2006 Fiscal Year Final Research Report Summary
Elucidation of adverse events of methotrexate based on genomic and proteomic analysis in childhood leukemia patients
| Project/Area Number |
17590122
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Kobe University |
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Principal Investigator |
SAKAEDA Toshiyuki Kobe University Hospital, School of Medicine, Associate Professor, 医学部附属病院, 助教授 (00304098)
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| Co-Investigator(Kenkyū-buntansha) |
OKUMURA Katsuhiko Kobe University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (60025707)
OKAMURA Noboru Kobe University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (60379401)
YAGI Mariko Kobe University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (60362787)
TAKESHIMA Yasuhiro Kobe University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (40281141)
NAKAMURA Tsutomu Kobe University Hospital, School of Medicine, Pharmacist, 医学部附属病院, 薬剤師 (80379411)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Methotrexate / Acute lymphoblastic leukemia / Malignant lymphoma / Genetic polymorphism / Glutathione S-transferase / Reduced folate carrier |
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| Research Abstract |
Methotrexate is administered in high doses to treat childhood acute lymphoblastic leukemia and malignant lymphoma. Hepatotoxicity and bone marrow suppression often limit its use, however. We tried to determine the genetic polymorphisms associated with the hepatotoxicity and elimination of methotrexate. Genetic polymorphisms of glutathione S-transferase (GST) genes including GSTT1 positive/null, GSTM1 positive/null, and GSTP1 A313G, and genes for reduced folate carrier 1G80A (RFC1 G80A), methylenetetrahydrofolate reductase C677T (MTHFR C677T), and breast cancer resistant protein C421A (BCRP C421A) were determined for 26 patients by the polymerase chain reaction (PCR) method or by direct sequencing. A high frequency of hepatotoxicity (P = 0.035) was observed for patients with GSTM1 positive and RFC1 AA(80), and serum concentrations of methotrexate 48 h after the start of infusion were higher for patients with the TT(677) genotype of MTHFR (P = 0.028). In conclusion, GSTM1 positive/null and RFC1 G80A polymorphisms could be predictors for hepatotoxicity, and the MTHFR C677T polymorphism.is associated with elimination of methotrexate.
In addition, asparaginase-induced acute pancreatitis is a critical problem in maintenance therapy. We tried to clarify the genetic polymorphisms associated with pancreatitis, but no polymorphism to predict pancreatitis was found.
Theses results could be useful information in treatment for childhood acute lymphoblastic leukemia and malignant lymphoma.
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