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2006 Fiscal Year Final Research Report Summary

Elucidation of adverse events of methotrexate based on genomic and proteomic analysis in childhood leukemia patients

Research Project

Project/Area Number 17590122
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionKobe University

Principal Investigator

SAKAEDA Toshiyuki  Kobe University Hospital, School of Medicine, Associate Professor, 医学部附属病院, 助教授 (00304098)

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)
Project Period (FY) 2005 – 2006
KeywordsMethotrexate / Acute lymphoblastic leukemia / Malignant lymphoma / Genetic polymorphism / Glutathione S-transferase / Reduced folate carrier
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.

  • Research Products

    (12 results)

All 2007 2006 2005

All Journal Article (12 results)

  • [Journal Article] Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood acute lymphoblastic leukemia and malignant lymphoma.2007

    • Author(s)
      Imanishi H
    • Journal Title

      J Hum Genet 第52巻・第2号

      Pages: 166-171

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood lymphoblastic leukemia and malignant lymphoma.2007

    • Author(s)
      Imanishi H
    • Journal Title

      Journal of Human Genetics 52-2

      Pages: 166-171

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] MDR1 C3435T polymorphism is predictive of later onset of ulcerative colitis in Japanese.2006

    • Author(s)
      Osuga T
    • Journal Title

      Biol Pharm Bull 第29巻・第2号

      Pages: 324-329

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Prediction of systemic exposure to cyclosporine in Japanese pediatric patients.2006

    • Author(s)
      Sakaeda T
    • Journal Title

      J Hum Genet 第51巻・第11号

      Pages: 969-976

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] MDR1 haplotype frequencies in Japanese and Caucasian, and in Japanese patients with colorectal cancer and esophageal cancer.2006

    • Author(s)
      Komoto C
    • Journal Title

      Drug Metab Pharmacokinet 第21巻・第2号

      Pages: 126-132

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] MDR1 C3435T polymorphism is predictive of later onset of ulcerative colitis in Japanese.2006

    • Author(s)
      Osuga T
    • Journal Title

      Biological Pharmaceutical Bulletin 29-2

      Pages: 324-329

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Prediction of systemic exposure to cyclosporine in Japanese pediatric patients.2006

    • Author(s)
      Sakaeda T
    • Journal Title

      Journal of Human Genetics 51-11

      Pages: 969-976

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] MDR1 haplotype frequencies in Japanese and Caucasian, and in Japanese patients with colorectal cancer and esophageal cancer.2006

    • Author(s)
      Komoto C
    • Journal Title

      Drug Metabolism and Pharmacokinetics 21-2

      Pages: 126-132

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Cyclosporin A absorption profiles in children with nephrotic syndrome.2005

    • Author(s)
      Nozu K
    • Journal Title

      Pediatr Nephrol 第20巻・第7号

      Pages: 910-913

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Simultaneous determination of single nucleotide polymorphisms of MDR1 genes by electrochemical DNA chip.2005

    • Author(s)
      Nakamura T
    • Journal Title

      Drug Metab Pharmacokinet 第20巻・第3号

      Pages: 219-225

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Cyclosporin A absorption profiles in children with nephrotic syndrome.2005

    • Author(s)
      Nozu K
    • Journal Title

      Pediatric Nephrology 207-7

      Pages: 910-913

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Simultaneous determination of single nucleotide polymorphisms of MDR1 genes by electrochemical DNA chip.2005

    • Author(s)
      Nakamura T
    • Journal Title

      Drug Metabolism and Pharmacokinetics 20-3

      Pages: 219-225

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2008-05-27  

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