WO2014077409A1 - Agent pour atténuer l'effet secondaire du sunitinib - Google Patents

Agent pour atténuer l'effet secondaire du sunitinib Download PDF

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WO2014077409A1
WO2014077409A1 PCT/JP2013/081210 JP2013081210W WO2014077409A1 WO 2014077409 A1 WO2014077409 A1 WO 2014077409A1 JP 2013081210 W JP2013081210 W JP 2013081210W WO 2014077409 A1 WO2014077409 A1 WO 2014077409A1
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sunitinib
derivatives
vitamin
salt
side effect
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Japanese (ja)
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雅 本間
洋志 鈴木
貴洋 雨宮
春喜 久米
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国立大学法人東京大学
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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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the present invention relates to an anticancer agent sunitinib side effect reducing agent and a sunitinib-containing anticancer agent with reduced side effects.
  • Sunitinib is a platelet-derived growth factor receptor (PDGFR- ⁇ and PDGFR- ⁇ ), vascular endothelial growth factor receptor (VEGFR-1, VEGFR-2 and VEGFR-3), stem cell factor receptor (KIT), fms-like tyrosine
  • PDGFR- ⁇ and PDGFR- ⁇ vascular endothelial growth factor receptor
  • VEGFR-1, VEGFR-2 and VEGFR-3 stem cell factor receptor
  • KIT stem cell factor receptor
  • fms-like tyrosine By inhibiting the multiple receptor tyrosine kinase (RTK) activities of kinase 3 (FLT3), colony stimulating factor-1 receptor (CSR-1R) and glial cell-derived neurotrophic factor receptor (RET), various solids
  • RTK multiple receptor tyrosine kinase
  • FLT3 kinase 3
  • CSR-1R colony stimulating factor-1 receptor
  • RET glial cell-derived neurotrophic factor receptor
  • GIST gastrointestinal stromal tumor
  • renal cell carcinoma As cancers to be treated with sunitinib, gastrointestinal stromal tumor (GIST), renal cell carcinoma, and pancreatic neuroendocrine tumor are recognized.
  • advanced renal cell carcinoma is regarded as the first line according to treatment guidelines, and its effectiveness is extremely high and widely used.
  • an object of the present invention is to provide means for reducing the side effects of sunitinib.
  • PHKG1 / 2 phosphorylase kinase 1 and phosphorylase kinase 2 (PHKG1 / 2) in which sunitinib has inhibitory activity.
  • PHKG1 / 2 is a kinase that catalyzes glycogen metabolism, so when sunitinib was administered to mice and glycogen metabolism was examined, suppression of glycogen metabolism by sunitinib administration led to strong oxidative stress. As a result, it was found that hepatotoxicity, cardiotoxicity, thrombocytopenia and hypothyroidism occur.
  • the present invention provides the following [1] to [28].
  • Antioxidants include vitamin E or derivatives thereof, vitamin C or derivatives thereof, vitamin A or derivatives thereof, vitamin B 2 or derivatives thereof, cysteine or derivatives thereof, glutathione, polyphenols, carotenes, butylhydroxyanisole and The side effect reducing agent according to [1], which is at least one selected from dibutylhydroxytoluene.
  • An anticancer agent comprising a combination of sunitinib or a salt thereof and an antioxidant.
  • Antioxidants include vitamin E or derivatives thereof, vitamin C or derivatives thereof, vitamin A or derivatives thereof, vitamin B 2 or derivatives thereof, cysteine or derivatives thereof, glutathione, polyphenols, carotenes, butylhydroxyanisole and The anticancer agent according to [4], which is at least one selected from dibutylhydroxytoluene.
  • Antioxidants include vitamin E or derivatives thereof, vitamin C or derivatives thereof, vitamin A or derivatives thereof, vitamin B 2 or derivatives thereof, cysteine or derivatives thereof, glutathione, polyphenols, carotenes, butylhydroxyanisole and The combination according to [11], which is one or more selected from dibutylhydroxytoluene.
  • the combination according to [13], wherein the side effect of sunitinib or a salt thereof is one or more selected from thyroid function decline, thrombocytopenia, left ventricular ejection fraction decline, and liver marker elevation.
  • Antioxidants include vitamin E or derivatives thereof, vitamin C or derivatives thereof, vitamin A or derivatives thereof, vitamin B 2 or derivatives thereof, cysteine or derivatives thereof, glutathione, polyphenols, carotenes, butylhydroxyanisole, and The use according to [15], which is one or more selected from dibutylhydroxytoluene.
  • the use according to [15] or [16], wherein the side effect of sunitinib or a salt thereof is one or more selected from thyroid function decline, thrombocytopenia, left ventricular ejection fraction decline, and liver marker elevation.
  • [18] Use of sunitinib or a salt thereof and an antioxidant for the production of an anticancer agent.
  • Antioxidants include vitamin E or derivatives thereof, vitamin C or derivatives thereof, vitamin A or derivatives thereof, vitamin B 2 or derivatives thereof, cysteine or derivatives thereof, glutathione, polyphenols, carotenes, butylhydroxyanisole and The use according to [18], which is one or more selected from dibutylhydroxytoluene.
  • the anticancer agent is an anticancer agent with reduced side effects of sunitinib or a salt thereof.
  • sunitinib or a salt thereof is one or more selected from thyroid function decline, thrombocytopenia, left ventricular ejection fraction decline, and liver marker elevation.
  • a method for reducing side effects of sunitinib or a salt thereof which comprises administering an effective amount of an antioxidant.
  • Antioxidants include vitamin E or a derivative thereof, vitamin C or a derivative thereof, vitamin A or a derivative thereof, vitamin B 2 or a derivative thereof, cysteine or a derivative thereof, glutathione, polyphenols, carotenes, butylhydroxyanisole, and [21] The method according to [21], which is one or more selected from dibutylhydroxytoluene.
  • sunitinib or a salt thereof is one or more selected from thyroid function decline, thrombocytopenia, left ventricular ejection fraction decline, and liver marker elevation.
  • a method for treating cancer comprising administering an effective amount of sunitinib or a salt thereof and an antioxidant.
  • Antioxidants include vitamin E or derivatives thereof, vitamin C or derivatives thereof, vitamin A or derivatives thereof, vitamin B 2 or derivatives thereof, cysteine or derivatives thereof, glutathione, polyphenols, carotenes, butylhydroxyanisole and [25] The treatment method according to [25], which is one or more selected from dibutylhydroxytoluene.
  • the side effect of sunitinib or a salt thereof is one or more selected from thyroid function reduction, thrombocytopenia, left ventricular ejection fraction reduction, and liver marker elevation.
  • sunitinib and an antioxidant are used in combination, side effects of sunitinib, such as decreased thyroid function, thrombocytopenia, decreased left ventricular ejection fraction, increased liver marker, etc., can be reduced. Further, since the antitumor effect of sunitinib is not reduced by the combined use of the antioxidant, the combined use of sunitinib and the antioxidant is useful as an anticancer agent with reduced side effects. Furthermore, administration of sunitinib had side effects, and it was unavoidable to reduce the dose or discontinue administration, resulting in long-term sunitinib for patients who were unable to obtain the original excellent antitumor effect of sunitinib. It is possible to continue therapy. In such patients, the original excellent antitumor effect of sunitinib can be expected.
  • FIG. 1 A comparison of sunitinib and sorafenib kinase occupancy profiles is shown. Occupancy of each kinase was assessed based on the mean plasma non-binding concentration of each drug and the Kd value of each kinase.
  • Figure 2 shows SDS-PAGE analysis of recombinant proteins containing human or mouse PHKG1 / 2 kinase domains. This confirmed the purity of the protein obtained. Bands were stained with Coomassie Brilliant Blue. Shown are kinase inhibition profiles for human and mouse PHKG1 against sunitinib, N-decethylsunitinib and sorafenib.
  • FIG. 5 shows that ALT is elevated in sunitinib-treated mice. Shows that liver glycogen content is increased in sunitinib-treated mice.
  • concentration by a computer is shown.
  • FIG. 5 shows the knockdown effect of shPHKG2 adenovirus on the expression of PHKG2 mRNA in the liver.
  • Fig. 6 shows the knockdown effect of shPHKG2 adenovirus on the expression of liver PHKG2 protein.
  • FIG. 5 shows that the ratio of GSH to GSSG was maintained at regulatory levels in sunitinib and ⁇ -tocopherol nicotinate combination mice.
  • Figure 5 shows that the ratio of NADH to NADP + was maintained at regulatory levels in sunitinib and ⁇ -tocopherol nicotinate combination mice.
  • FIG. 6 shows the results of adjusting the values in sunitinib-treated mice combined with ⁇ -tocopherol nicotinate by reducing high ALT levels associated with sunitinib treatment.
  • the ratio of GSH to GSSG in the heart is reduced in sunitinib-treated mice, while ⁇ -tocopherol nicotinate combination shows that both ratios were maintained at regulatory levels.
  • the content of TBARS in the heart increased in sunitinib-treated mice, while the regulatory level was maintained with alpha tocopherol nicotinate. It shows that the mRNA expression level of the enzyme involved in energy metabolism was changed to sunitinib and sorafenib treatment.
  • the amount of ATP in the heart shows that there was no change with sunitinib and sorafenib treatment.
  • the serum concentration of troponin T (an index of cardiac dysfunction) increased in sunitinib-treated mice, while the regulatory level was maintained by the combined use of ⁇ -tocopherol nicotinate.
  • the ratio of GSH to GSSG is reduced in platelets of sunitinib-treated mice, while ⁇ -tocopherol nicotinate combination shows that both ratios were maintained at regulatory levels.
  • TBSRS content is elevated in platelets of sunitinib-treated mice, while ⁇ -tocopherol nicotinate combined maintains both regulatory levels.
  • Annexin V on the cell surface is elevated in platelets of sunitinib-treated mice, while alpha-tocopherol nicotinate combination maintained both regulatory levels.
  • Circulating platelet half-life is reduced in sunitinib-treated mice, while alpha-tocopherol nicotinate combined maintains half-life at regulatory levels.
  • the ratio of NADPH to NADP + was reduced in the thyroid of sunitinib-treated mice, while the combination of ⁇ -tocopherol nicotinate showed that both ratios were maintained at regulatory levels.
  • the ratio of GSH to GSSG was reduced in the thyroid of sunitinib-treated mice, while the combination of ⁇ -tocopherol nicotinate showed that both ratios were maintained at regulatory levels.
  • the TBSRS content of the thyroid increased in the platelets of sunitinib-treated mice, while the regulatory level was maintained with ⁇ -tocopherol nicotinate. Serum FT4 concentrations were only slightly reduced in sunitinib-treated mice, indicating that FT3 values remained unaffected.
  • Serum TSH levels were reduced in sunitinib-treated mice, while ⁇ -tocopherol nicotinate combined maintained regulatory levels.
  • the sunitinib-mediated increase in TSH levels was suppressed by the combination of octreotide, indicating that serum ST3 and ST4 levels were significantly reduced. It shows that the combined use of octreotide also greatly reduced the thyroid T3 and T4 levels.
  • the effect of an antioxidant on the platelet count increased by sunitinib administration is shown.
  • the effect of the antioxidant with respect to TSH raised by sunitinib administration is shown.
  • the effect of the antioxidant with respect to troponin T raised by sunitinib administration is shown.
  • the effect of the antioxidant with respect to NT-proBNP raised by sunitinib administration is shown.
  • the effect of the antioxidant with respect to ALT which rose by sunitinib administration is shown.
  • the change of the lung cancer tumor volume in combined use of sunitinib and tocopherol nicotinate is shown.
  • the change of the lung cancer tumor weight in combined use of sunitinib and tocopherol nicotinate is shown.
  • the change of the lung weight in combined use of sunitinib and tocopherol nicotinate is shown.
  • sunitinib is an anticancer agent having direct antitumor activity and tumor angiogenesis inhibitory action against solid cancer by inhibiting a plurality of receptor kinase activities.
  • Sunitinib has the chemical name N- [2- (diethylamino) ethyl] -5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indole-3-ylidene) methyl] -2 , 4-dimethyl-1H-pyrrole-3-carboxamide.
  • the salt of sunitinib is not limited as long as it is a pharmaceutically acceptable salt, but an acid addition salt is preferable, and malate is particularly preferable.
  • the cancer that can be treated by administration of sunitinib may be solid cancer, but renal cell carcinoma (RCC), gastrointestinal stromal tumor (GIST), and pancreatic neuroendocrine tumor (pNET) are preferable.
  • RCC renal cell carcinoma
  • GIST gastrointestinal stromal tumor
  • pNET pancreatic neuroendocrine tumor
  • the active ingredient of the side effect reducing agent of sunitinib or a salt thereof of the present invention is an antioxidant, but an antioxidant involved in the redox system in the living body is preferable, and it can be administered to humans safely.
  • the antioxidant which has is more preferable.
  • antioxidants that can be used include vitamin E or derivatives thereof, vitamin C or derivatives thereof, vitamin A or derivatives thereof, vitamin B 2 or derivatives thereof, cysteine or derivatives thereof, glutathione, polyphenols, carotenes, butyl One or more selected from hydroxyanisole and dibutylhydroxytoluene are preferred.
  • vitamin E examples include tocopherol acetate and tocopherol nicotinate.
  • vitamin C ascorbic acid
  • ascorbic acid fatty acid esters such as ascorbyl palmitate
  • ascorbic acid inorganic acid esters such as ascorbic acid phosphate, ascorbic acid calcium salts, ascorbic acid ester salts such as sodium ascorbic acid phosphate, etc.
  • Vitamin A includes retinol, retinal, retinoic acid and their dehydro forms.
  • Examples of vitamin A derivatives include tretinoin.
  • vitamin B 2 (riboflavin) derivatives examples include riboflavin butyrate.
  • cysteine derivatives include carbocysteine, methylcysteine, ethylcysteine, acetylcysteine, and the like.
  • polyphenols include catechins, anthocyanins, tannins, rutins, isoflavones, chlorogenic acids, ellagic acids, lignans, curcumins, coumarins, and sesamin.
  • vitamin E or its derivatives are preferred.
  • antioxidants showed the side effect reducing effect of sunitinib or its salt. That is, the cause of the high side effect frequency of sunitinib or a salt thereof has never been known.
  • the inventors have studied that glycogen metabolism is suppressed by administration of sunitinib, resulting in hepatotoxicity, cardiotoxicity, thrombocytopenia, hypothyroidism, It was found that glycogen metabolism is increased by administration, and side effects caused by sunitinib can be suppressed. It was also found that the antitumor effect of sunitinib is not affected by the combined use of antioxidants.
  • the side effect reducing agent of this invention should just contain the antioxidant, and can be set as the composition suitable for various dosage forms. Moreover, it can also mix
  • kits An anticancer agent and an antioxidant-containing composition containing sunitinib or a salt thereof can be used as a kit.
  • each composition constituting the kit can be made into various known preparation forms.
  • each composition is stored in various commonly used containers according to the preparation form, It can be set as the kit for cancer treatment in the containing mammal.
  • anticancer agents containing sunitinib or a salt thereof are commercially available in oral dosage forms, a composition containing an antioxidant or a composition containing sunitinib or a salt thereof and an antioxidant is orally administered.
  • a dosage form is preferred.
  • an antioxidant or a combination of sunitinib or a salt thereof and an antioxidant, if necessary, an excipient, a binder, a disintegrant, a lubricant, a colorant, a taste mask -After adding a flavoring agent etc., a tablet, a coated tablet, a granule, a powder, a capsule etc. can be manufactured by a conventional method.
  • excipient examples include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid.
  • binder examples include water, ethanol, 1-propanol, 2-propanol, simple syrup, glucose solution, ⁇ -starch solution, gelatin solution, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, Shellac, calcium phosphate, polyvinylpyrrolidone and the like can be mentioned.
  • Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
  • Examples of the lubricant include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol.
  • Examples of the colorant include titanium oxide and iron oxide.
  • Examples of the flavoring / flavoring agent include sucrose, orange peel, citric acid, tartaric acid and the like.
  • the dosage of the antioxidant varies depending on the kind of the antioxidant.
  • the daily dosage per adult is about 0.1 mg to 10 g, preferably about 5 mg to 5 g.
  • the amount of vitamin E is preferably 7.0 to 800 mg per day.
  • the amount of vitamin C is preferably 50 to 2000 mg per day.
  • the amount of retinol is preferably 0.1 to 30 mg per day.
  • the amount of vitamin B 2 is preferably 1 to 120 mg per day.
  • cysteine or a derivative thereof the amount of cysteine is preferably 10 to 1000 mg per day.
  • glutathione 10 to 1000 mg per day is preferable.
  • polyphenols 10 mg to 5 g per day is preferable.
  • sunitinib or a salt thereof is a commonly used dose.
  • 50 mg / day of sunitinib is orally administered for 4 weeks daily, and then withdrawn for 2 weeks. . Repeat this as one course.
  • 37.5 mg of sunitinib per adult can be orally administered once a day, and the dose can be increased to 50 mg once a day.
  • the antioxidant may be administered during the sunitinib administration period, may be simultaneously with the administration of sunitinib, or may be administered orally once to 3 times a day regardless of the administration interval of sunitinib.
  • a composition containing an antioxidant and sunitinib or a salt thereof is used, it is administered simultaneously.
  • DMEM fetal bovine serum
  • PCSM penicillin streptomycin
  • 293FT cells were cultured at Tesque, Kyoto, Japan.
  • HEK293 cells were cultured in DMEM medium supplemented with 10% FBS and 1% PCSM.
  • Primary hepatocytes were isolated, seeded onto collagen-coated plates, and cultured in William E medium (Sigma Aldrich, Carlsbad, CA, USA) supplemented with 10% FBS, 2 mM L-glutamine and 1% PCSM.
  • IC 50 value In the measurement of IC 50 value, a prescribed concentration of drug was added to the reaction mixture. The ATP concentration was fitted to a standard model, and the IC 50 value was measured based on Powell's nonlinear least square method with the same load factor. The assay was performed using Engineer® software (Micromath, St. Louis, MO).
  • Model simulation Based on previous studies (PLoS compatational biology 7: e1002272 (2011) and Biochimica et biophysica acta 1673: 149-159 (2004)), a solution including glycogen metabolism was used to simulate the relationship between phosphorylase kinase activity and GSH levels in the liver.
  • a cell biology markup language (SBML) model was constructed using Cell Designer 4.2, including the sugar pathway and the pentose phosphate pathway.
  • Initial values of kinetic parameters not included in previous studies were obtained from the Sabio-RK database.
  • Kinetic parameter values were measured using COPASI software by fitting the model to intrahepatic GSH / GSSG levels and NADPH / NADP + levels at steady state. Using the determined parameters, sensitivity analysis was performed using COPASI.
  • mice 6-week-old C57BL6 / J mice (male) were purchased from Japan SLC (Shizuoka, Japan) and sunitinib (0.167 mg / g diet; estimated 26.7 mg / kg / day) or sorafenib (0.129 mg / g diet) for 14 days MIF diet (Oriental Yeast Industry, Tokyo, Japan) containing an estimated 20.6 mg / kg / day). The drug dose was adjusted so that the plasma drug concentration in mice was maintained at the same level as in patients.
  • mice were fed a diet containing both ⁇ -tocopherol nicotinate (0.189 mg / g diet; estimated 30 mg / kg / day) and sunitinib for 14 days.
  • BSO was administered intraperitoneally (6 mmol / kg at 1 and 11 hours)
  • sunitinib was administered orally (8 mg / kg at 0 hours, and 6 mg / kg at 6, 12 and 18 hours).
  • the mice were killed and the organs and cells of interest were assayed.
  • Serum ALT concentration was measured using L type WAKO GPT J2 kit (Wako) and Dimension Xpand analyzer (Siemens, Berlin, Germany) according to the protocol.
  • L type WAKO GPT J2 kit Wi-Fi Protected Access (Wako)
  • Dimension Xpand analyzer Siemens, Berlin, Germany
  • the excised tissue specimen was homogenized in 6% metaphosphoric acid (Wako) and centrifuged at 15,000 rpm for 5 minutes at 40 ° C., and the glutathione concentration in the tissue was measured. The supernatant was divided into two aliquots, one of which was used for the assay of total glutathione concentration, and for the other, 2-vinylpyridine (Nacalai Tesque) was added to mask the GSH.
  • the electrical resistance method was used to measure the platelet count.
  • TSH concentration was measured according to the protocol.
  • FT3, FT4, total T3, and total T4 concentrations were measured using ARCHITECT analyzer i 1000SR (Abbott Japan) using the corresponding kits.
  • Sunitinib m / z 399.48-283.1; N-decethylsunitinib: m / z 371.27-283.1; sorafenib: m / z 465.35-252.1; metoprolol: m / z 268.23-116.03 were used as internal standards.
  • the plasma sample was deproteinized with 4 volumes of acetonitrile (Nacalai Tesque), and the supernatant was used for the assay.
  • Virus production and propagation were performed according to the protocol. Crude adenovirus was purified by cesium chloride density gradient ultracentrifugation. The titer of purified virus was measured using the Adeno-X TM Rapid Titer Kit (Clontech), after which 1 ⁇ 10 9 ifu adenovirus was injected intravenously into mice. Mice died 72 hours after adenovirus administration and related tissues and cells were assayed.
  • RNA isoplus reagent TaKaRa, Shiga, Japan
  • ReverTra Ace Toyobo Engineering, Osaka, Japan
  • SYBR® GreenER TM qPCR SuperMix Universal Eco Real-Time PCR system
  • Eco Real-Time PCR system Illumina, San Diego, CA
  • mice PHKG2 5′-GCA CCA GAG ATC CTT AAA T-3 ′ (SEQ ID NO: 3) and 5′-TAG CAT CAG GAT TTG GCG C-3 ′ (SEQ ID NO: 4);
  • ⁇ -actin 5′-CCG GAA GGA AAA CTG ACA GC-3 ′ (SEQ ID NO: 5) and 5′-GTG GTG GTG AAG CTG TAG CC-3 ′ (SEQ ID NO: 6).
  • Example 1 (Inhibition of off-target PHKG1 / 2 by sunitinib) Based on the speculation that differences in the incidence and severity of side effects induced by sunitinib and sorafenib are related to preferential inhibition of off-target kinases by sunitinib, a comprehensive comparison of the kinase occupancy profiles of the two drugs ( FIG. 1A).
  • PHKG1 serine / threonine kinase 17a
  • PHKG2 phosphorylase kinase gamma 1 (muscle)
  • PHKG2 phosphorylase kinase gamma 2
  • BMP2K BMP2-induced kinase
  • PHKG1 and PHKG2 The distribution pattern of PHKG1 and PHKG2 is tissue specific, the former is expressed in skeletal muscle, heart and thyroid, while the latter is expressed in liver and testis (Molecular genetics and metabolism 92: 234-242 (2007)).
  • Sunitinib is thought to affect glucose metabolism homeostasis, which is important for the normal physiology of all tissues and organs, by inhibiting both isomers.
  • mutations in the PHKG2 gene form the basis for type IV glycogen storage disease (GSD), which can cause cirrhosis (Clinics in endocrinology and metabolism 5: 579-598 (1976)).
  • Rats with a gsd / gsd mutation in PHKG2 show a marked decrease in liver glycogen phosphorylase activity and develop symptoms similar to those associated with type IV GSD (The Biochemical journal 188: 99-106 (1980)). . Therefore, in this study we focused on PHKG1 / 2.
  • a recombinant protein consisting of human and mouse PHKG1 / 2 kinase domains fused at the N-terminus with His-tag was obtained using the mammalian cell expression system (FIG. 1B), and its in vitro kinase activity was determined by sunitinib and its Analysis was performed with or without the active metabolite N-desethylsunitinib.
  • Example 2 (Sunitinib suppresses hepatic glycogen metabolism through PHKG2 inhibition and causes oxidative stress in the liver) Considering the results of Example 1, the mechanism of sunitinib-related toxicity was investigated in vivo using a mouse model. C57BL / 6 mice (6 weeks old, male) were given sunitinib or sorafenib for 14 days, and the plasma concentration of each drug was measured by liquid chromatography tandem mass spectrometry. The content of sunitinib or sorafenib in the mouse chow was adjusted so that the plasma concentrations were the respective clinical concentrations (sunitinib: 40-70 ng / mL, sorafenib: 2500-5000 ng / mL).
  • sunitinib may suppress glycogen metabolism through inhibition of PHKG2, which is an isoform of the catalytic subunit of phosphorylase kinase expressed in the liver. Therefore, in order to further investigate the mechanism of hepatotoxicity caused by sunitinib, we analyzed the effects of sunitinib on glycolysis and pentose phosphate pathway. Using metabolic pathway diagrams, the effect of PHKG2 inhibition on metabolic homeostasis was estimated by a computational model approach. The model was constructed by combining the previous model with various kinetic parameter values determined by fitting the model to experimental data obtained from drug-untreated mice.
  • the NADPH / NADP + ratio is related to the redox balance in cells because NADPH is required to reduce GSSG to GSH, so the amounts of GSSG and GSH in the liver were also measured.
  • sunitinib decreased GSH while increasing GSSG, and the ratio of GSH to GSSG in the liver of sunitinib-treated mice was 90% lower than in control mice and sorafenib-treated mice (FIG. 2G).
  • Example 3 (Oxidative stress induced by sunitinib increases the sensitivity of hepatocytes to sunitinib) Since oxidative stress is well known to exacerbate liver injury, the above results suggest that continuous oral administration of sunitinib enhances the hepatotoxicity of the drug. This hypothesis was verified by examining the effects of short-term administration of sunitinib after intraperitoneal administration of buthionine sulfoximine (BSO) to mice to deplete liver GSH (FIG. 3A). As a result, serum ALT levels increased significantly in the BSO + sunitinib group, but not in the BSO alone group (Fig. 3B), supporting the increased sensitivity of the liver to sunitinib due to oxidative stress in the liver.
  • BSO buthionine sulfoximine
  • Example 4 (Oxidative stress induced by sunitinib is involved in cardiotoxicity) Clinical problems associated with sunitinib treatment include related heart disease. Nevertheless, the onset of reduced left ventricular ejection fraction is relatively rare. In the heart, the PHKG1 isoform was expressed and, like PHKG2, was shown to be inhibited by sunitinib and its metabolites (FIG. 1). Therefore, it was speculated that sunitinib induces oxidative stress in heart tissue as well as liver. This is because when either sunitinib or sorafenib was administered to mice for 14 days, cardiac glycogen accumulation was significantly higher in sunitinib-treated mice than in control mice, but not in sorafenib-treated mice.
  • FIG. 4A A significant decrease in cardiac glucose-6-phosphate levels was also observed in response to sunitinib, but not sorafenib (FIG. 4B).
  • FIG. 4B we examined whether oxidative stress was generated in heart tissue exposed to sunitinib.
  • the administration of sunitinib significantly decreased the NADPH / NADP + ratio and the GSH / GSSG ratio compared to control mice, while the TBARS amount increased significantly, but was not observed with sorafenib administration (FIGS. 4C-E).
  • the heart consumes large amounts of ATP.
  • ATP is normally supplied through an oxidative phosphorylation pathway in which acetyl-CoA is synthesized during ⁇ -oxidation of fatty acids.
  • ATP is generated through glycolysis from recent research in spontaneously hypertensive rats (SHR), and at that time, the expression of two components, enolase and lactate dehydrogenase, is increased, and enoyl-CoA is involved in the ⁇ -oxidation pathway. It was shown to be accompanied by reduced expression of pyruvate dehydrogenase involved in hydrolatanase and TCA cycle. These changes in the desired pathway of energy metabolism are thought to protect the heart tissue from the excessive amount of ROS produced when ATP production proceeds via oxidative phosphorylation under hypertensive conditions.
  • Example 5 The cause of the decrease in platelet count is due to oxidative stress induced by sunitinib.
  • Phosphorylase kinase of either the catalytic subunit PHKG1 or PHKG2 is ubiquitously expressed in mammalian organs (Molecular genetics and metabolism 92: 234-242 (2007)).
  • sunitinib induces oxidative stress by inhibiting phospholyase and suppressing glycogen metabolism.
  • the clinical dose limiting toxicity of sunitinib is determined by platelet count reduction and side effects in treated patients (Non-Patent Document 4). Therefore, the next experiment focused on the relationship between sunitinib-induced platelet count reduction and oxidative stress.
  • glycogen in platelets in the liver and heart of mice fed with sunitinib or sorafenib for 14 days was measured.
  • glycogen accumulation was observed, but in the control group and sorafenib administration group, glycogen accumulation was not observed (FIG. 5A).
  • sunitinib significantly reduced the NADPH / NADP + and GSH / GSSG ratios and increased TBARS (FIGS. 5B-D).
  • oxidative stress increases the phagocytosis of cells by macrophages by allowing calcium ions to flow into cytosole, up-regulating phospholipid scrambling activity, and presenting phosphatidylserine (PS) on the cell membrane surface.
  • PS phosphatidylserine
  • platelets were collected from control mice, sunitinib, and sorafenib-treated mice, and annexin V, which is known to selectively bind to PS, was fluorescently labeled to confirm the binding between the annexin V and platelets. Similar to the findings described above, platelets collected from sunitinib-treated mice bound higher amounts of Annexin V than platelets collected from control and sorafenib-treated mice (FIG. 5E). However, the amount of annexin V bound to platelets collected from mice administered with a combination of ⁇ -tocopherol nicotinate and sunitinib maintained a control amount (FIG. 5E).
  • Example 6 Oletidative stress caused by sunitinib causes thyroid dysfunction. It has been reported that thyroid dysfunction and hyperthyroid stimulating hormoneemia are side effects often seen in patients who have received sunitinib treatment (Non-patent Document 5). Therefore, we investigated whether thyroid dysfunction was caused by oxidative stress induced by sunitinib. Similar to liver, heart and platelets, glycogen was significantly accumulated in the thyroid of mice fed sunitinib for 14 days, but this was not observed in control mice or mice fed sorafenib (FIG. 6A). ). A significant decrease in the NADPH / NADP + ratio or GSH / GSSG ratio and a significant increase in TBARS were only seen in sunitinib-treated mice (FIGS.
  • Thyroid hormone is produced in the thyroid follicle by the catalytic action of thyroid peroxidase (TPO), which requires oxygen peroxide (Molecular and cellular endocrinology 343: 32-44 (2011)).
  • TPO thyroid peroxidase
  • Carbon peroxide is produced by dual oxidase 2, an enzyme that NADPH functions as a coenzyme and expressed in follicular epithelial cells (Molecular and cellular endocrinology 343: 32-44 (2011)). Therefore, treatment with sunitinib seems to suppress the production of thyroid hormone by reducing the amount of NADPH in the thyroid gland.
  • Serum thyroid hormone levels are known to be tightly controlled by thyroid hormone feedback (The Journal of physiology 195: 29-37 (1968)), and the above observations are for patients with latent hypothyroidism Reminiscent of symptoms seen in Latent hypothyroidism shows a persistently high TSH signal to ensure sufficient amounts of FT3 and FT4 when the function of the thyroid gland that produces thyroid hormone decreases (Lancet 379: 1142-1154 (2012) ).
  • octreotide known to reduce TSH secreted by the pituitary gland and inhibit feedback action
  • was given to mice fed with kinase inhibitors. was administered.
  • the serum FT3 and FT4 values were significantly lower than the control values, similar to T3 and T4 in the thyroid gland. This is consistent with the conclusion that sunitinib suppresses thyroid hormone synthesis (FIGS. 6G-H).
  • Example 7 (Sunitinib induces glycogen accumulation and oxidative stress generation in patients.)
  • the effect of sunitinib on glycogen metabolism and the ability of the drug to induce oxidative stress were evaluated by measuring changes in blood glycogen and serum TBARS.
  • blood glycogen levels and serum TBARS levels of mice fed with sunitinib or sorafenib for 14 days and mice in the control group were measured.
  • Significant increases in blood glycogen levels and serum TBARS levels were observed only in the sunitinib-administered group (FIGS. 7A-B).
  • the combination of sunitinib and ⁇ -tocopherol nicotinate decreased the amount of serum TBARS (FIG. 7B).
  • Example 8 The effects of antioxidants on serum TBARS (thiobarbituric acid-reactive substance), platelet count, TSH (thyroid hormone), troponin T, NT-proBNP and ALT, which are increased by sunitinib administration, were examined by the aforementioned mouse experiments. . The results are shown in FIGS. 8A to 8F. As shown in FIGS. 8A-8F, all antioxidants significantly reduced the oxidative stress markers that were elevated by sunitinib administration. Of these, the effect of tocopherol nicotinate was most excellent.
  • the dosage (oral administration) of various oxidizing agents is as follows. Vitamin A: 192.9 mg / kg / day. Riboflavin butyrate: 5.1 mg / kg / day.
  • Ascorbic acid 77.1 mg / kg / day. Nicotinic acid ⁇ -tocopherol: 25.7 mg / kg / day. ⁇ -Tocopherol acetate: 12.9 mg / kg / day. Cysteine: 20.6 mg / kg / day. Glutathione: 12.9 mg / kg / day. Carbocysteine: 64.3 mg / kg / day. Methylcysteine: 12.9 mg / kg / day. Ethylcysteine: 12.9 mg / kg / day. Acetylcysteine: 1470 mg / kg / day.
  • Example 9 Tumor-bearing mice were prepared by subcutaneous administration of 1 ⁇ 10 6 Lewis lung cancer cells, and sunitinib (26.7 mg / kg / day) alone or sunitinib (26.7 mg / kg / day) and tocopherol nicotinate (30 mg / kg / day) day) was administered for 2 weeks. The antitumor effect was observed after 2 weeks. The results are shown in FIGS. 9A to 9C. FIG. 9 shows that the antitumor effect of sunitinib is not affected by administration of tocopherol nicotinate (antioxidant).

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Abstract

La présente invention concerne un procédé pour atténuer un effet secondaire du sunitinib par utilisation du sunitinib et d'un antioxydant conjointement. Il a été découvert que l'effet secondaire du sunitinib est provoqué par une augmentation du stress oxydatif et du glycogène dans le sang, et il a été découvert que l'effet secondaire est atténué par utilisation d'un antioxydant conjointement avec le sunitinib.
PCT/JP2013/081210 2012-11-19 2013-11-19 Agent pour atténuer l'effet secondaire du sunitinib WO2014077409A1 (fr)

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JP2016102673A (ja) * 2014-11-27 2016-06-02 国立大学法人秋田大学 複数種類の抗がん剤の血中濃度の連続測定方法
JP2019504100A (ja) * 2016-02-04 2019-02-14 ステム セル セラノスティクス，インコーポレイテッド 化学療法による心毒性を阻止するための医薬組成物および方法
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JP2022017518A (ja) * 2016-02-04 2022-01-25 エスシーティー ツー エルエルシー 化学療法による心毒性を阻止するための医薬組成物および方法
JP7058396B2 (ja) 2016-02-04 2022-04-22 エスシーティー ツー エルエルシー 化学療法による心毒性を阻止するための医薬組成物および方法
US11786503B2 (en) 2016-02-04 2023-10-17 Auransa Inc. Pharmaceutical compositions and methods for countering chemotherapy induced cardiotoxicity
CN111789952A (zh) * 2020-05-21 2020-10-20 上海市第六人民医院 一种治疗肾透明细胞癌的药物组合物及其应用
CN115060819A (zh) * 2022-06-08 2022-09-16 重庆大学附属肿瘤医院 基于hplc-ms/ms单峰法同时测定人血浆中sun及su12662的方法
CN115060819B (zh) * 2022-06-08 2023-09-01 重庆大学附属肿瘤医院 基于hplc-ms/ms单峰法同时测定人血浆中sun及su12662的方法

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