WO2013125675A1 - 併用抗がん剤の感受性判定マーカー - Google Patents

併用抗がん剤の感受性判定マーカー Download PDF

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WO2013125675A1
WO2013125675A1 PCT/JP2013/054488 JP2013054488W WO2013125675A1 WO 2013125675 A1 WO2013125675 A1 WO 2013125675A1 JP 2013054488 W JP2013054488 W JP 2013054488W WO 2013125675 A1 WO2013125675 A1 WO 2013125675A1
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Prior art keywords
substance
sensitivity
salt
substances
cancer
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French (fr)
Japanese (ja)
Inventor
祐介 谷川原
章戸 西牟田
盾哉 津崎
寛行 高橋
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Yakult Honsha Co Ltd
Keio University
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Yakult Honsha Co Ltd
Keio University
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Priority to EP13752246.2A priority Critical patent/EP2818870A4/en
Priority to CN201380010388.7A priority patent/CN104169721A/zh
Priority to JP2014500945A priority patent/JP6141824B2/ja
Priority to EP20214606.4A priority patent/EP3812009A1/en
Priority to EP17202053.9A priority patent/EP3326632B1/en
Priority to US14/379,945 priority patent/US9733256B2/en
Publication of WO2013125675A1 publication Critical patent/WO2013125675A1/ja
Anticipated expiration legal-status Critical
Priority to US15/635,293 priority patent/US10481160B2/en
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    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
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    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y10T436/201666—Carboxylic acid

Definitions

  • the present invention relates to an anticancer drug sensitivity determination marker used for determining whether or not a cancer of a subject patient has therapeutic reactivity to an anticancer drug, and its application.
  • anticancer agents such as alkylating agents, platinum preparations, antimetabolites, anticancer antibiotics, and anticancer plant alkaloids. These anticancer drugs may or may not be effective depending on the type of cancer. Furthermore, it is known that even the types of cancer that are recognized as effective may or may not be effective depending on the individual patient. Whether or not an anticancer drug shows an effect on such individual patient's cancer is called anticancer drug sensitivity.
  • Oxaliplatin is a platinum complex antineoplastic agent. Like other cisplatin (CDDP) and carboplatin (CBDCA), which are other platinum complex antineoplastic agents, the mechanism of action is thought to be DNA synthesis inhibition and protein synthesis inhibition by crosslinking with DNA bases. L-OHP exhibits an antitumor effect even for colorectal cancer in which CBDCA is ineffective, and exhibits an antitumor spectrum different from that of conventional platinum complex antineoplastic agents. In January 2004, it was approved as a first-line treatment for metastatic colorectal cancer in combination with fluorouracil (5-FU) / levofolinate (LV) in January 2004.
  • fluorouracil 5-FU
  • LV levofolinate
  • 5-FU is a fluorinated pyrimidine anticancer drug developed in 1957 and is still a basic drug for digestive cancer chemotherapy.
  • 5-FU incorporated into cancer cells is mainly composed of inhibition of thymidylate synthase (TS) caused by active metabolite fluorodeoxyuridine-5′-monophosphate (FdUMP), and also has the main mechanism of action. It exhibits a cell-killing effect due to RNA dysfunction caused by 5-fluorouridine triphosphate (FUTP).
  • TS thymidylate synthase
  • FdUMP active metabolite fluorodeoxyuridine-5′-monophosphate
  • Chemotherapy for advanced and metastatic colorectal cancer is centered on key drugs such as irinotecan (CPT-11) and L-OHP, which appeared in the 1990s, and 5-FU, which has been a central drug for colorectal cancer treatment.
  • CPT-11 irinotecan
  • L-OHP L-OHP
  • 5-FU 5-FU
  • the clinical outcomes including survival rate have been dramatically improved, but the number of patients who are treated successfully is about half, taking the risk of serious side effects. The effect is not obtained in half of patients who received anticancer drugs.
  • the cancer chemotherapy treatment schedule is long-term, and after determining how many cool treatments have been performed while observing the occurrence of side effects, it is determined whether the effect has been obtained or whether the administration should be continued as is. Until then, it took a long time, expensive medical expenses, and side effects have occurred. Therefore, if there is a means for predicting whether an effect can be obtained for each patient before treatment or early in treatment, the burden on the patient and the occurrence of side effects can be reduced, and medical costs can be reduced.
  • An object of the present invention is to provide an anticancer drug sensitivity determination marker capable of discriminating treatment responsiveness of individual patients and a new cancer treatment means using the same.
  • the present inventors cultured human cancer cell lines and covered intracellular metabolic changes after exposure to 5-FU / L-OHP using a capillary electrophoresis-time-of-flight mass spectrometer (CE-TOFMS). Analysis of anticancer drug sensitivity determination markers, we found a peak in which high levels of intracellular sensitivity were observed after exposure to 5-FU / L-OHP in highly sensitive cells.
  • CE-TOFMS capillary electrophoresis-time-of-flight mass spectrometer
  • Substances on the amino acid metabolism system (Asp, Gly, Arg, N-Acetyl-beta-alanine, N-Acetylornithine, Cadaverine, Systemic acid, 2-Aminoadiacid acid, GABA (gamma-aminobacetic acid-Gamma) -Ala-Lys, Glu- lu, S-lactoylglutathione), substances on nucleic acid metabolism (Guanosine, CMP, UMP, 1-methyladenosine, UDP, CTP), substances on pentose phosphate pathway (Sedoheptulose 7-phosphate), substances on glycolysis (Dihydryx) phosphate, 2,3-diphosphoglyceric acid, pyruvic acid), substance on TCA circuit (Malic acid), substance on polyamine metabolic system (N 1 -acetylspermine, N-acetylputrescine, N 8 -acetylspermidine, putres
  • a peak in which a marked increase in intracellular level was observed after exposure to 5-FU / L-OHP in a low-sensitivity cell was a substance on the amino acid metabolism system (N, N-dimethylglycine, 3-methylhistidine, N 5 -Ethylglutamine, glutathione), a substance on the nucleic acid metabolic system (dATP), butyric acid, triethanolamine, 1-methylnicotinamide.
  • dATP nucleic acid metabolic system
  • a peak in which a significant decrease in intracellular level was observed after exposure to 5-FU / L-OHP in a highly sensitive cell was found, and the peak was found to be a substance on the amino acid metabolism system (Cysteine-glutathione) or on the nucleic acid metabolism pathway.
  • the substance (Adenine) is a substance on the pentose phosphate pathway (PRPP).
  • PRPP pentose phosphate pathway
  • a peak in which a marked decrease in intracellular level was observed after exposure to 5-FU / L-OHP in low sensitivity cells was found, and the peaks were found to be NADH and NAD + .
  • GABA it discovered that the intracellular level before chemical
  • CE-TOFMS for blood samples from patients with colorectal cancer, it was found that patients with low therapeutic response to bevacizumab combined mFOLFOX6 therapy have high blood GABA levels. It was.
  • the concentration of these metabolites in a biological sample derived from a cancer patient is used as an index, whether or not the cancer of the cancer patient has sensitivity to an anticancer drug is determined. It can be determined, and if the concentration and fluctuation of these metabolites are used as an index, screening of anticancer drug sensitivity-enhancing agents becomes possible, and further, the anticancer drug sensitivity-enhancing agent and the anti-sensitivity targeted.
  • the present inventors have found that the therapeutic effect of the anticancer drug can be dramatically improved by using a cancer drug together, and the present invention has been completed.
  • the present invention relates to a substance on an amino acid metabolism system, a substance on a nucleic acid metabolism system, a substance on a pentose phosphate pathway, a substance on a glycolysis system, a substance on a TCA circuit, a substance on a polyamine metabolism system, and 7,8 Oxaliplatin or its salt or one or more molecules selected from dihydrobiopterin, 6-phosphoglyconic acid, butyric acid, triethanolamine, 1-methylnicotinamide, NADH, NAD + and substances on the metabolic system in which these molecules are involved, or oxaliplatin or its salt
  • the present invention provides a marker for determining sensitivity of an anticancer drug containing the salt.
  • the present invention also provides a method for determining the sensitivity of an anticancer agent comprising oxaliplatin or a salt thereof and fluorouracil or a salt thereof, characterized by measuring the above-mentioned substance in a specimen.
  • the present invention also includes a protocol for measuring the above-mentioned substance in a specimen, and a method for determining the sensitivity of an anticancer drug containing oxaliplatin or a salt thereof and fluorouracil or a salt thereof, A kit is provided.
  • the present invention provides a screening method for an agent for enhancing sensitivity to an anticancer agent containing oxaliplatin or a salt thereof and fluorouracil or a salt thereof using the expression variation of the substance as an index.
  • this invention provides the sensitivity enhancement agent with respect to the anticancer agent containing the oxaliplatin or its salt obtained by said screening method, and fluorouracil or its salt. Furthermore, this invention provides the composition for cancer treatment containing said anticancer agent sensitivity enhancer, an anticancer agent containing oxaliplatin or its salt, and fluorouracil or its salt.
  • the anticancer drug treatment reactivity of each patient can be accurately determined before anticancer drug administration or early after the start of anticancer drug administration, It is possible to select anti-cancer drugs with higher therapeutic effects, and as a result, it is possible to prevent the progression of cancer and the increase in side effects associated with continuous administration of anti-cancer drugs that cannot be expected to have therapeutic effects, and further reduce the burden on patients. Reduction of medical expenses can also be expected.
  • this marker it is possible to screen for drugs that enhance the sensitivity of anticancer drugs, and if the anticancer drug and anticancer drug sensitivity-enhancing agent are used in combination, the effect of cancer treatment will jump dramatically. Improve.
  • the measurement reagent of the anticancer drug sensitivity determination marker of the present invention is useful as an anticancer drug sensitivity determination reagent.
  • One of the anticancer drug sensitivity determination markers in the present invention is a substance on an amino acid metabolism system (also referred to as an amino acid metabolism substance), and as the substance, any substance that varies the concentration of an amino acid metabolism substance in the metabolism system is used. Substances are included, and substances that enhance or inhibit metabolism to amino acid metabolic substances, substances that promote or inhibit metabolism from amino acid metabolic substances, and the like can be mentioned.
  • One of the anticancer drug sensitivity determination markers in the present invention is a substance on a nucleic acid metabolism system (also referred to as a nucleic acid metabolism substance), which includes all substances that change the concentration of the nucleic acid metabolism substance. Examples thereof include substances that enhance or inhibit metabolism to nucleic acid metabolizing substances, substances that promote or inhibit metabolism from nucleic acid metabolizing substances, and the like. Of these, guanosine, CMP, UMP, 1-methyladenosine, UDP, CTP, dATP, and adenine are preferable, and guanosine, UMP, UDP, and CTP are particularly preferable.
  • One of the anticancer drug sensitivity determination markers in the present invention is a substance on the pentose phosphate pathway (also referred to as a substance on the pentose phosphate pathway), and as the substance, all substances that vary the concentration of the substance on the pentose phosphate pathway And substances that enhance or inhibit metabolism to substances on the pentose phosphate pathway, substances that promote or inhibit metabolism from substances on the pentose phosphate pathway, and the like. Of these, Sedoheptulose 7-phosphate and PRPP are particularly preferable.
  • One of the anticancer drug sensitivity determination markers in the present invention is a substance on glycolysis (also referred to as a glycolysis substance), which includes all substances that change the concentration of the glycolysis substance. Examples thereof include substances that enhance or inhibit metabolism to glycolytic substances, substances that promote or inhibit metabolism from glycolytic substances, and the like. Of these, dihydroxyacetone phosphate, 2,3-diphosphoglyceric acid, and pyruvic acid are preferable, and dihydroxyacetone phosphate is particularly preferable.
  • One of the anticancer drug sensitivity determination markers in the present invention is a substance on the TCA circuit (also referred to as a substance on the TCA circuit), and the substance includes all substances that change the concentration of the substance on the TCA circuit. , Substances that enhance or inhibit metabolism to substances on the TCA cycle, substances that promote or inhibit metabolism from substances on the TCA circuit, and the like. Of these, Malic acid is particularly preferable.
  • One of the anti-cancer drug sensitivity determination markers in the present invention is a substance on the polyamine metabolic system (also referred to as a polyamine metabolic system substance), and the substance includes all substances that vary the concentration of the polyamine metabolic system substance in the metabolic system. Substances are included and include substances that enhance or inhibit metabolism to polyamine metabolizing substances, substances that promote or inhibit metabolism from polyamine metabolizing substances, and the like. Of these, N 1 -acetylspermine, N-acetylputrescine, N 8 -acetylspermidine, putrescine, spermine and spermidine are particularly preferred.
  • One of the anticancer drug susceptibility determination markers in the present invention is 7,8-Dihydrobiopterin or a substance on a metabolic system related thereto (also referred to as 7,8-Dihydrobiopterin metabolic substance).
  • 7,8-Dihydrobiopterin metabolic substance also referred to as 7,8-Dihydrobiopterin metabolic substance.
  • all substances that change the concentration of 7,8-Dihydrobiopterin in the metabolic system are included.
  • Substances that enhance or inhibit metabolism to 7,8-Dihydrobiopterin from 7,8-Dihydrobioterin Examples include substances that promote metabolism or substances that inhibit metabolism. Of these, 7,8-Dihydrobioterin is particularly preferred.
  • One of the anticancer drug susceptibility determination markers in the present invention is 6-phosphogluconic acid or a substance on a metabolic system related thereto (also referred to as 6-phosphogluconic acid metabolite), and the substance is 6-phosphogluconic acid.
  • 6-phosphogluconic acid or a substance on a metabolic system related thereto
  • all substances that change the concentration of 6-phosphogluconic acid in the metabolic system are included, and substances that promote or inhibit metabolism to 6-phosphogluconic acid, substances that promote metabolism from 6-phosphogluconic acid, or Inhibiting substances are included. Of these, 6-phosphogluconic acid is particularly preferred.
  • One of the anticancer drug susceptibility determination markers in the present invention is butyric acid or a substance on the metabolic system involved in this (also referred to as butyric acid metabolite), and in addition to butyric acid, Examples include all substances that vary the concentration of butyric acid, such as substances that enhance or inhibit metabolism to butyric acid, substances that promote or inhibit metabolism from butyric acid, and the like. Of these, Butyric acid is particularly preferable.
  • One of the anti-cancer drug sensitivity determination markers in the present invention is triethanolamine or a substance on the metabolic system (also referred to as triethanolamine metabolite), which includes triethanolamine, and the concentration of triethanolamine in the metabolic system. All substances that change the above are included, and substances that enhance or inhibit metabolism to triethanolamine, substances that promote or inhibit metabolism from triethanolamine, and the like can be mentioned. Of these, triethanolamine is particularly preferred.
  • One of the anticancer drug susceptibility determination markers in the present invention is 1-methylnicotinamide or a substance on the metabolic system involved with this (also referred to as 1-methylnicotinamide metabolite), and the substance includes, in addition to 1-methylnicotinamide, Includes all substances that vary the concentration of 1-methylnicotinamide in the metabolic system, including substances that enhance or inhibit metabolism to 1-methylnicotinamide, substances that promote or inhibit metabolism from 1-methylnicotinamide, etc. It is done. Of these, 1-methylnicotinamide is particularly preferred.
  • NADH or a substance on the metabolic system (also referred to as NADH metabolic substance) in which this is involved, and the substance includes NADH and the concentration of NADH in the metabolic system. All substances that vary the above are included, including substances that enhance or inhibit metabolism to NADH, substances that promote or inhibit metabolism from NADH, and the like. Of these, NADH is particularly preferred.
  • NAD + or metabolic on substances which are involved
  • NAD + also called metabolic substances
  • the material other NAD + the metabolic It contains all substances of varying the concentration of NAD +, substances that substance or inhibit enhancing the metabolism to NAD +, such substances that substance or inhibit stimulate metabolism from NAD + can be mentioned. Of these, NAD + is particularly preferred.
  • DLD-1 which is less sensitive
  • these substances are useful as sensitivity determination markers for anticancer agents including 5-FU and L-OHP.
  • Cysteine-glutathione, Adenine, PRPP as shown in Examples below, showed a significant decrease in intracellular levels in HCT116, which is highly sensitive after 5-FU / L-OHP exposure, but is insensitive In DLD-1, there was no significant change in intracellular level as in HCT116, or the intracellular level increased compared to the control group. Therefore, these substances are useful as sensitivity determination markers for anticancer agents including 5-FU and L-OHP.
  • NADH and NAD + showed a significant decrease in intracellular level in DLD-1, which is hyposensitive after exposure to 5-FU / L-OHP, as shown in Examples below, but HCT116, which is hypersensitive. However, no significant change in intracellular level was observed as in DLD-1. Therefore, these substances are useful as sensitivity determination markers for anticancer agents including 5-FU and L-OHP.
  • GABA showed a significant increase in intracellular level in HCT116, which is highly sensitive, after exposure to 5-FU / L-OHP.
  • DLD-1 which is less sensitive, did not show a significant change in intracellular level as HCT116.
  • the present inventors have found that the intracellular level before drug treatment is higher in DLD-1, which is less sensitive than HCT116, which is highly sensitive.
  • blood levels were high in many colorectal cancer patients with poor therapeutic response to mFOLFOX6 therapy combined with bevacizumab. Therefore, GABA is useful as a sensitivity determination marker for anticancer agents containing 5-FU and L-OHP.
  • the anticancer agent which is the target of the anticancer drug sensitivity determination marker of the present invention is an anticancer agent containing oxaliplatin or a salt thereof and fluorouracil or a salt thereof, but is metabolized in the body and converted to oxaliplatin or fluorouracil.
  • the anticancer agent to be used is also a target of the anticancer agent sensitivity determination marker of the present invention. Specifically, since tegafur and capecitabine are metabolized in the body and converted to fluorouracil, tegafur and capecitabine are also used in the present invention for determining sensitivity to anticancer agents.
  • an anticancer agent containing oxaliplatin or a salt thereof and tegafur or a salt thereof, or an anticancer agent containing oxaliplatin or a salt thereof and capecitabine or a salt thereof is an anticancer agent of the present invention. It becomes the target of the drug sensitivity determination marker.
  • the anticancer agent which is the target of the anticancer drug sensitivity determination marker of the present invention is an anticancer agent containing oxaliplatin or a salt thereof and fluorouracil or a salt thereof, and is used in combination with this anticancer agent.
  • cyclophosphamide cyclophosphamide
  • ifosfamide ifosfamide
  • thiotepa thiotepa
  • melphalan melphalan
  • busulfan nisulfine
  • nimustine nimustine
  • dacarbazine procarbazine
  • procarbazine procarbazine
  • temozolomide procarbazine
  • cisplatin carboplatin ( arboplatin, nedaplatin, methotrexate, pemetrexed, uracil, uracil, doxifluridine, gimeracil / teracil, gimeracil, teracil.
  • 6-mercaptopurine fludarabine, pentostatin, cladribine, hydroxyurea, doxorubicin Epirubicin, daunorubicin, idarubicin, pirarubicin, mitoxantrone, amrubicin, actinomycin D (t) ), Mitomycin C, aclarubicin, dinostatin, vincristine, vindesine, vinblastine, vinorelbine, vinorelbine Ritaxel (paclitaxel), docetaxel (docetaxel), irinotecan (irinotecan), irinotecan active metabolite (SN-38), nogitecan (nogetecan, topotenone), etoposide (etoposide), prednisone (etoposide) ), Toremifene, medroxyprogesterone, anastrozole, exemestane, letrozole, rituximab, im
  • a combination with one or more anticancer agents selected from irinotecan, SN-38, cetuximab, bevacizumab, dasatinib, panitumumab, hololinate and levofolinate is preferable, and particularly selected from irinotecan, cetuximab, bevacizumab, hololinate and levofolinate.
  • Combinations of the above anticancer agents are preferred, and examples of combinations of oxaliplatin or a salt thereof and an anticancer agent containing fluorouracil or a salt thereof include levofolinate, holinato, levofolinate and bevacizumab; holinato and bevacizumab; Cetuximab; folinate and cetuximab; or irinotecan.
  • these metabolic substances in a sample may be measured.
  • the specimen include biological samples derived from subjects having cancer (cancer patients) such as blood, serum, plasma, urine, tumor tissue / cells, ascites, pleural effusion, cerebrospinal fluid, stool, sputum, and the like. Serum is particularly preferred.
  • lip, oral and pharyngeal cancer typified by pharyngeal cancer
  • digestive organ cancer typified by esophageal cancer
  • stomach cancer colon / rectal cancer
  • lung cancer Respiratory and intrathoracic organ cancer, bone and joint cartilage cancer, cutaneous malignant melanoma, squamous cell carcinoma and other skin cancers, mesothelioma and mesothelioma Tissue cancer, breast cancer, uterine cancer, female genital cancer represented by ovarian cancer, male genital cancer represented by prostate cancer, urinary tract cancer represented by bladder cancer, brain tumor Representative eye, brain and central nervous system cancer, thyroid and other endocrine adenocarcinoma, non-Hodgkin lymphoma, lymphoid leukemia, lymphoid tissue, hematopoietic tissue and related tissue cancer, and these as the primary focus Include metastatic tissue cancers, especially non-small cell lung cancer, small cell lung cancer, small cell lung cancer, small cell lung
  • the means for measuring these metabolic substances in a sample may be appropriately determined depending on the substance to be measured.
  • CE-TOFMS various mass spectrometers such as gas chromatography-mass spectrometry (GC-MS), HPLC, immunological It can be measured by a measurement method, biochemical measurement method or the like.
  • GC-MS gas chromatography-mass spectrometry
  • HPLC HPLC
  • immunological It can be measured by a measurement method, biochemical measurement method or the like.
  • the anticancer drug sensitivity determination marker in the present invention not only determines the anticancer drug treatment responsiveness, but also prevents an increase in side effects associated with continuous administration of an anticancer drug that cannot be expected to have a medicinal effect. Contribute greatly.
  • the anticancer drug sensitivity determination marker in the present invention not only determines the anticancer drug treatment responsiveness, but also prevents an increase in side effects associated with continuous administration of an anticancer drug that cannot be expected to have a medicinal effect. Contribute greatly.
  • Cysteine-glutathione, Adenine, and PRPP To determine the sensitivity of Cysteine-glutathione, Adenine, and PRPP to the target anticancer drug, measure the concentrations of these metabolic substances in biological samples from cancer patients before and after the administration of the anticancer drug. However, if the concentration of these metabolites decreases after administration compared to before administration of the anticancer agent or falls below a predetermined standard, the cancer is sensitive to the anticancer agent, and before and after the administration of the anticancer agent. If the concentration of these metabolite substances in the cancer does not change or exceeds a predetermined standard, it can be determined that the cancer is not sensitive to an anticancer drug.
  • the anticancer drug sensitivity determination marker in the present invention not only determines the anticancer drug treatment responsiveness, but also prevents an increase in side effects associated with continuous administration of an anticancer drug that cannot be expected to have a medicinal effect. Contribute greatly.
  • the concentration of these metabolic substances in a biological sample derived from a cancer patient before and after administration of the anticancer agent is measured. If the concentration of these metabolic substances after administration is lower than before administration of the cancer drug, or if it falls below the prescribed standard, the cancer is not anticancer drug sensitive, and these metabolic systems before and after administration of the anticancer drug If the concentration of the substance does not change or exceeds a predetermined standard, it can be determined that the cancer is sensitive to an anticancer drug.
  • the anticancer drug sensitivity determination marker in the present invention not only determines the anticancer drug treatment responsiveness, but also prevents an increase in side effects associated with continuous administration of an anticancer drug that cannot be expected to have a medicinal effect. Contribute greatly.
  • the concentration of these metabolic substances in a biological sample derived from a cancer patient before and after administration of the anticancer agent is measured, and the anticancer agent is measured. If the concentration of these metabolites increases after administration compared to before administration or exceeds the prescribed standard, the cancer is sensitive to anticancer drugs. If the concentration does not change or falls below a predetermined standard, it can be determined that the cancer is not sensitive to anticancer agents. In addition, if the concentration of these metabolic substances is determined to be higher than the prescribed standard concentration before administration of the anticancer agent or before administration of the anticancer agent in each treatment cycle, the cancer is It can be determined that there is no sensitivity to the target anticancer drug.
  • the anticancer drug sensitivity determination marker in the present invention not only determines the anticancer drug treatment responsiveness, but also prevents an increase in side effects associated with continuous administration of an anticancer drug that cannot be expected to have a medicinal effect. Contribute greatly.
  • kits including a protocol for measuring these metabolic substances in a sample.
  • the kit includes a reagent for measuring these metabolic substances, a method for using the measuring reagent, a standard for determining the presence or absence of anticancer drug sensitivity, and the like.
  • These standards include standard concentrations and standard ratios of these metabolic substances, concentrations and ratios that are judged to be high, concentrations and ratios that are judged to be low, factors that affect measurement results, and the degree of the impact. These concentrations can be set for each target anticancer agent. Using the reference, it can be determined as described above.
  • N, N-dimethylglycine, 3-methylhistidine, N 5 -ethylglutamine, glutathione, dATP, butyric acid, triethanolamine, and 1-methylnicotine anti-tumor expression and anti-tumor expression change of anti-cancer agent exposure.
  • Drug sensitizers can be screened. That is, in vitro or in vivo, N, N-dimethylglycine, 3-methylhistidine, N 5 -ethylglutamine, glutathione, dATP, butyric acid, triethanolamine, and 1-methylin exposure Increases sensitivity to anticancer drugs.
  • N, N-dimethylglycine, 3-methylhistidine, N 5 -ethylglutamine, glutathione, dATP, butyric acid, triethanolamine, and 1-methine are small in N, N-dimethylglycine, 3-methylhistidine, and in vitro after exposure to anticancer agents.
  • a substance that enhances the sensitivity of the anticancer agent (anticancer agent sensitivity-enhancing agent).
  • N-Dimethylglycine 3-Methylhistidine , N 5 -Ethylglutamine, glutathione, dATP, Butyric acid, the variation of Triethanolamine, 1-Methylnicotinamide
  • the substance is a substance that enhances the sensitivity of the anticancer agent (anticancer agent sensitivity enhancing agent).
  • anticancer drug sensitivity-enhancing agents can be screened by using expression of Cysteine-glutathione, Adenine, and PRPP after exposure to anticancer agents, specifically, by promoting the change or reducing the concentration. That is, substances that promote or decrease the concentration of Cysteine-glutathione, Adenine, and PRPP after exposure to anticancer agents in vitro or in vivo enhance the sensitivity of anticancer agents.
  • a substance that promotes or lowers the concentration of Cysteine-glutathione, Adenine, and PRPP in cells after exposure to the anticancer drug is a substance that enhances the sensitivity of the anticancer drug (anticancer drug).
  • Agent sensitivity enhancer is screened by using expression of Cysteine-glutathione, Adenine, and PRPP after exposure to anticancer agents, specifically, by promoting the change or reducing the concentration. That is, substances that promote or decrease the concentration of Cysteine-glutathione, Adenine, and PRPP after exposure to anticancer agents in
  • substances that promote or reduce the concentration of Cysteine-glutathione, Adenine, and PRPP after exposure to anticancer drugs in cancer-bearing animals are substances that enhance the sensitivity of the anticancer drugs (anti-antigens). Cancer drug sensitivity enhancer).
  • an anticancer agent sensitivity-enhancing agent can be screened. That is, a substance that reduces the fluctuation of NADH and NAD + after exposure to an anticancer agent in vitro or in vivo enhances anticancer agent sensitivity.
  • a substance that reduces changes in NADH and NAD + in cells after exposure to an anticancer drug is a substance that enhances the sensitivity of the anticancer drug (anticancer drug sensitivity enhancer).
  • a substance that reduces the fluctuation of NADH and NAD + after exposure to an anticancer drug in a cancer-bearing animal is a substance that enhances the sensitivity of the anticancer drug (anticancer drug sensitivity enhancer). is there.
  • anticancer drug sensitivity enhancing agents can be screened. That is, a substance that lowers the concentration of GABA before exposure to an anticancer agent in vitro or in vivo, or a substance that promotes fluctuation or increases the concentration after exposure to an anticancer agent enhances anticancer agent sensitivity.
  • a substance that decreases the concentration of GABA in the cell is a substance that enhances the sensitivity of the anticancer drug ( Anticancer drug sensitivity enhancer).
  • substances that promote or increase the concentration of GABA in cells after exposure to anticancer drugs in various cancer cell lines are substances that enhance the sensitivity of the anticancer drugs (anticancer drugs).
  • Agent sensitivity enhancer In vivo, a substance that lowers the concentration of GABA before exposure to an anticancer agent in a cancer-bearing animal, or a substance that promotes or increases the concentration of GABA after exposure to an anticancer agent It is a substance that enhances the sensitivity of an agent (anticancer agent sensitivity enhancer).
  • anticancer drugs can be screened using the anticancer drug sensitivity determination marker of the present invention as an index. That is, if the concentration of the anticancer drug sensitivity determination marker varies in vitro or in vivo with a certain substance, the substance is an anticancer drug. For example, in vitro, if a substance is exposed to various cancer cell lines and the concentration of the anticancer drug sensitivity determination marker varies compared to before exposure, the substance is an anticancer drug. Moreover, if the concentration of the anticancer drug sensitivity determination marker varies after administration of a substance in a cancer-bearing animal, the substance is an anticancer drug.
  • the concentration variation of the anti-cancer drug sensitivity determination marker appears earlier than the tumor shrinkage or cell killing effect. Whether or not the substance is useful as an anticancer agent can be determined in a shorter time. A significant effect can be expected from the viewpoint of reducing labor and costs associated with the development of anticancer drugs.
  • the combined form of the anticancer agent sensitivity-enhancing agent and the anticancer agent targeted for sensitivity enhancement may be a single composition containing both of these components. There may be. In addition, these components may be different administration routes.
  • the anticancer agent to be used here is an anticancer agent containing oxaliplatin or a salt thereof and fluorouracil or a salt thereof, and other anticancer agents used in combination with this anticancer agent are particularly Examples include, but are not limited to, cyclophosphamide, ifosfamide, thiotepa, melphalan, busulfan, nimustine, ranimustine, ranimustine, (Procarbazine), temozolomide, cisplatin, carboplatin , Nedaplatin, methotrexate, pemetrexed, uracil, doxifluridine, gimeracil / eteracin, eitabine, citabin, eitabine 6-mercaptopurine, fludarabine, pentostatin, cladribine, hydroxyurea, doxorubicin, epirubicin ubicin, daunorubicin, idarubic
  • a combination with one or more anticancer agents selected from irinotecan, SN-38, cetuximab, bevacizumab, dasatinib, panitumumab, hololinate and levofolinate is preferable, and particularly selected from irinotecan, cetuximab, bevacizumab, hololinate and levofolinate.
  • Combinations of the above anticancer agents are preferred, and examples of combinations of oxaliplatin or a salt thereof and an anticancer agent containing fluorouracil or a salt thereof include levofolinate, holinato, levofolinate and bevacizumab; holinato and bevacizumab; Cetuximab; folinate and cetuximab; or irinotecan.
  • Example 1 (1) Method (a) Cells used Two types of human colon cancer cell lines (high sensitivity: HCT116, low sensitivity: DLD-1) were used. HCT116 was obtained from Yakult Honsha Co., Ltd., and DLD-1 was obtained from Dainippon Sumitomo Pharma Co., Ltd. These cells were treated at 37 ° C., 5% CO 2 at 37 ° C. and 5% CO 2 using a Doublebeco's modified Eagle's Medium (DMEM) containing 10% Fetal Bovine Serum (Invitrogen) at ⁇ 100 mm / Tissue Culture Disc (IWAKI). Cultured under.
  • DMEM Doublebeco's modified Eagle's Medium
  • IWAKI Tissue Culture Disc Cultured under.
  • Drug L-OHP bulk powder was obtained from Yakult Honsha Co., Ltd. 5-FU bulk powder was obtained from Sigma-Aldrich Japan Co., Ltd.
  • N N-dimethylglycine, 3-methylhistidine, N 5 -ethylglutamine, glutathione, dATP, and Butyric acid , Triethanolamine, 1-Methylnicotinamide.
  • Cysteine-glutathione, Adenine, and PRPP were found as metabolites in which the intracellular level was significantly decreased after exposure to 5-FU / L-OHP in highly sensitive cells.
  • NADH and NAD + were found as metabolites in which intracellular cells showed a marked decrease in intracellular levels after exposure to 5-FU / L-OHP in low-sensitivity cells.
  • Example 2 Study in human clinical trial using mFOLFOX6 therapy combined with bevacizumab Method Cancer chemotherapy (concomitant use of bevacizumab) with fluorouracil 400 mg / square meter (rapid IV), levofolinate 200 mg / square meter, fluorouracil 2,400 mg / square meter (continuous infusion) with oxaliplatin 85 mg / square meter, bevacizumab 5 mg / kg In a cancer patient who performed mFOLFOX6 therapy), the efficacy and safety of cancer chemotherapy was examined, and a phase II clinical trial was conducted in which an exploratory study was also conducted on the individual difference factors.
  • the subjects were unresectable advanced / recurrent cases and no prior treatment with chemotherapy, immunotherapy or radiotherapy.
  • Specific selection criteria include (1) histopathologically confirmed cases of colon cancer or rectal cancer, (2) advanced / recurrent cases that cannot be resected, and (3) have measurable lesions.
  • Cases (4) Cases without prior treatment with chemotherapy, immunotherapy or radiotherapy (only postoperative adjuvant chemotherapy with fluorouracil drugs can be registered if completed 6 months before the recurrence confirmation date) , (5) Cases where the age at the time of registration is 20 years or older, (6) Cases where Performance status (ECOG scale) is 0 or 1, (7) Cases that can be expected to survive for more than 3 months, (8) Major organ functions Patients who do not have a high degree of damage (bone marrow, liver, kidney, heart, lung, etc.) and clinical laboratory values conducted within 14 days (not including the registration date) before registration meet the following criteria.
  • the metabolome contained in the patient serum before the start of drug administration in each cycle was analyzed simultaneously by CE-TOFMS for 13 cases in which the test treatment was completed early.
  • the metabolome extraction method, metabolome measurement, and data analysis were in accordance with Example 1.
  • the patient's treatment sensitivity was determined based on the best overall effect (the best effect recorded from the start of treatment to exacerbation / relapse).

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US10481160B2 (en) 2019-11-19
US20150038522A1 (en) 2015-02-05
EP3326632A1 (en) 2018-05-30
JP2018169409A (ja) 2018-11-01
EP3326632B1 (en) 2021-04-07
JP6381735B2 (ja) 2018-08-29
CN104169721A (zh) 2014-11-26

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