title: Association between polymorphisms of dihydrofolate reductase and gamma glutamyl hydrolase genes and toxicity of high dose methotrexate in children with acute lymphoblastic leukemia.
abstract: Methotrexate (MTX) is an important drug for the treatment of childhood acute lymphoblastic leukemia (ALL). However, related toxicity occurs in many organs which may cause interruption of treatment, morbidity, and mortality. Single nucleotide polymorphisms (SNPs) of dihydrofolate reductase (DHFR) and gamma glutamyl hydrolase (GGH) are known to alter their enzymatic activity and thus affect the metabolism of MTX and influence the effectiveness. Therefore, we hypothesized that genetic variations of DHFR and GGH genes may influence the risk of toxicity after high dose MTX. The study population comprised of 105 children with ALL who were treated according to the modified St Jude Total XV protocol. The patients received 2.5 or 5 g/m2 of MTX for 5 doses during the consolidation phase. Genotyping of DHFR 829C>T and GGH -401C>T was performed using a polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). The GGH-401CT and TT genotypes were associated with increased risk of leukopenia and thrombocytopenia after high dose MTX (OR 2.97, 95%CI; 1.24-7.13 and OR 4.02, 95%CI; 1.58-10.26). DHFR 829C>T was not associated with toxicity. In conclusion, the GGH -401CT and TT genotypes were found to increase the risk of severe leukopenia and thrombocytopenia after exposure to high dose MTX for childhood ALL therapy.
authors.affiliation: Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Napatrupron
authors.initials: N
authors.lastname: Koomdee
authors.forename: Suradej
authors.initials: S
authors.lastname: Hongeng
authors.forename: Suntaree
authors.initials: S
authors.lastname: Apibal
authors.forename: Samart
authors.initials: S
authors.lastname: Pakakasama
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007223:Infant; D007970:Leukopenia / Q000209:etiology / Q000235:genetics; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D013921:Thrombocytopenia / Q000209:etiology / Q000235:genetics; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics*
chemical_list: D013762:Tetrahydrofolate Dehydrogenase; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate