ELEVATION OF HOMOCYSTEINE AND EXCITATORY AMINO-ACID NEUROTRANSMITTERSIN THE CSP OF CHILDREN WHO RECEIVE METHOTREXATE FOR THE TREATMENT OF CANCER

Purpose: Folate deficiency, either by diet or drug, increases plasma h omocysteine (Hcy). Hcy damages cerebrovascular endothelium, and hyperh omocysteinemia is a risk factor for stroke, Hey is metabolized to exci tatory amino acid (EAA) neurotransmitters, such as homocysteic acid (H CA) and cysteine sulfinic acid (CSA), which may cause seizures and exc itotoxic neuronal death. We postulated that excess Hcy and EAA neurotr ansmitters may partly mediate methotrexate (MTX)-associated neurotoxic ity. Patients and Methods: In this retrospective analysis, we used hig h-performance liquid chromatography (HPLC) to measure Hey, HCA, and CS A in CSF from two groups of children: (1) a control group of patients with no MTX exposure, and (2) a treatment group of patients who had re ceived MTX no mare than 7 days before a scheduled lumbar puncture. Res ults: The treatment group had a significantly (P = .0255) greater conc entration of Hcy in CSF (0.814 mu mol/L +/-0.215 [mean +/- SEM], n = 2 3) than the control group (0.210 mu mol/L +/- 0.028, n = 34). HCA and CSA were not detected in CSF from control patients (n = 29); however, MTX caused marked accumulation of CSF HCA (119.1 mu mol/L +/- 32.0, n = 16) and CSA (28.4 mu mol/L +/- 7.7, n = 16) in the treatment group, patients with neurologic toxicity at the time of lumbar puncture had m any of the highest concentrations of Hey, HCA, and CSA. Conclusion: Th ese data support our hypothesis that MTX-associated neurotoxicity may be mediated by Hcy and excito-toxic neurotransmitters. (C) 1997 by Ame rican Society of Clinical Oncology.