WO2013125675A1 - 併用抗がん剤の感受性判定マーカー - Google Patents
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- 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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- 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
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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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Abstract
Description
さらに、大腸癌患者血液検体を対象とし、血中代謝物をCE-TOFMSを用いて網羅的に解析した結果、ベバシズマブ併用mFOLFOX6療法に対する治療反応性の低い患者で血中GABAレベルが高いことを見出した。
かかる知見に基づき、さらに検討した結果、がん患者由来の生体試料中のこれら代謝物の濃度を指標とすれば、当該がん患者のがんが抗がん剤に対する感受性を有するか否かを判定できること、また、これら代謝物の濃度や変動を指標とすれば抗がん剤感受性亢進剤のスクリーニングが可能になること、さらに当該抗がん剤感受性亢進剤と感受性亢進の対象となる抗がん剤を併用すれば、当該抗がん剤の治療効果が飛躍的に向上することを見出し、本発明を完成した。
また、本発明は、検体中の上記の物質を測定することを特徴とするオキサリプラチン又はその塩とフルオロウラシル又はその塩を含む抗がん剤の感受性判定方法を提供するものである。
また、本発明は、検体中の上記の物質を測定するためのプロトコールを含むことを特徴とするオキサリプラチン又はその塩とフルオロウラシル又はその塩を含む抗がん剤の感受性判定方法を実施するためのキットを提供するものである。
さらに本発明は、上記の物質の発現変動を指標とするオキサリプラチン又はその塩とフルオロウラシル又はその塩を含む抗がん剤に対する感受性亢進剤のスクリーニング方法を提供するものである。
さらにまた本発明は、上記のスクリーニング方法により得られたオキサリプラチン又はその塩とフルオロウラシル又はその塩を含む抗がん剤に対する感受性亢進剤を提供するものである。
さらに本発明は、上記の抗がん剤感受性亢進剤と、オキサリプラチン又はその塩とフルオロウラシル又はその塩を含む抗がん剤を含有するがん治療用組成物を提供するものである。
対象とする抗がん剤に対して感受性を有さない場合は、その薬効を期待することができず、このような薬効の期待できない抗がん剤の投与が続けられた場合、がんの進行、副作用の増大が危惧される。このように、本発明における抗がん剤感受性判定マーカーは、抗がん剤治療反応性の判定のみならず、薬効の期待できない抗がん剤の継続投与に伴う副作用の増大を防ぐことにも大きく貢献する。
対象とする抗がん剤に対して感受性を有さない場合は、その薬効を期待することができず、このような薬効の期待できない抗がん剤の投与が続けられた場合、がんの進行、副作用の増大が危惧される。このように、本発明における抗がん剤感受性判定マーカーは、抗がん剤治療反応性の判定のみならず、薬効の期待できない抗がん剤の継続投与に伴う副作用の増大を防ぐことにも大きく貢献する。
対象とする抗がん剤に対して感受性を有さない場合は、その薬効を期待することができず、このような薬効の期待できない抗がん剤の投与が続けられた場合、がんの進行、副作用の増大が危惧される。このように、本発明における抗がん剤感受性判定マーカーは、抗がん剤治療反応性の判定のみならず、薬効の期待できない抗がん剤の継続投与に伴う副作用の増大を防ぐことにも大きく貢献する。
対象とする抗がん剤に対して感受性を有さない場合は、その薬効を期待することができず、このような薬効の期待できない抗がん剤の投与が続けられた場合、がんの進行、副作用の増大が危惧される。このように、本発明における抗がん剤感受性判定マーカーは、抗がん剤治療反応性の判定のみならず、薬効の期待できない抗がん剤の継続投与に伴う副作用の増大を防ぐことにも大きく貢献する。
対象とする抗がん剤に対して感受性を有さない場合は、その薬効を期待することができず、このような薬効の期待できない抗がん剤の投与が続けられた場合、がんの進行、副作用の増大が危惧される。このように、本発明における抗がん剤感受性判定マーカーは、抗がん剤治療反応性の判定のみならず、薬効の期待できない抗がん剤の継続投与に伴う副作用の増大を防ぐことにも大きく貢献する。
(1)方法
(a)使用細胞
2種類のヒト大腸癌細胞株(高感受性:HCT116、低感受性:DLD-1)を用いた。HCT116は株式会社ヤクルト本社より、DLD-1は大日本住友製薬株式会社より入手した。これらの細胞は、10% Fetal Bovine Serum (インビトロジェン社) を含むDoulbecco’s modified Eagle’s Medium(DMEM) を用いて、φ100mm/Tissue Culture Dish(IWAKI)にて37℃、5%CO2の条件下で培養した。
(b)薬剤
L-OHP原末は、株式会社ヤクルト本社より入手した。また、5-FU原末は、シグマアルドリッチジャパン株式会社より入手した。
両細胞に対して、100μmol/Lの5-FU及び10μmol/LのL-OHPを含む培地に交換することにより抗がん剤曝露を開始した(抗がん剤を含まない培地を用いたものをコントロール群とした)。0hr、4hr、12hr、24hr、48hr曝露後に氷上にて5%マンニトール(4℃)で細胞を洗浄後、素早くメタノール(4℃、内部標準物質含有)を添加することにより酵素を失活させ、-80℃で保存した。なお、細胞数算出用の細胞を代謝物抽出用の細胞とは別に準備し、同様の処理を行った後セルカウントを行い、細胞数補正に用いた。
-80℃保存メタノール溶液に、クロロホルムとミリQ水を加え液―液抽出を行い、夾雑成分を除去した。代謝物を含む水―メタノール層を採取し、分画分子量5000Daの遠心限外ろ過フィルターを用いて除タンパクを行った後、ろ液を減圧乾燥し、-80℃にて保存した。測定直前にミリQ水に溶解させ、メタボローム測定に供した。
細胞内代謝物の網羅的測定はAgilent Technologies社のキャピラリー電気泳動―飛行時間型質量分析計(CE-TOFMS)にて行った。陽イオン性代謝物の網羅的測定ではキャピラリーの出口が陰極となるように電圧を印加し、また、陰イオン性代謝物の網羅的測定ではキャピラリーの出口が陽極となるように電圧を印加し、m/z=50~1000の代謝物を一斉に定量分析した。
各細胞サンプルからCE-TOFMSにより検出されたピークは、既にm/z及び移動時間が明らかとなっている約500の標品データとの照合により同定した。代謝物量はピーク面積を内部標準物質のピーク面積で除し、標本による差を補正した。
感受性の異なる2種類のヒト大腸癌細胞(高感受性:HCT-116、低感受性:DLD-1)について、5-FU/L-OHP 24時間曝露後の細胞内メタボロームデータに着目し、5-FU/L-OHP曝露後に変動が認められた代謝物をピックアップした(図1)。その結果、高感受性細胞で5-FU/L-OHP曝露後細胞内レベルの顕著な上昇が認められる代謝物として、Asp、Gly、Arg、N-Acetyl-beta-alanine、N-Acetylornithine、Cadaverine、Cysteic acid、2-Aminoadipic acid、GABA(gamma-aminobutyric acid)、gamma-Glu-Cys、beta-Ala-Lys、Glu-Glu、S-Lactoylglutathione、Guanosine、CMP、UMP、1-Methyladenosine、UDP、CTP、Sedoheptulose 7-phosphate、Dihydroxyacetone phosphate、2,3-diphosphoglyceric acid、Pyruvic acid、Malic acid、N1-アセチルスペルミン、N-アセチルプトレシン、N8-アセチルスペルミジン、プトレシン、スペルミン、スペルミジン、7,8-Dihydrobiopterin、6-Phosphogluconic acidを見出した。また、低感受性細胞で5-FU/L-OHP曝露後細胞内レベルの顕著な上昇が認められる代謝物として、N,N-Dimethylglycine、3-Methylhistidine、N5-Ethylglutamine、glutathione、dATP、Butyric acid、Triethanolamine、1-Methylnicotinamideを見出した。また、高感受性細胞で5-FU/L-OHP曝露後細胞内レベルの顕著な低下が認められる代謝物として、Cysteine-glutathione、Adenine、PRPPを見出した。また、低感受性細胞で5-FU/L-OHP曝露後細胞内レベルの顕著な低下が認められる代謝物として、NADH、NAD+を見出した。
ベバシズマブ併用mFOLFOX6療法によるヒト臨床試験による検討
1.方法
フルオロウラシル400mg/平方メートル(急速静注)、レボホリナート200mg/平方メートル、フルオロウラシル2,400mg/平方メートル(持続点滴静注)にオキサリプラチン85mg/平方メートル、ベバシズマブ5mg/kgを併用投与するがん化学療法(ベバシズマブ併用mFOLFOX6療法)を実施したがん患者において、がん化学療法の有効性及び安全性を検討するとともに、それらの個体差要因についても探索的検討を実施する第2相臨床試験を行った。対象は切除不能な進行・再発症例であり、且つ化学療法、免疫療法又は放射線療法による前治療のない症例とした。具体的な選択基準は、(1)病理組織学的に結腸癌あるいは直腸癌であることが確認されている症例、(2)治癒切除不能な進行・再発症例、(3)測定可能病変を有する症例、(4)化学療法、免疫療法または放射線療法による前治療のない症例(フルオロウラシル系薬剤による術後補助化学療法に限り、再発確認日から6ヶ月前に終了していれば登録可能とする)、(5)登録時の年齢が20歳以上の症例、(6)Performance status(ECOG scale)が0または1の症例、(7)3ヶ月以上の生存が期待できる症例、(8)主要臓器機能(骨髄、肝、腎、心、肺など)に高度な障害が無く、かつ登録前14日以内(登録日を含めず)に実施した臨床検査値が以下の基準を満たす症例。白血球数4,000/立方ミリメートル以上12,000/立方ミリメートル以下、好中球数2,000/立方ミリメートル以上、ヘモグロビン量9.0g/dL以上、血小板数100,000/立方ミリメートル以上、AST100IU/L以下、ALT100IU/L以下、総ビリルビン1.5mg/dL以下、血清クレアチニン1.5mg/dL以下、尿蛋白1+以下(定性)、プロトロンビン時間国際標準比表示1.5以下。(9)本試験登録前に、遺伝子多型検査やプロテオーム・メタボローム分析を含む試験の参加について、患者本人による署名、日付が記載された同意書が得られている症例、とし、除外基準を、(1)登録前14日以内に輸血、血液製剤およびG-CSF等の造血因子製剤の投与を行った症例、(2)重篤な薬剤過敏症の既往を有する症例、(3)同時性および無病期間が5年未満の異時性重複癌を有する症例、(4)感覚異常または知覚不全のある症例、(5)臨床上問題となる感染症を有する症例、(6)HBs抗原陽性の症例、(7)登録前28日以内の心電図等で、臨床上問題となる心疾患を有する症例、(8)胸部単純X線像等にて明らかな間質性肺炎、肺線維症を有する症例、(9)治療を必要とする胸水、腹水または心嚢水を有する症例、(10)下痢(水様便を含む)を呈する症例、(11)脳転移を有することが明らかな症例、または臨床的な症状から脳転移が疑われる症例、(12)血栓塞栓症の既往を有する症例、(13)登録前28日以内に開腹術または腸管切除術、登録前14日以内にストーマの造設、切開を伴う生検、または外傷に対する縫合処置を行った症例、(14)血小板機能を抑制する薬剤(アスピリン製剤あるいは非ステロイド抗炎症薬を投与中の症例、(15)コントロール不良な消化管潰瘍を有する症例、(16)過去12ヶ月以内に消化管穿孔の既往を有する症例、(17)コントロール不良な高血圧を有する症例、(18)コントロール不良な糖尿病を有する症例、(19)強心配糖体を投与中の症例、(20)精神病または精神症状を合併しており試験への参加が困難と判断される症例、(21)妊娠中または授乳中の女性、授児を希望する男女、避妊する意思のない男女、(22)担当医師が本試験の有効性・安全性を評価するのに不適当と判断した症例、とした。試験治療として各サイクル第1日目にベバシズマブ、オキサリプラチン、フルオロウラシル(急速静注)、レボホリナート、第1日目から第3日目にかけてフルオロウラシル(持続点滴静注)の投与を行った。1サイクルを2週間(14日間)とし、中止基準に該当しない限り最大24サイクルまで投与を行った。
患者の治療感受性を最良総合効果に基づいて判定した結果、13例中、安定(SD)症例は6例、部分奏効(PR)症例は7例であった。各サイクルにおける薬剤投与開始前の患者血清中に含まれるメタボロームをCE-TOFMSにて一斉解析した結果、部分奏効(PR)症例の血中GABAレベルは全症例で低く、安定(SD)症例6例中4例で血中GABAレベルが高いことが明らかとなった(図3)。
Claims (16)
- アミノ酸代謝系上の物質、核酸代謝系上の物質、ペントースリン酸経路上の物質、解糖系上の物質、TCA回路上の物質、ポリアミン代謝系上の物質並びに7,8-Dihydrobiopterin、6-Phosphogluconic acid、Butyric acid、Triethanolamine、1-Methylnicotinamide、NADH、NAD+及びそれら分子が関与する代謝系上の物質から選ばれる1以上の分子からなる、オキサリプラチン又はその塩とフルオロウラシル又はその塩を含む抗がん剤の感受性判定マーカー。
- アミノ酸代謝系上の物質が、Asp、Gly、Arg、N-Acetyl-beta-alanine、N-Acetylornithine、Cadaverine、Cysteic acid、2-Aminoadipic acid、GABA、gamma-Glu-Cys、beta-Ala-Lys、Glu-Glu、S-Lactoylglutathione、N,N-Dimethylglycine、3-Methylhistidine、N5-Ethylglutamine、glutathione及びCysteine-glutathioneから選ばれる1以上の分子である請求項1記載の感受性判定マーカー。
- 核酸代謝系上の物質が、Guanosine、CMP、UMP、1-Methyladenosine、UDP、CTP、dATP及びAdenineから選ばれる1以上の分子である請求項1記載の感受性判定マーカー。
- ペントースリン酸経路上の物質が、Sedoheptulose 7-phosphate及び/又はPRPPである請求項1記載の感受性判定マーカー。
- 解糖系上の物質が、Dihydroxyacetone phosphate、2,3-diphosphoglyceric acid及びPyruvic acidから選ばれる1以上の分子である請求項1記載の感受性判定マーカー。
- TCA回路上の物質が、Malic acidである請求項1記載の感受性判定マーカー。
- ポリアミン代謝系上の物質が、N1-アセチルスペルミン、N-アセチルプトレシン、N8-アセチルスペルミジン、プトレシン、スペルミン及びスペルミジンから選ばれる1以上の分子である請求項1記載の感受性判定マーカー。
- 検体中の請求項1~7のいずれか1項記載の物質を測定することを特徴とするオキサリプラチン又はその塩とフルオロウラシル又はその塩を含む抗がん剤の感受性判定方法。
- 検体が、がんを有する被験者由来の生体試料である請求項8記載の判定方法。
- 検体が、オキサリプラチン又はその塩とフルオロウラシル又はその塩を含む抗がん剤を投与された、がんを有する被験者由来の生体試料である請求項8又は9記載の判定方法。
- 検体中の請求項1~7のいずれか1項記載の物質を測定するためのプロトコールを含むことを特徴とする請求項8~10のいずれか1項記載の判定方法を実施するためのキット。
- 検体が、がんを有する被験者由来の生体試料である請求項11記載のキット。
- 検体が、オキサリプラチン又はその塩とフルオロウラシル又はその塩を含む抗がん剤を投与された、がんを有する被験者由来の生体試料である請求項11又は12記載のキット。
- 請求項1~7のいずれか1項記載の物質の発現変動を指標とするオキサリプラチン又はその塩とフルオロウラシル又はその塩を含む抗がん剤に対する感受性亢進剤のスクリーニング方法。
- 請求項14記載の方法により得られたオキサリプラチン又はその塩とフルオロウラシル又はその塩を含む抗がん剤に対する感受性亢進剤。
- 請求項15記載の感受性亢進剤と、オキサリプラチン又はその塩とフルオロウラシル又はその塩を含む抗がん剤を含有するがん治療用組成物。
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EP17202053.9A EP3326632B1 (en) | 2012-02-23 | 2013-02-22 | Combined anticancer drug sensitivity-determining marker |
US14/379,945 US9733256B2 (en) | 2012-02-23 | 2013-02-22 | Combined anticancer drug sensitivity-determining marker |
CN201380010388.7A CN104169721A (zh) | 2012-02-23 | 2013-02-22 | 并用抗癌剂的感受性判定标记 |
EP13752246.2A EP2818870A4 (en) | 2012-02-23 | 2013-02-22 | COMBINED MARKER FOR DETERMINING THE SENSITIVITY TO ANTICREMENT |
JP2014500945A JP6141824B2 (ja) | 2012-02-23 | 2013-02-22 | 併用抗がん剤の感受性判定マーカー |
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EP3326632A1 (en) | 2012-02-23 | 2018-05-30 | Keio University | Combined anticancer drug sensitivity-determining marker |
WO2018181759A1 (ja) | 2017-03-31 | 2018-10-04 | 学校法人慶應義塾 | 併用抗がん剤の感受性の判定マーカー |
WO2019188446A1 (ja) | 2018-03-29 | 2019-10-03 | 学校法人慶應義塾 | イリノテカンを含む抗がん剤療法の感受性判定マーカー |
WO2020067228A1 (ja) | 2018-09-28 | 2020-04-02 | 学校法人慶應義塾 | 併用抗がん剤の感受性の判定マーカー |
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EP3812009A1 (en) | 2012-02-23 | 2021-04-28 | Keio University | Combined anticancer drug sensitivity-determining marker |
WO2018181759A1 (ja) | 2017-03-31 | 2018-10-04 | 学校法人慶應義塾 | 併用抗がん剤の感受性の判定マーカー |
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WO2020067228A1 (ja) | 2018-09-28 | 2020-04-02 | 学校法人慶應義塾 | 併用抗がん剤の感受性の判定マーカー |
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