title: Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood acute lymphoblastic leukemia and malignant lymphoma.
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. The objective of this study was 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 1 G80A (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.
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Imanishi
authors.affiliation: Department of Clinical Evaluation of Pharmacotherapy, Kobe University Graduate School of Medicine, 1-5-6, Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Okamura
authors.affiliation: Department of Clinical Evaluation of Pharmacotherapy, Kobe University Graduate School of Medicine, 1-5-6, Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Yagi
authors.affiliation: Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Noro
authors.affiliation: Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Moriya
authors.affiliation: Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hayakawa
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeshima
authors.affiliation: Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
authors.affiliation: Department of Clinical Evaluation of Pharmacotherapy, Kobe University Graduate School of Medicine, 1-5-6, Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan. okumurak@med.kobe-u.ac.jp.|Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. okumurak@med.kobe-u.ac.jp.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Okumura
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007223:Infant; D008107:Liver Diseases / Q000235:genetics*; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D012307:Risk Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D008727:Methotrexate; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C413545:glutathione S-transferase T1; C496556:GSTP1 protein, human