Homocysteine, Pharmacogenetics, and Neurotoxicity in Children With Leukemia

Abstract

Purpose: Despite its clinical success, methotrexate (MTX) therapy is associated with toxicities such as seizures, the pathogenesis of which remains unclear. It has been suggested that hyperhomocysteinemia is caused by MTX and is responsible for its neurotoxic effects. The purposes of this study were to explore whether hyperhomocysteinemia was related to MTX administration and toxicity and whether homocysteine or MTX toxicity differed by methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier (RFC) genetic polymorphisms. Patients and Methods: We studied 53 children with newly diagnosed acute lymphoblastic leukemia who were consecutively treated on a single clinical protocol that included two courses of high-dose MTX (high-dose methotrexate [HDMTX]; 2.5 or 5.0 g/m2 per day) as consolidation therapy. Results: The study participants’ median plasma homocysteine concentrations at 23 and 44 hours after HDMTX (9.00 μmol/L and 10.12 μmol/L, respectively) were greater than the concentrations immediate...