title: Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma.
abstract: The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism. The authors studied 15 children with acute lymphoblastic leukemia or lymphoblastic lymphoma who were treated using protocols that included high-dose methotrexate (3.0 g/m), for an overall total of 43 courses. Methotrexate-induced toxicities and the plasma methotrexate concentrations were evaluated retrospectively. Hematologic toxicity was the most frequently observed toxicity, appearing in 87% of the patients. In a subset of patients (47%), elevation of liver transaminase levels showed a repeated tendency to develop. High plasma methotrexate concentrations at 48 hours after the methotrexate infusion were not significantly related to methotrexate-induced toxicities except for mucositis. A generalized estimating equation analysis revealed that vomiting during the high-dose methotrexate treatment was more pronounced in patients who had a larger number of G alleles at the RFC1 80G>A polymorphism. No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms. This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Shimasaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mori
authors.forename: Hazuki
authors.initials: H
authors.lastname: Samejima
authors.forename: Reiko
authors.initials: R
authors.lastname: Sato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Naohisa
authors.initials: N
authors.lastname: Yahagi
authors.forename: Chiharu
authors.initials: C
authors.lastname: Torii
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoshihara
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tanigawara
authors.forename: Takao
authors.initials: T
authors.lastname: Takahashi
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kosaki
mesh_terms: D000293:Adolescent; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006402:Hematologic Diseases / Q000139:chemically induced* / Q000235:genetics; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000633:toxicity*; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D012189:Retrospective Studies; D013280:Stomatitis / Q000139:chemically induced
chemical_list: D000964:Antimetabolites, Antineoplastic; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate