association avec un ou plusieurs agents antitumoraux choisis parmi les agents antitumoraux à base de taxane. Dans un mode de réalisation, la présente invention concerne une composition destinée à traiter le cancer de la prostate ou le cancer ovarien.
PCT/JP2013/052231 2011-08-02 2013-01-31 Procédé de traitement du cancer par l'utilisation combinée de médicaments WO2014118946A1 (fr)

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Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CAHLIN C. ET AL.: "Effect of cyclooxygenase and nitric oxide synthase inhibitors on tumor growth in mouse tumor models", CANCER RES., vol. 60, no. 6, 15 March 2000 (2000-03-15), pages 1742 - 1749 *
CHIDA N. ET AL.: "Pharmacological profile of FR 260330, a novel orally active inducible nitric oxide synthase inhibitor", EUR J PHARMACOL., vol. 509, no. 1, 2005, pages 71 - 76 *
THOMSEN LL. ET AL.: "Selective inhibition of inducible nitric oxide synthase inhibits tumor growth in vivo: studies with 1400W, a inhibitor", CANCER RES., vol. 57, no. 15, pages 3300 - 3304 *
TOSHIYUKI SUWA ET AL.: "NO Gosei Sogaizai: L-NAME no Gan Kekkan Shinsei ni Taisuru Sayo", JOURNAL OF JAPAN SURGICAL SOCIETY, vol. 106, 5 April 2005 (2005-04-05), pages 373 *
UNEDA S. ET AL.: "A nitric oxide synthase inhibitor, N(G)-nitro-1-arginine-methyl-ester, exerts potent antiangiogenic", BR J HAEMATOL., vol. 120, no. 3, 2003, pages 396 - 404 *

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