382 DECREASED FOLATE ASSOCIATED WITH METHOTREXATE POLY GLUTAMATE ACCUMULATION IN CHRONICALLY TREATED MONKEYS

Abstract

Methotrexate (MTX) a mainstay of continuation therapy for acute lymphoblastic leukemia is associated with hepatic and neurotoxicity. The metabolism of MTX to polyglutamates (MTXGLUn), which have long intracellular halflives may be partially responsible for these toxicities. In an effort to model the pharmacodynamics of repetitive, low dose MTX and the folate deficiency previously shown in red cells and livers from patients, the tissue content of MTX and folate from monkeys treated for 1 yr with 50 mgMTX/m2 was analyzed. In addition, the MTXGLUn profiles were also determined by HPLC and radioligand binding assay. The MTX content (pmol/g wet weight) of liver, kidney, brain, testes were 2817, 836 4.9 and 44 respectively. The folate content (pmol/g wet weight) of these same tissues was 11500, 4485, 32 and 474. Control values for folates were 31064, 6500, 286 and 1355 respectively. The predominant MTX derivative(s) found were MTXGLU3-5 but GLU6-7 were easily detectable. Of special interest was the significant folate deficiency found in the brain (90% loss compared to control). Since inborn errors of folate metabolism often present with severe neurological problems not unlike those associated with MTX toxicity (including cerebral calcifications), the biochemical abnormalities associated with repetitive, low dose MTX therapy and its attendant folate deficiency may be responsible for the observed toxicity. Supported by ACS CH228, a scholar award of the Leukemia Society of America, and the NCI.