WO2015137383A1 - Adjuvant pour chimiothérapie anticancéreuse - Google Patents

Adjuvant pour chimiothérapie anticancéreuse Download PDF

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WO2015137383A1
WO2015137383A1 PCT/JP2015/057119 JP2015057119W WO2015137383A1 WO 2015137383 A1 WO2015137383 A1 WO 2015137383A1 JP 2015057119 W JP2015057119 W JP 2015057119W WO 2015137383 A1 WO2015137383 A1 WO 2015137383A1
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cancer
period
agent
chemotherapeutic agent
chemotherapy
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PCT/JP2015/057119
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English (en)
Japanese (ja)
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純也 米田
佐藤　英明
麻美 萩原
咲乃 杉木
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味の素株式会社
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a glutamine metabolism inhibitor, a cancer chemotherapeutic adjuvant, a cancer treatment and / or prevention agent, or a cancer treatment and / or prevention medical food containing an aromatic amino acid as an active ingredient.
  • Chemotherapy is a treatment method that uses cancer drugs to suppress the division of cancer cells and destroy them.
  • Anticancer agents include anticancer antibiotics, platinum preparations, alkylating agents, antimetabolites, plant alkaloids, molecular targeted therapeutic agents, hormonal agents, etc., but it is difficult to completely cure cancer with any drug, and recurrence due to drug resistance There are many cases to do.
  • it is difficult for chemotherapy to act specifically on cancer cells such as nausea, loss of appetite, hair loss, stomatitis, leukopenia, thrombocytopenia, liver dysfunction, renal dysfunction, interstitial pneumonia, etc. Often with serious side effects.
  • cancer cells particularly cancer cells having drug resistance, proliferate during this drug withdrawal period, and there is a risk of recurrence and metastasis.
  • Non-Patent Documents 1-3 Glutamine metabolism is a pathway for the production of lactic acid from glutamine, and is an important energy source in cancer cells. Many inhibition of growth of cancer cells is achieved by inhibiting glutaminase, a glutamine metabolizing enzyme. Attempts have been made (Non-patent Document 4, Patent Document 1, etc.). In addition, glutaminase is known to play an important role in central nervous system diseases such as HIV-related dementia and multiple sclerosis (Non-Patent Document 5).
  • MYC which is an oncogene
  • glutamine transporters such as SCT2 and SLC7A1
  • miRNA-23a / b a glutamine metabolizing enzyme.
  • It is known to induce indirectly and promote glutamine metabolism (Non-Patent Documents 6 and 7).
  • An ATP binding cassette expressed on the surface of a cancer cell is known as one of molecules involved in drug resistance because it pumps an anticancer drug out of the cell and lowers the intracellular concentration.
  • Non-patent Document 2 an amino acid preparation for cancer characterized by containing an amino acid is known.
  • this document only describes that a composition containing at least D-valine and seven essential amino acids other than L-valine showed a tumor growth inhibitory effect.
  • an active mixture containing an amino acid such as L-phenylalanine and other small molecules has antitumor activity (Non-patent Document 10).
  • Non-patent Document 10 an active mixture containing an amino acid such as L-phenylalanine and other small molecules has antitumor activity.
  • Non-patent Document 10 discloses in a mixture of amino acids, and there is no description until L-phenylalanine treats or prevents cancer.
  • an aromatic amino acid such as phenylalanine has an action of inhibiting glutamine metabolism as the mechanism.
  • Non-patent Document 11 Furthermore, there is a report that the antitumor effect of an anticancer agent is enhanced by using L-phenylalanine together with the anticancer agent (Non-patent Document 11).
  • the administration time is the same as that of the anticancer agent, and the antitumor effect of the anticancer agent is promoted as an expected effect, and the anticancer agent cannot be administered to restore physical strength from side effects. This is different from the present invention which expects to suppress the growth of cancer during the drug holiday by administration of L-phenylalanine.
  • an L-phenylalanine-containing immune system activator adjusts the physical condition of cancer patients and the like and suppresses the progression of symptoms (Patent Document 3).
  • L-phenylalanine is administered after discontinuing administration of an anticancer agent for some reason, and in order to recover from a side effect of a patient during a drug holiday (that is, during a treatment period with an anticancer agent).
  • the period during which the administration of the anticancer agent is suspended is different from the present invention in which the effect of anticancer agent treatment is expected to be promoted during the suspension period (predetermined in the treatment schedule).
  • the patent document is a case where the anticancer agent is not expected to be effective or the side effect is severe, and the administration of the anticancer agent is then performed as an alternative after the administration of the anticancer agent is stopped. This is different from the present invention which expects to be administered.
  • An object of the present invention is to provide a cancer chemotherapeutic adjuvant, a cancer treatment and / or prevention agent, or a medical food for cancer treatment and / or prevention, which has a glutamine metabolism inhibitory action and is safer. To do.
  • an aromatic amino acid has an excellent glutamine metabolism inhibitory action on cancer cells, and is a cancer chemotherapeutic adjuvant, cancer treatment and / or It has been found that the composition is useful as a prophylactic agent, or a medical food for cancer treatment and / or prevention, and the present invention has been completed.
  • the present invention relates to the following.
  • a cancer therapeutic and / or prophylactic agent containing an aromatic amino acid as an active ingredient [2] The cancer therapeutic and / or prophylactic agent according to [1] above, which is taken during cancer chemotherapy. [3] The cancer therapeutic and / or prophylactic agent according to the above [2], which is taken during a drug holiday during a cancer chemotherapy period. [4] The cancer therapeutic and / or prophylactic agent according to the above [3], wherein the period of drug withdrawal is from 5 days to 6 weeks.
  • the cancer chemotherapeutic agent is one or more selected from the group consisting of dacarbazine, tegafur, gemcitabine, nedaplatin, fluorouracil, and cisplatin, and the period of drug withdrawal is from 7 days to 4 weeks,
  • the cancer chemotherapeutic agent is dacarbazine
  • the period of withdrawal is 13 days to 4 weeks
  • the cancer chemotherapeutic agent is tegafur
  • the period of withdrawal is 7 to 14 days
  • the chemotherapeutic agent is gemcitabine
  • the duration of withdrawal is 1 week
  • the cancer chemotherapy agent is nedaplatin
  • the duration of withdrawal is 4 weeks
  • the cancer chemotherapy agent is fluorouracil
  • withdrawal If the cancer chemotherapeutic agent is cisplatin, the withdrawal period is 1 to 3 weeks, and if the cancer chemotherapeutic agent is a multi-drug combination of cisplatin and gemcitabine
  • the cancer therapeutic and / or prophylactic agent according to any one of [3] to [5] above, wherein the medium period is 13 days.
  • a medical food for cancer treatment and / or prevention containing an aromatic amino acid as an active ingredient [12] The medical food for cancer treatment and / or prevention according to [11] above, wherein the medical food is taken during cancer chemotherapy. [13] The medical food for cancer treatment and / or prevention according to [12] above, wherein the medical food is taken during a drug holiday during a cancer chemotherapy period. [14] The medical food for cancer treatment and / or prevention according to [13] above, wherein the period of drug withdrawal is from 5 days to 6 weeks.
  • the cancer chemotherapeutic agent is one or more selected from the group consisting of dacarbazine, tegafur, gemcitabine, nedaplatin, fluorouracil, and cisplatin, and the period of drug withdrawal is from 7 days to 4 weeks, A medical food for cancer treatment and / or prevention according to the above [13] or [14].
  • the cancer chemotherapeutic agent is dacarbazine
  • the period of withdrawal is from 13 days to 4 weeks
  • the cancer chemotherapeutic agent is tegafur
  • the period of withdrawal is from 7 days to 14 days.
  • the duration of withdrawal is 1 week
  • the cancer chemotherapy agent is nedaplatin
  • the duration of withdrawal is 4 weeks
  • the cancer chemotherapy agent is fluorouracil
  • withdrawal If the cancer chemotherapeutic agent is cisplatin, the withdrawal period is 1 to 3 weeks, and if the cancer chemotherapeutic agent is a multi-drug combination of cisplatin and gemcitabine
  • the cancer chemotherapeutic agent is one or more selected from the group consisting of dacarbazine, tegafur, gemcitabine, nedaplatin, fluorouracil, and cisplatin, and the period of drug withdrawal is from 7 days to 4 weeks, The cancer chemotherapeutic adjuvant according to [22] or [23] above.
  • the cancer chemotherapeutic agent is dacarbazine
  • the period of withdrawal is from 13 days to 4 weeks
  • the cancer chemotherapeutic agent is tegafur the period of withdrawal is from 7 days to 14 days
  • the chemotherapeutic agent is gemcitabine the duration of withdrawal is 1 week
  • the cancer chemotherapy agent is nedaplatin
  • the duration of withdrawal is 4 weeks
  • the cancer chemotherapy agent is fluorouracil
  • withdrawal If the cancer chemotherapeutic agent is cisplatin, the withdrawal period is 1 to 3 weeks, and if the cancer chemotherapeutic agent is a multi-drug combination of cisplatin and gemcitabine
  • the cancer chemotherapeutic adjuvant according to any one of the above [22] to [24], wherein the inside period is 13 days.
  • a glutamine metabolism inhibitor comprising an aromatic amino acid as an active ingredient.
  • the glutamine metabolism inhibitor according to the above [33] which inhibits metabolism of cancer cells.
  • the glutamine metabolism inhibitor provided by the present invention which contains an aromatic amino acid as an active ingredient, has an excellent glutamine metabolism inhibitory effect on cancer cells at a safe dose that does not exhibit toxicity. Therefore, it is possible to provide a cancer chemotherapeutic adjuvant, a cancer treatment and / or prevention agent with high safety and reduced side effects, or a medical food for cancer treatment and / or prevention.
  • the cancer chemotherapeutic adjuvant of the present invention is administered during a drug holiday during the cancer chemotherapeutic agent administration period at the time of cancer chemotherapy, so that cancer cells during the drug holiday, particularly cancer with drug resistance It can suppress cell growth and prevent cancer recurrence and metastasis.
  • the aromatic amino acid is a substance with established safety
  • the glutamine metabolism inhibitor or cancer chemotherapeutic adjuvant of the present invention is highly safe and is not limited to pharmaceutical use, but can be used for foods and medical foods. Is also possible.
  • FIG. 1 shows the amino acid concentration balance in the tumor tissue of 3LL subcutaneous transplantation model mice administered with L-phenylalanine.
  • FIG. 2 is a graph showing the glutamine concentration in the tumor. The vertical axis of the graph represents the glutamine concentration in the tumor (pmol / mg tissue). The horizontal axis of the graph indicates the administered amino acid.
  • FIG. 3 is a graph showing a tumor growth inhibitory effect in a mouse lung cancer 3LL subcutaneous transplantation model. The vertical axis of the graph represents the tumor volume (mm 3 ). The horizontal axis of the graph indicates the time (days) after cancer cell transplantation.
  • FIG. 4 is a graph showing the effect of suppressing lung metastasis in a mouse breast cancer 4T1 spontaneous lung metastasis model.
  • FIG. 5 is a graph showing the effect of combined administration of an anticancer drug and a) L-phenylalanine or b) L-threonine in a mouse lung cancer 3LL subcutaneous transplantation model.
  • the vertical axis of the graph represents the tumor volume (mm 3 ).
  • FIG. 6 is a graph showing the pharmacokinetic test results using a mouse breast cancer 4T1 cell subcutaneous transplantation model.
  • the vertical axis of the graph represents blood phenylalanine concentration ( ⁇ M).
  • the horizontal axis of the graph represents the time (hour) after administration of L-phenylalanine.
  • Glutamine metabolism inhibitor of the present invention cancer chemotherapeutic adjuvant, or cancer treatment and / or prevention agent (hereinafter sometimes collectively referred to as “agent of the present invention”), cancer treatment and / or prevention medical.
  • the food is characterized by containing an aromatic amino acid as an active ingredient.
  • the aromatic amino acid means an amino acid having an aromatic ring in the side chain.
  • the aromatic ring may have a substituent.
  • the substituent selected from the following substituent A group is mentioned, for example.
  • the number of the substituents is 1 to the maximum number that can be substituted, more preferably 1 to 3, and still more preferably 1.
  • the substituent group A is: (1) a halogen atom; (2) hydroxy group; (3) a nitro group; (4) a cyano group; (5) a C 1-10 alkyl group; (6) a C 2-10 alkenyl group; (7) C 2-10 alkynyl group; (8) a C 3-7 cycloalkyl group; (9) a C 6-14 aryl group; (10) a C 7-16 aralkyl group; (11) heterocyclic group; (12) a C 1-6 alkoxy group; (13) a C 3-7 cycloalkyloxy group; (14) a C 6-14 aryloxy group; (15) C 7-16 aralkyloxy group; (16) Heterocycle-oxy group; (17) a C 1-6 alkyl-carbonyloxy group; (18) a C 3-7 cycloalkyl-carbonyloxy group; (19) a C 6-14 aryl-carbonyloxy group; (20) a C 7-16 aral
  • aromatic amino acid of the present invention examples include phenylalanine, tyrosine, tryptophan, histidine and the like. Phenylalanine and tyrosine are preferable, and phenylalanine is particularly preferable.
  • the aromatic amino acid of the present invention can be used alone or in combination of two or more aromatic amino acids.
  • the agent of the present invention can inhibit metabolism in cancer cells by inhibiting the glutamine metabolic pathway in cancer cells.
  • the glutamine metabolic pathway in cells other than cancer cells, it is useful as a preventive and / or therapeutic agent for HIV-related dementia and multiple sclerosis.
  • the target cancer cells are not particularly limited, but cancer cells having enhanced glutamine metabolism and drug resistance are preferred.
  • cancer stem cells can be mentioned.
  • the agent of the present invention is an agent containing an aromatic amino acid whose safety has been established as an active ingredient, and suppresses the growth of cancer cells, particularly cancer cells having drug resistance, by inhibiting the glutamine metabolic pathway in cancer cells. It is useful as an adjuvant for cancer chemotherapy because it suppresses cancer recurrence and / or metastasis.
  • cancer chemotherapy adjuvant refers to the proliferation of cancer cells having drug resistance during the drug holiday period by administration during the drug holiday period during the administration period of the anticancer drug at the time of cancer chemotherapy. Is an agent that suppresses cancer and prevents recurrence and / or metastasis of cancer.
  • the “period of withdrawal” refers to a period during which the anticancer drug administration is suspended for recovery from the side effects of the patient during the treatment period with the anticancer drug, and is predetermined in the treatment schedule. It means a rest period. Unlike the case where administration of an anticancer drug is discontinued after replacement of the anticancer drug due to reasons such as the anticancer drug being ineffective or having serious side effects, it is planned to administer the anticancer drug and the agent of the present invention alternately. Means if The period of drug withdrawal varies depending on the type of anticancer drug and treatment method. The period of drug withdrawal is preferably 5 days to 6 weeks. More preferably, it is 7 days to 4 weeks.
  • the cancer chemotherapeutic agent is one or more selected from the group consisting of dacarbazine, tegafur, gemcitabine, nedaplatin, fluorouracil, and cisplatin
  • the period of drug withdrawal is 7 days to 4 weeks.
  • dacarbazine (trade name: dacarbazine, Kyowa Hakko Kogyo Co., Ltd.) is administered daily for 5 days in the case of malignant melanoma, and then is withdrawn for 4 weeks.
  • Tegafur (trade name: TS-1, Taiho Pharmaceutical Co., Ltd.) is administered daily for 28 days, then withdrawn for 14 days or withdrawn for 7 days.
  • Gemcitabine (trade name: Gemzar, Eli Lilly Japan) is administered once a week for 3 consecutive weeks, and the fourth week (1 week) is withdrawn.
  • Nedaplatin (trade name: Akpra, Shionogi & Co., Ltd.) will be withdrawn for 4 weeks after administration. Repeat this as one course.
  • Fluorouracil (trade name: 5-FU, Kyowa Hakko Kogyo Co., Ltd.) is administered intravenously over 4 to 5 days and administered at intervals of 3 weeks or longer (drug holiday).
  • Cisplatin (trade name: Platocin, Pfizer, Kyowa Hakko Kogyo Co., Ltd.) is withdrawn from the drug for at least 1 to 3 weeks after administration.
  • cancers to which the present invention is applied include cancers in which administration of an antitumor agent is effective.
  • lung cancers eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.
  • breast cancer Eg, invasive ductal cancer, non-invasive ductal cancer, inflammatory breast cancer, etc.
  • prostate cancer eg, hormone-dependent prostate cancer, hormone-independent prostate cancer, etc.
  • pancreatic cancer eg, pancreatic duct cancer, etc.
  • Gastric cancer eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma, etc.
  • colon cancer eg, gastrointestinal stromal tumor, etc.
  • rectal cancer eg, gastrointestinal stromal tumor, etc.
  • colon cancer eg, Familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor, etc.
  • the aromatic amino acid contained as an active ingredient in the agent of the present invention can be any of L-form, D-form, and DL-form, preferably L-form and DL-form, and more preferably Is the L-form.
  • the aromatic amino acid for example, those obtained from hydrolysis of natural proteins derived from animals or plants can be used, or those obtained by fermentation or chemical synthesis methods can be used.
  • Each aromatic amino acid can be used not only in a free form but also in the form of a salt, a chemically modified aromatic amino acid or a salt thereof, and the like.
  • the salt form include acid addition salts and base addition salts, but any form can be adopted as long as it is a chemically acceptable salt.
  • the salt form is preferably a pharmaceutically acceptable salt.
  • chemically modified aromatic amino acids include compounds in which the amino group of the aromatic amino acid is acylated or alkylated (for example, N-acetylphenylalanine, N-methylphenylalanine, N-benzylphenylalanine, N-acetyltyrosine).
  • N-methyltyrosine, N-benzyltyrosine, etc. compounds in which the carboxy group of an aromatic amino acid is esterified (for example, phenylalanine methyl ester, phenylalanine ethyl ester, phenylalanine t-butyl ester, phenylalanine benzyl ester, tyrosine methyl ester, Tyrosine ethyl ester, tyrosine t-butyl ester, tyrosine benzyl ester, etc.).
  • it may be used in the form of a peptide in which two or more aromatic amino acids or other amino acids are peptide-bound.
  • These compounds can be produced from aromatic amino acids by a method known per se.
  • Examples of the pharmaceutically acceptable salt include a salt with an acid, a salt with a base, and a salt with an amino acid.
  • Examples of the acid that forms a pharmaceutically acceptable salt by adding to an aromatic amino acid include inorganic acids such as hydrogen chloride, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, maleic acid.
  • An organic acid such as acid, fumaric acid or monomethyl sulfuric acid may be mentioned.
  • Examples of the base that forms a pharmaceutically acceptable salt by adding to an aromatic amino acid include, for example, metal hydroxides such as sodium and potassium, metal carbonates such as calcium, inorganic bases such as ammonia, ethylenediamine, Examples include organic bases such as propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, and triethanolamine.
  • Examples of amino acids that are added to aromatic amino acids to form pharmaceutically acceptable salts include lysine, arginine, aspartic acid, glutamic acid and the like. According to a method known per se, each salt can be obtained by reacting an aromatic amino acid with an inorganic acid, an organic acid, an inorganic base, an organic base, or an amino acid.
  • the agent of the present invention is useful as a medicine and food, and its application target includes mammals (for example, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.).
  • mammals for example, humans, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, etc.
  • the subject of application of the agent of the present invention is preferably a human.
  • the intake of the agent of the present invention may be appropriately adjusted according to the body weight or size of the animal.
  • the administration method when the agent of the present invention is used as a medicine may be either oral administration or parenteral administration.
  • the dosage form for oral administration include liquids such as powders, granules, capsules, tablets, chewables and the like, liquids such as solutions and syrups, and parenteral dosage forms include injections. , Infusion agents, nasal / pulmonary sprays, and the like.
  • the aromatic amino acid is preferably administered orally to the subject.
  • intravenous or arterial administration is possible as an infusion.
  • the agent of the present invention can be prepared by using an appropriate pharmaceutically acceptable carrier such as an excipient, a binder, a lubricant, a solvent, a disintegrant, a solubilizing agent, a suspension, as required in the preparation. It can be formulated as a pharmaceutical composition by blending agents, emulsifiers, isotonic agents, stabilizers, soothing agents, preservatives, antioxidants, flavoring agents, coloring agents, etc. It may be referred to as “the composition of the invention”). The agent of the present invention can be formulated into a dosage form as shown above by an ordinary method. As an aspect of the composition of the present invention, it is preferable that all active ingredients of aromatic amino acids are contained in the same composition from the viewpoint of easy administration, but each of the aromatic amino acids is used alone. Or may be contained in a plurality of compositions in any combination.
  • an appropriate pharmaceutically acceptable carrier such as an excipient, a binder, a lubricant, a solvent, a disintegrant,
  • excipients examples include sugars such as lactose, glucose, D-mannitol, organic excipients such as starches and celluloses such as crystalline cellulose, and inorganic excipients such as calcium carbonate and kaolin.
  • a lubricant pregelatinized starch, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, D-mannitol, trehalose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.
  • fatty acid salts such as stearic acid and stearate, talc, silicates, etc., purified water, physiological saline, etc.
  • Cellulose and starch, etc. used as a solubilizer include polyethylene glycol, propylene glycol, trehalose, benzyl benzoate, ethanol, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and the like.
  • a tonicity agent sodium lauryl sulfate, gum arabic, gelatin, lecithin, glyceryl monostearate, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium and the like, polysorbates, polyoxyethylene hydrogenated castor oil, etc.
  • Sodium chloride, potassium chloride, sugars, glycerin, urea, etc., and stabilizers such as polyethylene glycol, sodium dextran sulfate, and other amino acids.
  • stabilizers such as polyethylene glycol, sodium dextran sulfate, and other amino acids.
  • glucose, calcium gluconate, procaine hydrochloride, etc. and as preservatives, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. are antioxidants.
  • the agent include sulfite and ascorbic acid
  • examples of the flavoring agent include sweeteners and fragrances that are commonly used in the pharmaceutical field
  • coloring agent include colorants that are commonly used in the pharmaceutical field. It is done.
  • the content of the aromatic amino acid contained in the composition of the present invention can be appropriately set according to the form of the preparation.
  • the content of aromatic amino acid is usually 1 to 80% by weight, preferably 10 to 80% by weight, based on the whole composition.
  • the content of the aromatic amino acid is usually 1 to 80% by weight, preferably 10 to 50% by weight, based on the whole composition.
  • the content of aromatic amino acid is usually 50 to 100% by weight, preferably 90 to 100% by weight, based on the whole composition.
  • “content” indicates the ratio of the total weight of aromatic amino acids in the weight of the composition of the present invention.
  • an aromatic amino acid when included in one composition, its content is the ratio of the total weight of the aromatic amino acid to the weight of the composition, and each active ingredient is When included in a plurality of compositions alone or in any combination, the content is a ratio of the total weight of aromatic amino acids to the total weight of each composition.
  • the “weight ratio” indicates the ratio of the weight of the aromatic amino acids contained in the composition of the present invention.
  • the aromatic amino acids when included in one composition, the content of the aromatic amino acids are included in a plurality of compositions alone or in any combination, the ratio of the weight of each aromatic amino acid contained in each composition.
  • the dose (intake) of the agent or composition of the present invention to humans varies depending on the age, body weight, disease state, administration method, etc. of the subject patient, but usually, aromatic amino acid 0.00005- 10 g (for example, phenylalanine 0.00005-6 g, tyrosine 0.00005-6 g).
  • aromatic amino acid 0.00005- 10 g for example, phenylalanine 0.00005-6 g, tyrosine 0.00005-6 g.
  • aromatic amino acid 0.00005- 10 g
  • 0.001-9 g of aromatic amino acids eg, 0.005-5 g of phenylalanine, 0.005-4 g of tyrosine
  • 7 g eg, phenylalanine 0.005 to 4 g, tyrosine 0.005 to 3 g.
  • the daily dose for an adult is usually about 0.01 to 8 g, preferably about 0.1 to 6 g as a total amount of aromatic amino acids, and this is preferably 1 to 5 times as needed. Is administered in 2 to 4 divided doses.
  • the agent or composition of this invention contains the salt of an aromatic amino acid, calculation of a dose shall be performed after converting all the salts of an aromatic amino acid into a free body.
  • the timing of administration is not particularly limited in relation to meals, and may be any of before meals, between meals, and after meals. Also, the administration period is not particularly limited.
  • the administered (ingested) amount varies depending on the symptom, age or weight of the subject of administration (ingestion), or the form of the adjuvant or administration (intake) method.
  • the standard is 0.00005-7g phenylalanine and 0.00005-6g tyrosine per day. In the case of general adults, it is preferably 0.005 to 7 g of phenylalanine and 0.005 to 6 g of tyrosine, more preferably 0.005 to 5 g of phenylalanine and 0.005 to 4 g of tyrosine.
  • the total amount of amino acids is preferably about 0.01 to 9 g per day.
  • the cancer chemotherapeutic adjuvant of the present invention can be administered (taken) in a daily amount or divided into several times.
  • the form of cancer chemotherapy adjuvant, administration (intake) method, administration (intake) period, etc. are not particularly limited.
  • an aromatic amino acid (preferably phenylalanine) as an active ingredient in the unit is about 1 to 7 g, preferably about 2 to 5 g per administration (ingestion).
  • 3 g can be contained.
  • an aromatic amino acid which is an active ingredient used in the present invention
  • the above calculation as an active ingredient of a drug used for the purpose of treatment, prevention, etc. of the disease targeted by the present invention As the range has been determined, it is necessary to include this in the calculation for aromatic amino acids that are ingested or administered for other purposes, for example, due to the need for a normal diet or for the treatment of another disease There is no principle. For example, it is not necessary in principle to calculate by subtracting the amount of aromatic amino acid per day taken from the normal diet from the daily dose of the active ingredient in the present invention.
  • the actual dose ratio is the ratio of a single dose or a daily dose per administration subject (ie, patient).
  • the weight ratio corresponds to the dose ratio.
  • the ratio of the total amount of aromatic amino acids in each preparation administered once or daily corresponds to the weight ratio.
  • the agent or composition of the present invention can also be used in the form of food.
  • a food When used as a food, it may be any general dietary form containing an active ingredient of the food of the present invention, that is, an aromatic amino acid.
  • drinks such as soft drinks and powdered drinks can be prepared by adding an appropriate flavor. Specifically, for example, it can be eaten and eaten mixed with juice, milk, confectionery, jelly, yogurt, candy and the like. It is also possible to provide such foods as health functional foods or dietary supplements.
  • Functional health foods contain health functional ingredients that affect the body's physiological functions and biological activities, and are taken for specific health purposes in the diet. Expected food.
  • the health functional food is sometimes referred to as a functional food, a functional label food, a health food (including a nutritional supplement), and the like.
  • Functional foods or functionally labeled foods are foods made by taking advantage of the functions of bioregulatory components contained in foods, and health foods are a group of foods that are generally considered to help promote health. Say. These include nutritional supplements based on specific nutrients.
  • the health functional food of the present invention includes food for specified health use and functional food for nutrition, and can be prevented from developing and developing cancer by feeding as a daily dietary supplement in patients suffering from cancer.
  • the health functional food can be prepared by the same preparation technique as that for the pharmaceutical composition, or a general food preparation technique. Vitamins and other supplements may be added.
  • the agent of the present invention can also be used as a concentrated liquid food or food supplement.
  • a food supplement When used as a food supplement, it can be prepared in the form of tablets, capsules, powders, granules, suspensions, chewables, syrups and the like.
  • food supplement refers to those taken for the purpose of supplementing nutrition in addition to those taken as food, and also includes nutritional supplements and supplements.
  • the term “concentrated liquid food” is adjusted to a concentration of about 1 kcal / ml, and the qualitative composition of each nutrient is sufficiently taken into consideration so that a significant excess or deficiency of nutrients does not occur even after long-term single intake. It is a comprehensive nutritional food (liquid food) designed based on daily nutritional requirements.
  • the agent of the present invention can also be used as a “medical food”.
  • Medical food is a food ingredient having an effect on a specific disease, such as the present invention, characterized in that it is located between a pharmaceutical and a health supplement and is prescribed under the guidance of a doctor. It is a nutritional food for medical use that has been proven to be safe as a food and effective and effective against certain diseases. Examples of medical foods include Axona (R) (Caprylic Triglyceride) for patients with Alzheimer's disease, and Limbrel (R) (flavovoxid TM ) for patients with rheumatoid arthritis.
  • R Axona
  • R Caprylic Triglyceride
  • Limbrel R
  • flavovoxid TM for patients with rheumatoid arthritis.
  • phenylalanine When ingested as a food or medical food, the intake varies depending on the symptoms, age or weight of the subject, or the form or ingestion method of the food or medical food.
  • the standard is 0.00005-6g of tyrosine. In the case of general adults, it is preferably 0.005 to 7 g of phenylalanine and 0.005 to 6 g of tyrosine, more preferably 0.005 to 5 g of phenylalanine and 0.005 to 4 g of tyrosine.
  • the total amount of amino acids is preferably about 0.01 to 9 g per day.
  • the food or medical food of the present invention can be taken in the above-mentioned daily amount at one time or divided into several times.
  • the form of food or medical food, intake method, intake period, etc. are not particularly limited.
  • mice 1 g / kg phenylalanine was shown to have a pharmacological effect in mice (Examples 3 and 4). Since the mouse ingests 20 g / kg / day of protein, the effects of the present invention can be obtained by ingesting phenylalanine in 1/20 of the daily protein intake. On the other hand, in mice (Example 6) and humans (Proc Natl Acad Sci US A .: 96 (6), 3160-3164 (1999)), the metabolic rate of phenylalanine is almost the same.
  • the food or medical food of the present invention contains about 2-4 g / day, preferably about 2-3 g / day, more preferably about 3 g / day of an aromatic amino acid (preferably phenylalanine) once. Or in several divided doses.
  • an aromatic amino acid preferably phenylalanine
  • Aromatic amino acids have already been widely used in the fields of medicine and food, and safety has been established.
  • the acute toxicity (LD 50 ) in the agents and compositions of the present invention containing phenylalanine is 16 g / kg or higher when administered orally to rats.
  • the agent or composition of the present invention is useful as a glutamine metabolism inhibitor or a cancer chemotherapy adjuvant, a cancer treatment and / or prevention agent, or a cancer treatment and / or prevention medical food, It can also be used in combination with existing anticancer agents.
  • “combination” means use before, simultaneously with, or after administration of an existing anticancer agent, and also includes use as a compounding agent in which both are mixed.
  • the cancer chemotherapy in the present invention is a treatment method that uses an anticancer agent to suppress the division of cancer cells and destroy the cancer cells.
  • Cancer chemotherapy includes postoperative adjuvant chemotherapy and preoperative chemotherapy.
  • the postoperative adjuvant chemotherapy in the present invention is cancer chemotherapy performed after surgery, and the preoperative chemotherapy in the present invention is cancer chemotherapy performed before surgery.
  • the cancer chemotherapeutic agent in the present invention is an anticancer agent used for cancer chemotherapy, which acts directly or indirectly on cancer cells and contributes to suppression of cancer cell proliferation or metastasis, killing of cancer cells or suppression of cancer cell generation.
  • the anti-cancer antibiotic, platinum preparation, alkylating agent, antimetabolite, plant alkaloid, molecular target therapeutic agent, hormone agent and the like can be mentioned.
  • an existing anticancer agent that can be used in combination with the agent or composition of the present invention, it acts directly or indirectly on cancer cells and contributes to suppression of cancer cell proliferation or metastasis, killing of cancer cells or suppression of cancer cell generation.
  • the compound is not particularly limited, and examples thereof include anticancer antibiotics, platinum preparations, alkylating agents, antimetabolites, plant alkaloids, molecular target therapeutic agents, and hormonal agents.
  • Anticancer antibiotics refer to antibiotics belonging to anticancer agents (DNA-damaging anticancer agents) that suppress the growth of cancer cells by causing damage to DNA or RNA associated with cancer cells.
  • anthracycline-type anticancer agents such as adriamycin, epidoxorubicin, epirubicin, daunorubicin, aclarubicin, pirarubicin, amrubicin, idarubicin; Mycin D, dinostatin stimamarer and the like.
  • Platinum preparations are the bases of DNA, guanine and adenine that bind to the N-7 position at two chlorine atom sites, form crosslinks in the DNA strand, and inhibit DNA synthesis to proliferate cancer cells. It refers to an anticancer agent that exerts an inhibitory effect.
  • the platinum preparation is not particularly limited, and examples thereof include cisplatin, carboplatin, nedaplatin, oxaliplatin and the like.
  • An alkylating agent refers to an anticancer agent that exerts an effect of inhibiting the growth of cancer cells by cleaving by alkylating DNA.
  • alkylating agent include, but are not limited to, nitrogen mustards such as nitrogen mustard, nitrogen mustard N-oxide, chlorambucil, ifosfamide, cyclophosphamide, and melphalan; ethyleneimines such as carbocon and thiotepa Sulfonic acid esters such as busulfan and improsulfan tosylate; nitrosoureas such as nimustine, ranimustine, dacarbazine and procarbazine, and temozolomide.
  • nitrogen mustards such as nitrogen mustard, nitrogen mustard N-oxide, chlorambucil, ifosfamide, cyclophosphamide, and melphalan
  • ethyleneimines such as carbocon and thiotepa Sulfonic acid esters such as busulfan and
  • An antimetabolite is a substance that has a chemical structure similar to that of a nucleic acid material when cancer cells divide or proliferate, preventing DNA synthesis and inhibiting cancer cell metabolism. It refers to an anticancer drug that suppresses.
  • the antimetabolite include, but are not limited to, pyrimidine antimetabolite such as 5-fluorouracil (5-FU), tegafur, carmofur, doxyfluridine, floxuridine, cytarabine, enocitabine, gemcitabine; mercaptopurine, thioguanine, phosphorus
  • purine antimetabolites such as fludarabine acid and thioinosine
  • antifolate antimetabolites such as methotrexate, trimethoprim, and pyrimethacin.
  • Plant alkaloids include vinca alkaloids that inhibit the formation of microtubules that affect cancer cell division, taxanes that cause abnormal microtubule formation and inhibit the division of cancer cells, and DNA cleavage and reactivation during cell division.
  • Examples include topoisomerase inhibitors that kill topoisomerase by inhibiting topoisomerase acting on binding.
  • vinca alkaloids include vinblastine, vincristine, vindesine, vinorelbine, and the like.
  • taxanes include docetaxel and paclitaxel.
  • topoisomerase inhibitors include irinotecan, nogitecan, etoposide, sobuzoxane and the like.
  • the molecular target therapeutic agent refers to an anticancer agent having an activity of killing cancer cells by targeting a molecule involved in cancer cell growth and inhibiting the molecule.
  • the molecular target therapeutic agent is not particularly limited, and examples thereof include imatinib, gefitinib, erlotinib, vandetanib, sunitinib, sorafenib, rituximab, cetuximab, infliximab, trastuzumab, bevacizumab and the like.
  • Hormonal agents refer to anticancer agents that act on hormones involved in the division or proliferation of cancer cells. Although it does not specifically limit as a hormonal agent, For example, anastrozole, exemestane, ethinyl estradiol, chlormadinone, goserelin, tamoxifen, bicalutamide, flutamide, prednisolone, leuprorelin, letrozole etc. are mentioned.
  • anticancer agents include those that induce necrosis as forms of antitumor effects and those that induce apoptosis, and anticancer agents that cause cancer regrowth are anticancer agents that induce necrosis, such as 5-FU and doxorubicin. Vinorelbine, paclitaxel, docetaxel and the like.
  • agents may be used alone or in combination with the agent or composition of the present invention, or two or more thereof may be used in combination.
  • the dose, administration period, and administration interval of the drug used in combination with the agent or composition of the present invention can be appropriately set according to the disease state, the subject patient, and the like.
  • EXAMPLE 1 Mouse Lung Cancer 3LL cells by amino acid concentration balance titration of tumor tissue in the subcutaneous transplant model C57BL / 6 mice into mouse lung carcinoma 3LL cells (1x10 6 cells) to produce a subcutaneous transplant model mouse by subcutaneous implantation, agent The effect was examined.
  • the subcutaneously transplanted model mice were allowed to freely drink a 45 mM L-phenylalanine aqueous solution for 48 hours from day 5 to day 7 after cancer cell transplantation and for 48 hours from day 12 to day 14. After excising the tumor tissue on the 14th day, it was immediately frozen in liquid nitrogen and crushed with a crusher.
  • the ground tissue sample was homogenized in a homogenate solution (80% MeOH / 20% Phe-d5 aqueous solution) and then extracted with chloroform.
  • APDS derivatization reagent (3-aminopyridyl-N-hydroxysuccinimidyl carbamate) was added to the extracted amino acid, and the mixture was derivatized by heating at 55 ° C. for 10 minutes, and then API4000 LC-MS / MS system (AB). The amino acid concentration was measured by SCIEX).
  • a wheel diagram was prepared by plotting the ratio of each amino acid in the tumor tissue of a mouse that was allowed to freely drink an L-phenylalanine aqueous solution when the concentration of each amino acid in the tumor tissue of a control mouse that had been infused with water was taken as 100%. .
  • changes in amino acid composition by L-phenylalanine specifically, a significant increase in glutamine concentration and a significant decrease in glutamate, glycine, alanine, and methionine concentrations were shown (FIG. 1).
  • Example 2 Intratumoral glutamine concentration of mouse lung cancer 3LL cell subcutaneous transplantation model
  • the above-mentioned C57BL / 6 mouse was subcutaneously transplanted with mouse lung cancer 3LL cell subcutaneous transplantation model mouse, 48 hours from day 5 to day 7 after cancer cell transplantation, and For 48 hours from the 12th day to the 14th day, an aqueous solution containing 9 kinds of essential amino acids including L-phenylalanine at the concentrations shown in Table 1 was allowed to drink freely. As a result, only the L-phenylalanine administration group showed a significant increase in the glutamine concentration in the tumor (FIG. 2).
  • Example 3 Murine Lung Cancer 3LL Cell Subcutaneous Transplant Model Cancer Growth Inhibitory Effect
  • a mouse lung cancer 3LL cell (1 ⁇ 10 6 cells) was subcutaneously transplanted into a C57BL / 6 mouse, and a subcutaneously transplanted model mouse was prepared, and its efficacy was examined. did.
  • the subcutaneously transplanted model mice were allowed to freely drink a 45 mM L-phenylalanine aqueous solution for 48 hours from day 5 to day 7 after cancer cell transplantation and for 48 hours from day 12 to day 14.
  • the tumor volume on the 15th day after transplantation was 1000 mm 3 in the group in which the control group freely drank 45 mM L-phenylalanine aqueous solution compared to 3000 mm 3 .
  • the tumor growth inhibitory effect of L-phenylalanine was shown (FIG. 3).
  • Example 4 Mouse Breast Cancer 4T1 Spontaneous Lung Metastasis Model Inhibition of Metastasis Effect
  • mouse breast cancer 4T1 cells (5 ⁇ 10 4 cells) were orthotopically transplanted into the milk fat layer to produce a breast cancer model mouse. It was investigated. The primary lesion was excised on the 21st day after the cancer cell transplantation, and a 45 mM L-phenylalanine aqueous solution was administered by the free drinking method from the 23rd day to the 30th day. On the 30th day, the lungs were removed and fixed in formalin, and the number of metastatic nodules in the lungs was counted under a microscope. As a result, the number of metastatic nodules in the mouse lung of the L-phenylalanine administration group was significantly reduced compared to the control group. L-phenylalanine showed an inhibitory effect on lung metastasis (FIG. 4).
  • Example 5 Effect of Combined Administration of Anticancer Agent and L-Phenylalanine or L-Threonine in Mouse Lung Cancer 3LL Cell Subcutaneous Transplant Model
  • the anticancer agent 5-FU was introduced from the fifth day after cancer cell transplantation.
  • a single (10 mg / kg) or anticancer agent 5-FU (10 mg / kg) and 45 mM L-phenylalanine aqueous solution or 400 mM L-threonine aqueous solution were administered in combination by the free drinking method.
  • the administration schedule is shown in Table 2.
  • Example 6 Pharmacokinetic test using mouse breast cancer 4T1 cell subcutaneous transplantation model (PK test) Pharmacokinetic studies were performed using subcutaneously transplanted model mice in which mouse breast cancer 4T1 cells (5 ⁇ 10 5 cells) were subcutaneously transplanted into Balb / c mice by a conventional method and reared for 23 days.
  • the first blood collection time was set to 0 h, and immediately after that, L-phenylalanine was forcibly administered orally in a volume of 1 g / kg, and then 50 ⁇ l from the subclavian vein in the time course of 0.5, 1, 2, 4, 8 (h). The blood collection was repeated with reference to.
  • the amino acid concentration in blood was measured by the API4000 LC-MS / MS system (AB SCIEX) described above. As a result, it was revealed that the half-life of phenylalanine in the blood was 1 hour 30 minutes (FIG. 6). Since the half-life of phenylalanine in human blood is 1 hour (Proc Natl Acad Sci US A .: 96 (6), 3160-3164 (1999)), metabolism of phenylalanine in human and mouse The speed was shown to be about the same.
  • cancer chemotherapeutic adjuvant, cancer treatment and / or prevention agent having excellent glutamine metabolism inhibitory action on cancer cells, high safety and reduced side effects, or cancer treatment and / or
  • a preventive medical food can be provided.
  • the cancer chemotherapeutic adjuvant, the cancer treatment and / or prevention agent of the present invention, or the medical food for cancer treatment and / or prevention is a drug withdrawal period during the administration period of the cancer chemotherapeutic agent at the time of cancer chemotherapy.

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Abstract

L'invention a pour objectif de fournir un adjuvant pour chimiothérapie anticancéreuse qui présente d'excellentes propriétés du point de vue de la sécurité. Plus précisément, l'invention concerne un inhibiteur métabolique de glutamine, un adjuvant pour chimiothérapie anticancéreuse, un médicament pour le traitement ou la prévention du cancer, ou un aliment thérapeutique pour le traitement ou la prévention du cancer qui sont caractéristiques en ce qu'ils contiennent en tant que principe actif un acide aminé aromatique.
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WO2022009212A1 (fr) * 2020-07-09 2022-01-13 Technion Research And Development Foundation Ltd. Tyrosine, tryptophane et phénylalanine utilisés en tant qu'agonistes mtor médiant la dynamique du protéasome, compositions, méthodes et utilisations de ceux-ci en thérapie, et méthodes de pronostic concernant la pharmacorésistance

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JPS5841818A (ja) * 1981-09-07 1983-03-11 Sangi:Kk 抗腫瘍剤
JPH08508045A (ja) * 1993-11-09 1996-08-27 イムナル カーエフテー 癌性疾患の予防および治療のための製剤組成物、ならびにその製造法
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JPS5841818A (ja) * 1981-09-07 1983-03-11 Sangi:Kk 抗腫瘍剤
JPH08508045A (ja) * 1993-11-09 1996-08-27 イムナル カーエフテー 癌性疾患の予防および治療のための製剤組成物、ならびにその製造法
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022009212A1 (fr) * 2020-07-09 2022-01-13 Technion Research And Development Foundation Ltd. Tyrosine, tryptophane et phénylalanine utilisés en tant qu'agonistes mtor médiant la dynamique du protéasome, compositions, méthodes et utilisations de ceux-ci en thérapie, et méthodes de pronostic concernant la pharmacorésistance

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