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WO2010086964A1 - Thérapie de combinaison pour traitement d'un cancer - Google Patents

Thérapie de combinaison pour traitement d'un cancer Download PDF

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Publication number
WO2010086964A1
WO2010086964A1 PCT/JP2009/051314 JP2009051314W WO2010086964A1 WO 2010086964 A1 WO2010086964 A1 WO 2010086964A1 JP 2009051314 W JP2009051314 W JP 2009051314W WO 2010086964 A1 WO2010086964 A1 WO 2010086964A1
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Prior art keywords
inhibitor
group
pai
agent
cancer
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Japanese (ja)
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清 中戸川
正道 高木
真 赤嶋
健太郎 上田
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Shizuoka Coffein Co Ltd
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Shizuoka Coffein Co Ltd
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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a medicament comprising a combination of a plasminogen activator inhibitor-1 (PAI-1) inhibitor and a cytotoxic agent or cytostatic agent, particularly a medicament for inhibiting tumor growth and / or metastasis.
  • a pharmaceutical kit comprising a PAI-1 inhibitor and a cytotoxic or cytostatic agent, in particular tumor growth and Pharmaceutical kit for suppressing metastasis, method of suppressing tumor growth and / or metastasis administered by combining PAI-1 inhibitor and cytotoxic agent or cytostatic agent, and PAI-1 inhibitor
  • the present invention relates to a medicament for enhancing the effect of inhibiting tumor growth and / or metastasis of a cytotoxic agent or cytostatic agent as an active ingredient.
  • Major antitumor drugs used in the chemotherapy area of malignant tumors include fluorinated pyrimidine preparations, DNA topoisomerase inhibitors, taxane drugs, molecular targeted drugs, platinum drugs and anticancer antibiotics. It is done.
  • the mechanism of action related to anticancer activity varies, for example, 5-fluorouracil, a fluoropyrimidine preparation, a typical antitumor drug used in gastrointestinal cancer, inhibits the DNA synthesis pathway by thymidylate synthase Antitumor effect is manifested by things.
  • the major DNA topoisomerase inhibitor irinotecan hydrochloride is a semisynthetic derivative of camptothecin.
  • Taxane drugs are drugs that act on microtubules during cell division, and include docetaxel hydrate and paclitaxel.
  • molecular target drugs include bevacizumab, which is a vascular endothelial growth factor (VEGF) inhibitor, and cetuximab, panituzumab, which are epidermal growth factor receptor (EGFR) inhibitors.
  • VEGF vascular endothelial growth factor
  • EGFR epidermal growth factor receptor
  • Platinum-based drugs are drugs that specifically bind to DNA and exert an antitumor effect by inhibiting DNA replication during cell division. Examples of platinum-based drugs include cisplatin, nedaplatin, and oxaliplatin.
  • Anticancer antibiotics include actinomycins, mitomycins, anthracyclines and bleomycins, which act as DNA or RNA inhibitors and inhibit the growth and proliferation of cancer cells.
  • chemotherapeutic agents have useful anti-tumor effects, but bone marrow suppression, interstitial pneumonia, hair loss, heart failure, DIC, intestinal perforation, hair loss, peripheral neuropathy, cardiotoxicity, kidney damage, hearing and nerves Side effects such as disability, edema, shock, stomatitis, allergic symptoms, and hemolytic anemia often occur, and this is a great burden for patients in cancer treatment. Reducing the side effects of these chemotherapeutic agents is important in the treatment of cancer. As one of the measures for reducing the side effects, there can be considered a combination therapy that enables the dose of a chemotherapeutic agent having a strong side effect to be reduced by improving the anticancer action by the combined effect. To date, various combination therapies that combine multiple anticancer agents have been tried.
  • a combination of 5-fluorouracil and leucovorin and oxaliplatin, irinotecan and 5-fluorouracil and leucovorin, folic acid and 5-fluorouracil and irinotecan, irinotecan and folic acid and 5-fluorouracil, oxaliplatin and irinotecan Multi-drug combination therapy is performed by such means.
  • combination therapy using an anticancer drug such as irinotecan, paclitaxel, docetaxel, vinorelbine, gemcitabine, amrubicin and a platinum-based drug for advanced non-small cell lung cancer is performed.
  • ovarian cancer chemotherapy a combination of taxane taxol and a platinum preparation, and a combination of adriamycin and a platinum preparation cisplatin as a treatment for advanced / recurrent endometrial cancer are being studied.
  • combination therapy of methotrexate, vinblastine, adriamycin, and cisplatin and gemcitabine and cisplatin is being investigated for urothelial cancer.
  • pancreatic cancer is one of the most difficult cancers to treat and its results are not satisfactory.
  • Combination therapy with gemcitabine and other drugs has been actively attempted for patients with pancreatic cancer.
  • many combinations such as combination therapy of 5-fluorouracil and gemcitabine (Non-patent Document 1), combination therapy of oxaliplatin and gemcitabine (Non-patent document 2), combination therapy of irinotecan hydrochloride and gemcitabine (Non-patent document 3)
  • the results of trials with therapy have been reported, but none of them has been shown to have a significant increase in survival.
  • Patent Document 1 a report on the combined effect of a combination of a raf kinase inhibitor and irinotecan or gemcitabine (Patent Document 1), an EGFR inhibitor and irinotecan Report on combined use (Patent Document 2), Report on combined use of EGFR inhibitor and gemcitabine (Patent Document 3), Report on combined use of serine / threonine kinase PLK-1 inhibitor and irinotecan or gemcitabine (Patent Document 4), and NF
  • Patent Document 5 a report on the combined use of a protease inhibitor having - ⁇ B inhibitory activity and gemcitabine
  • Non-Patent Document 4 Reports on the antitumor effects of PAI-1 inhibitors are disclosed in Non-Patent Document 4, Patent Documents 6-10, and the like.
  • an existing anticancer drug cytotoxic agent or cytostatic agent.
  • the useful effects of each drug are synergistically amplified, but it is also possible that minor effects such as toxicity and side effects increase. Therefore, the effectiveness and safety of each drug used as a concomitant drug cannot be predicted in advance from the effectiveness and safety of the drug.
  • the problem to be solved by the present invention is to provide a combination therapy for suppressing the growth and / or metastasis of tumors by the combined use of individual drugs, in which the effectiveness and safety of each drug are secured and enhanced. There is.
  • the present inventors have conducted intensive research on a combination therapy combining an existing anticancer agent (cytotoxic agent or cytostatic agent) with another agent for the purpose of suppressing tumor growth and / or metastasis.
  • an antitumor effect possessed by a cytotoxic agent or cytostatic agent is improved by an unprecedented combination of a PAI-1 inhibitor and a cytotoxic agent or cytostatic agent. It came to make.
  • the present invention relates to a pharmaceutical comprising a combination of a plasminogen activator inhibitor-1 (PAI-1) inhibitor and a cytotoxic agent or cytostatic agent, particularly to suppress tumor growth and / or metastasis. It is related with the medicine for.
  • the present invention further relates to the use of a combination of a PAI-1 inhibitor and a cytotoxin or cytostatic agent for the manufacture of a medicament for inhibiting tumor growth and / or metastasis.
  • the present invention relates to a pharmaceutical kit comprising a PAI-1 inhibitor and a cytotoxin or cytostatic agent, in particular, a pharmaceutical kit for suppressing tumor growth and / or metastasis.
  • the present invention relates to a method for suppressing tumor growth and / or metastasis, comprising administering a PAI-1 inhibitor and a cytotoxic agent or cytostatic agent to a mammal including a human. Furthermore, the present invention relates to a medicament for enhancing the tumor growth and / or metastasis-suppressing effect of a cytotoxic agent or cytostatic agent containing a PAI-1 inhibitor as an active ingredient.
  • Combination therapy combining a PAI-1 inhibitor with a cytotoxic agent or cytostatic agent is an antitumor agent that is completely different from conventional combination therapy, and is used as a prophylactic, therapeutic agent for various malignant tumors, or for metastasis. It can be used as a prophylactic agent, and exhibits a high tumor growth inhibitory effect on pancreatic cancer cells, particularly in combination with gemcitabine. In addition, the combined effect can reduce the amount of cytotoxic agents and cytostatics having strong side effects, which is also effective from the viewpoint of the patient's quality of life (QOL).
  • QOL quality of life
  • the PAI-1 inhibitor used in the present invention includes the following formula (1) [In the formula (1), ring A represents benzoxazole, benzothiazole or pyrimidine; R 1 represents a hydroxyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, and a straight chain having 1 to 4 carbon atoms.
  • linear or branched alkyl group having 1 to 6 carbon atoms specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, Examples thereof include a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, an isohexyl group, and a neohexyl group.
  • linear or branched lower alkyl group having 1 to 4 carbon atoms include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert- A butyl group etc. are mentioned.
  • C 1-4 straight or branched lower alkoxy group include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert -Butoxy group and the like.
  • a methoxy group and an ethoxy group are preferable.
  • Specific examples of the “halogen atom” include a chlorine atom, a bromine atom, and a fluorine atom.
  • the propanedioic acid derivative represented by the formula (1) may be a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.
  • the salt of the propanedioic acid derivative represented by the formula (1) preferably used in the present invention is prepared from a pharmaceutically acceptable non-toxic base including an inorganic base and an organic base. I can do things. Salts derived from inorganic bases include potassium salts, sodium salts, calcium salts, magnesium salts, aluminum salts, ammonium salts, and the like. Particularly preferred are potassium salt and sodium salt.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include primary amine salts, secondary amine salts, tertiary amine salts, cyclic amine salts and the like. Further, when the structure of the propanedioic acid derivative represented by the formula (1) has a basic site, a salt can be prepared from a pharmaceutically acceptable non-toxic acid including an inorganic acid and an organic acid. . Examples of non-toxic acids include acetic acid, citric acid, succinic acid, tartaric acid, maleic acid, methane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like.
  • the propanedioic acid derivative represented by the formula (1) that is preferably used as a PAI-1 inhibitor is disclosed in Non-Patent Document 4 and Patent Document 10, and described in Patent Document 10 It can be manufactured by a method.
  • ring A is benzoxazole or pyrimidine
  • R 1 is a linear or branched alkyl group having 1 to 6 carbon atoms, cyclohexylmethoxy group, benzyl An oxy group (wherein the phenyl of the benzyloxy group may be substituted with a halogen atom) or a phenyl group (wherein the phenyl group is a straight or branched lower alkoxy having 1 to 4 carbon atoms)
  • R 2 and R 3 are hydrogen atoms
  • m is an integer of 1 or 2
  • two R 1 s may be the same or different from each other
  • W is an integer of 3 to 5, and the propanedioic acid derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof is more preferable.
  • propanedioic acid derivative represented by the formula (1) include the following compounds. (1). [3-[[6- (5-phenyl-2-benzoxazolyl) -2-naphthalenyl] oxy] propyl] propanedioic acid, (2). [5-[[6- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, (3). [5-[[6- [6- (cyclohexylmethoxy) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, (4).
  • Table 1 shows the structural formulas of the above-described compounds.
  • cytotoxic agent refers to a drug administered to kill or kill cancer cells
  • cytostatic agent refers to a drug administered to suppress tumor growth.
  • the cytotoxic agent or cytostatic agent used in the present invention may form a pharmaceutically acceptable non-toxic salt.
  • cytotoxins or cytostatics include DNA synthesis inhibitors, DNA topoisomerase type I inhibitors, DNA topoisomerase type II inhibitors, microtubule agents, vascular endothelial growth factor (VEGF) inhibitors, epithelium Examples include growth factor receptor (EGFR) inhibitors, alkylating agents, platinum complexes, anticancer antibiotics, hormone therapy agents, etc. In the present invention, one or more of these are combined with PAI-1 inhibitors. Have been used.
  • cytotoxic agent or cytostatic agent in the present invention include gemcitabine, capecitabine, 5-fluorouracil, methotrexate, irinotecan, etoposide, doxorubicin, vinorelbine, paclitaxel, vincristine, vinblastine, docetaxel, bevacizumab, gefititib,
  • gemcitabine capecitabine
  • 5-fluorouracil methotrexate
  • irinotecan etoposide
  • doxorubicin vinorelbine
  • paclitaxel vincristine
  • vinblastine docetaxel
  • bevacizumab gefititib
  • trastuzumab sorafenib
  • busulfan melphalan
  • cyclophosphamide cisplatin, carboplatin, oxaliplatin, mitomycin C, actinomycin D, tamoxifen, and anastrozole.
  • a preferred embodiment of the present invention includes a combination of a PAI-1 inhibitor and gemcitabine.
  • Other preferred specific examples include a combination of a PAI-1 inhibitor and irinotecan.
  • Gemcitabine is metabolized in cells by deoxycytidine kinase to the active nucleotides diphosphate and triphosphate, and is thought to directly and indirectly inhibit DNA synthesis.
  • Gemcitabine has broad antitumor activity against solid tumors such as pancreatic cancer, lung cancer, prostate cancer, ovarian cancer and breast cancer.
  • Irinotecan is believed to inhibit DNA synthesis by inhibiting DNA topoisomerase (type I), which performs single-strand breaks and recombination of DNA.
  • type I DNA topoisomerase binds to DNA and then cleaves one of the double-stranded DNA.
  • irinotecan or its active metabolite SN-38 forms a complex with type I DNA topoisomerase. It is considered that recombination of DNA is inhibited by stabilizing the complex.
  • Irinotecan has antitumor activity against solid tumors such as small cell lung cancer, non-small cell lung cancer, cervical cancer, ovarian cancer, gastric cancer and colorectal cancer.
  • tumor growth and / or metastasis can be effectively suppressed by a combination of a PAI-1 inhibitor and a cytotoxic agent or cytostatic agent.
  • the tumors targeted in the present invention include lung cancer, non-small cell lung cancer, breast cancer, pancreatic cancer, liver cancer, kidney cancer, bile duct cancer, esophageal cancer, stomach cancer, duodenal cancer, small intestine cancer, large intestine.
  • Colon, rectal cancer uterine cancer, ovarian cancer, bladder cancer, prostate cancer, thyroid cancer, parathyroid cancer, mesothelioma, leukemia, malignant lymphoma, melanoma, multiple myeloma
  • malignant tumors and colon or rectal precancerous polyps and precancerous lesions such as gastric epithelial malformations.
  • digestive tract cancer and digestive adenocarcinoma such as pancreatic cancer, liver cancer, bile duct cancer, esophageal cancer, stomach cancer, duodenal cancer, small intestine cancer, large intestine (colon, rectum) cancer It is said.
  • pancreatic cancer and colon (colon, rectal) cancer are particularly preferred.
  • the PAI-1 inhibitor and the cytotoxic agent or cytostatic agent may be administered simultaneously, or may be administered separately.
  • a pharmaceutically acceptable carrier can be a solid, liquid or gas, and the solid carrier includes gum arabic, agar, gelatin, talc, lactose and the like.
  • the liquid carrier include water, olive oil, sugar syrup, and the like, and examples of the gas carrier include nitrogen.
  • PAI-1 inhibitors are usually administered to mammals including humans orally, parenterally, transdermally, by injection, by inhalation or spray, sublingually, rectally, Or it can be administered vaginally.
  • a PAI-1 inhibitor preparation for oral administration is prepared by adding a pharmacologically and pharmaceutically acceptable additive, etc., if necessary, together with the above-mentioned pharmaceutically acceptable carrier, and by a conventional method. Or it can manufacture as a capsule. Moreover, it can also be set as the tablet or capsule containing both a PAI-1 inhibitor and a cytotoxic agent or a cytostatic.
  • Oral preparations include, for example, magnesium metasilicate aluminate, magnesium silicate, magnesium carbonate, calcium hydrogenphosphate, various starches, excipients such as dextrin, ethylcellulose (EC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose ( Additives such as binders such as HPC), sodium alginate, gelatin, and corrigents such as mannitol, citric acid, sodium citrate, and sugar, and other additives such as disintegrants, wetting agents, and coating agents can be used.
  • excipients such as dextrin, ethylcellulose (EC), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose ( Additives such as binders such as HPC), sodium alginate, gelatin, and corrigents such as mannitol, citric acid, sodium citrate, and sugar, and other additives such as disintegrants, wetting agents, and coating agents can be used.
  • Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, etc., for example suspensions such as methylcellulose, carboxymethylcellulose, sodium alginate, gelatin and propylene glycol, sucrose or Sweeteners such as saccharin, or emulsifiers such as gelatin, macrogol (PEG), and propylene glycol fatty acid esters can be included.
  • suspensions such as methylcellulose, carboxymethylcellulose, sodium alginate, gelatin and propylene glycol, sucrose or Sweeteners such as saccharin, or emulsifiers such as gelatin, macrogol (PEG), and propylene glycol fatty acid esters can be included.
  • An injection of a PAI-1 inhibitor can be prepared as a sterile aqueous solution. Furthermore, it can be in the form of a sterile powder for preparation into an injectable solution. Moreover, it can also be set as the injection containing both a PAI-1 inhibitor and a cytotoxic agent or a cytostatic agent.
  • a carrier for injection for example, water can be used as a solubilizing agent, and ethanol, glycerol, propylene glycol or the like can be used as a solubilizing agent.
  • pharmaceutical ingredients such as a pH adjuster, an isotonic agent, and a stabilizer can also be used.
  • Suitable forms for transdermal administration can be, for example, creams, ointments, lotions and the like. It can also be made into suppositories for rectal administration. Suppositories should be based on an appropriate substance such as cacao butter, lauric fat, macrogol, glycerogelatin, sodium stearate or mixtures thereof, and if necessary, add emulsifiers, suspending agents, preservatives, etc. Can do.
  • kits containing both a PAI-1 inhibitor and a cytotoxic agent or a cytostatic agent may be used.
  • the kit can be provided in the form of a single container or a plurality of containers.
  • each of the PAI-1 inhibitor and the cytotoxic agent or cytostatic agent can be contained in the form of a preparation as described above.
  • the propanedioic acid derivative having the PAI-1 inhibitory activity represented by the formula (1) can be administered by any of the administration routes described above, and the dose is 0.1 to 300 mg / kg to the patient. Can be administered. Furthermore, the PAI-1 inhibitor can be administered one or more times per day. Cytotoxic agents or cytostatic agents can be administered orally, rectally, by inhalation or by injection or infusion. Administration by injection means intravenous, intramuscular and subcutaneous. The dose of the cytotoxic agent or cytostatic agent may be administered at a dose that is usually employed, or may be administered at a dose lower than the dose.
  • the cytotoxin or cytostatic agent can be administered by any of the administration routes described above in combination with the PAI-1 inhibitor.
  • the PAI-1 inhibitor can be administered simultaneously with the cytotoxic agent or cytostatic agent. This can be done by administering a single formulation containing both a PAI-1 inhibitor and a cytotoxic or cytostatic agent, or by co-administering separate formulations.
  • it is not always necessary to simultaneously administer the PAI-1 inhibitor and the cytotoxic agent or cytostatic agent whereas the PAI-1 inhibitor is administered once or more per day, whereas the cytotoxic agent or cell proliferation
  • the inhibitor can be administered repeatedly after a certain period of time.
  • the PAI-1 inhibitor and cytotoxic agent or cytostatic agent may be administered by different routes. Cytotoxic agents or cytostatic agents may be administered parenterally and PAI-1 inhibitors may be administered orally. In this case as well, the administration conditions can be arbitrarily determined according to the prescribed formulation of the cytotoxic agent or cytostatic agent.
  • gemcitabine which is one of the preferred examples of the cytotoxic agent used in combination with the PAI-1 inhibitor, is marketed as an injectable hydrochloride in the form of hydrochloride, and is administered to the patient by intravenous injection or an appropriate infusion method.
  • irinotecan is also marketed in hydrochloride as an injectable drug and is administered to patients by intravenous injection or other suitable infusion method.
  • a drug containing a PAI-1 inhibitor as an active ingredient can be used to enhance the effect of suppressing tumor growth and / or metastasis of a cytotoxin or cytostatic agent.
  • the PAI-1 inhibitor can be administered simultaneously or separately with the cytotoxic agent or cytostatic agent in the above-mentioned preparation form, administration route and dosage.
  • mice Female mice (CLEA Japan, Inc.) were used.
  • the mouse is a strain commonly used as a cancer-bearing model animal, and a 6-week-old mouse was purchased and bred for 1 week, and then used for the test. Mice were raised under a 12-hour light / dark cycle, temperature of 21 to 25 ° C., and humidity of 40 to 75%, and were allowed to freely ingest powdered food and water for breeding sterile animals.
  • pancreat-1 of human pancreatic cancer cells was selected to test the combined effect of the cultured PAI-1 inhibitor and the cytotoxic agent gemcitabine.
  • HCT116 of human colon cancer cells was selected for the test of the combined effect with irinotecan.
  • Panc-1 cells and HCT116 cells were obtained from DS Pharma Biomedical Co., Ltd.
  • Panc-1 cells and HCT116 cells were subcultured according to a conventional method using Dulbecco's Modified Eagle's medium containing 10% fetal bovine serum (FBS) at 37 ° C. in 95% air-5% CO 2.
  • the cell concentration for transplantation into mice was adjusted to 1 ⁇ 10 7 cells / 0.1 mL serum-free medium at the time of use.
  • Gemcitabine used was a lyophilized preparation of gemcitabine hydrochloride (200 mg as gemcitabine in one vial) sold by Eli Lilly Japan.
  • irinotecan a lyophilized preparation of irinotecan hydrochloride (100 mg of irinotecan in one vial) manufactured by Yakult Honsha Co., Ltd. was used.
  • PAI-1 inhibitors include [5-[[6- [4-phenyl-6- (phenylmethoxy) -2-pyrimidinyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 2Na salt (SK-116) and [5-[[6- [5- (1,1-dimethylethyl) -2-benzoxazolyl] -2-naphthalenyl] oxy] pentyl] propanedioic acid, 2Na salt (SK-216) Company Shizuoka Caffeine Industry) was used.
  • SK-116 and SK-216 are white dry powders. SK-116 and SK-216 were mixed with sterile animal breeding powder feed CL-2 (Claire Japan) so that the content was 50 ppm, 100 ppm and 150 ppm according to the test plan.
  • Tumor xenograft test mice were inoculated with 0.1 mL of tumor cell Kendaku solution (1 ⁇ 10 7 cells) per mouse on the right flank. The tumors were allowed to grow for about 3 weeks and then divided into 10 groups. Tumor volume was calculated using the formula (L ⁇ W 2 ) / 2. Here, L represents the major axis of the tumor, and W represents the minor axis of the tumor.
  • L represents the major axis of the tumor
  • W represents the minor axis of the tumor.
  • Tumor growth inhibition rate (%) 100 ⁇ [100 ⁇ (T ⁇ T 0 ) / (C ⁇ C 0 )]
  • T is the average tumor volume of the treatment group on the drug administration end date
  • T 0 is the average tumor volume of the same group on the drug administration start date
  • C is the mean tumor volume of the control group medication end date
  • C 0 is the mean tumor volume of the control group medication start date.
  • Test plan Table 2 shows the test plan of the combined effect of PAI-1 inhibitor and gemcitabine using Panc-1 pancreatic cancer cells and the combined effect of PAI-1 inhibitor and irinotecan using HCT116 colon cancer cells Table 3 shows. During the test period, the control group was allowed to freely ingest a feed containing no test substance.
  • Test example 1 Method Using the materials described in detail in the above “Materials and Methods”, the following tests were performed according to each method. Each nude mouse was inoculated with 0.1 mL of tumor cell kendaku solution (1 ⁇ 10 7 cells) subcutaneously on the right flank. Three weeks later, the animals were grouped as 10 animals per group. The average tumor volume for each group was 138 ⁇ 15 mm 3 . In this test, the gemcitabine administration group was administered intraperitoneally with 80 mg / kg of gemcitabine once every 4 days ⁇ 3 schedule.
  • a feed prepared by mixing SK-216 at a concentration of 100 ppm was prepared, and the SK-216 combination feed was freely consumed for 44 days from the start to the end of the test.
  • gemcitabine was administered intraperitoneally at 80 mg / kg once every 4 days ⁇ 3 schedule, and for 44 days from the start to the end of administration, SK-216 was 50 ppm or Each feed mixed at a concentration of 100 ppm was freely ingested.
  • a feed containing no test substance was ingested freely.
  • mice were confirmed to be alive or dead, and the general condition was observed. During the study period, there were no deaths in each group and the health status was good. Food intake and body weight were measured once a week. As shown in FIG. 1, there was no statistically significant difference in the body weight (average weight) of each group of mice throughout the test period, and no adverse events were observed due to the combined administration of PAI-1 inhibitor and cytotoxic agent. It was. The tumor diameter was measured twice a week, and the tumor volume of all mice was calculated from the formula of (L ⁇ W 2 ) / 2. The change with time of the tumor volume (average value of each group) is shown in FIG. The inhibition rate of tumor growth was calculated based on the tumor volume of each group.
  • the tumor growth inhibition rate was 33.5% in the gemcitabine 80 mg / kg single administration group, whereas the “SK-216 (100 ppm) + gemcitabine 80 mg / kg” combination group was about 50%, and PAI-1 inhibition It was confirmed that gemcitabine potentiated the tumor growth inhibitory effect of the combination of drugs. From the above results, it was confirmed that the combined use of PAI-1 inhibitor and gemcitabine did not cause any adverse events, was highly safe, and the combined use of PAI-1 inhibitor enhanced the tumor growth inhibitory effect of gemcitabine It was done.
  • Test example 2 Method Using the materials described in detail in the above “Materials and Methods”, the following tests were performed according to each method. Each nude mouse was inoculated with 0.1 mL of tumor cell kendaku solution (1 ⁇ 10 7 cells) subcutaneously on the right flank. Three weeks later, the animals were grouped as 10 animals per group. The average tumor volume for each group was 226 ⁇ 20 mm 3 . In this test, the irinotecan-administered group was administered 40 mg / kg of irinotecan intravenously via the tail vein once every 4 days ⁇ 3 schedules.
  • the PAI-1 inhibitor administration group prepared a feed in which SK-116 was mixed at a concentration of 100 ppm, and freely ingested the SK-116 combined feed for 44 days from the start to the end of the test.
  • irinotecan 40 mg / kg was administered into the tail vein once every 4 days ⁇ 3 schedule, and SK-116 was administered at 100 ppm or 150 ppm for 36 days from the start to the end of administration.
  • Each of the feeds mixed at a concentration of 1 was freely ingested.
  • a feed containing no test substance was ingested freely.
  • mice were confirmed to be alive or dead, and the general condition was observed. During the study period, there were no deaths in each group and the health status was good. Food intake and body weight were measured once a week. As shown in FIG. 3, there was no statistically significant difference in the body weight (average weight) of the mice in each group throughout the test period, and no adverse events were observed due to the combined administration of the PAI-1 inhibitor and irinotecan.
  • the tumor diameter was measured twice a week, and the tumor volume of all mice was calculated from the formula of (L ⁇ W 2 ) / 2. The change with time of the tumor volume (average value of each group) is shown in FIG.
  • the inhibition rate of tumor growth was calculated based on the tumor volume of each group.
  • the tumor growth inhibition rate of the irinotecan 40 mg / kg single administration group was 51.1%, whereas the “SK-116 (100 ppm) + irinotecan 40 mg / kg” combination group was 66.3%, and PAI-1
  • irinotecan enhanced the tumor growth-suppressing effect by the combined use of an inhibitor. From the above results, it was confirmed that the combined use of the PAI-1 inhibitor and irinotecan did not cause any adverse events, was highly safe, and the combined use of the PAI-1 inhibitor enhanced the tumor growth inhibitory effect of irinotecan. It was done.
  • a combination of a PAI-1 inhibitor and a cytotoxic agent or cytostatic agent is an antitumor agent completely different from conventional combination therapies, and is used as a prophylactic, therapeutic agent for various malignant tumors, or a prophylactic agent for metastasis
  • it is extremely useful industrially because it exhibits a high tumor growth inhibitory effect on pancreatic cancer cells when used in combination with gemcitabine.
  • the combined effect can reduce the amount of a cytotoxic agent or cytostatic agent having strong side effects, which is beneficial from the viewpoint of the patient's “Quality of Life” (QOL).
  • FIG. 1 is a graph showing the weight fluctuation of nude mice during the test period in Test Example 1.
  • FIG. 2 shows the effect of gemcitabine (Gemzar) alone and in combination with a PAI-1 inhibitor (SK-216). Nude mice were transplanted with Panc-1 pancreatic cancer tumor cells. Three weeks later, each group was divided into 10 animals so that the average tumor volume of each group was 138 ⁇ 15 mm 3 . Each group was administered test substance and concomitant drug gemcitabine as set in the test plan. The graph shows the change over time in the tumor volume (mean value) of nude mice in each group.
  • FIG. 3 is a graph showing the weight fluctuation of nude mice during the test period in Test Example 2.
  • FIG. 4 shows the effect of irinotecan (CPT-11) alone and in combination with a PAI-1 inhibitor (SK-116).
  • Nude mice were transplanted with HCT116 colon cancer tumor cells. Three weeks later, each group was divided into 10 animals so that the average tumor volume of each group was 226 ⁇ 20 mm 3 .
  • Each group was administered test substance and concomitant drug irinotecan as set in the test plan.
  • the graph shows the change over time in the tumor volume (mean value) of nude mice in each group.

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Abstract

L'invention porte sur une thérapie de combinaison destinée à potentialiser l'effet d'inhibition de croissance tumorale et/ou de métastase, un inhibiteur de l'inhibiteur 1 de l'activateur de plasminogène étant combiné avec un agent cytotoxique ou un inhibiteur de croissance cellulaire.
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WO2014171464A1 (fr) * 2013-04-15 2014-10-23 株式会社レナサイエンス Nouvelle application d'inhibiteur de pai-1
CN108135894A (zh) * 2015-08-20 2018-06-08 卫材R&D管理有限公司 肿瘤治疗剂
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
US11186547B2 (en) 2014-08-28 2021-11-30 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer
US11598776B2 (en) 2011-06-03 2023-03-07 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US12226409B2 (en) 2017-05-16 2025-02-18 Eisai R&D Management Co., Ltd. Treatment of hepatocellular carcinoma
US12303505B2 (en) 2017-02-08 2025-05-20 Eisai R&D Management Co., Ltd. Tumor-treating pharmaceutical composition

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US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer
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US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor
CN108135894B (zh) * 2015-08-20 2021-02-19 卫材R&D管理有限公司 肿瘤治疗剂
CN108135894A (zh) * 2015-08-20 2018-06-08 卫材R&D管理有限公司 肿瘤治疗剂
US12220398B2 (en) 2015-08-20 2025-02-11 Eisai R&D Management Co., Ltd. Tumor therapeutic agent
US12303505B2 (en) 2017-02-08 2025-05-20 Eisai R&D Management Co., Ltd. Tumor-treating pharmaceutical composition
US12226409B2 (en) 2017-05-16 2025-02-18 Eisai R&D Management Co., Ltd. Treatment of hepatocellular carcinoma

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