Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood acute lymphoblastic leukemia and malignant lymphoma.
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.
Imanishi
Hiroyuki
H
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
Okamura
Noboru
N
Department of Clinical Evaluation of Pharmacotherapy, Kobe University Graduate School of Medicine, 1-5-6, Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
Yagi
Mariko
M
Department of Clinical Evaluation of Pharmacotherapy, Kobe University Graduate School of Medicine, 1-5-6, Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
Noro
Yukari
Y
Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
Moriya
Yuka
Y
Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
Nakamura
Tsutomu
T
Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
Hayakawa
Akira
A
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
Takeshima
Yasuhiro
Y
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
Sakaeda
Toshiyuki
T
Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
Matsuo
Masafumi
M
Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
Okumura
Katsuhiko
K
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.
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
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