Changes of cerebral biopterin and biogenic amine metabolism in leukemic children receiving 5 g/m2 intravenous methotrexate.

Abstract

Acute or subacute neurologic disorders can be observed in patients receiving high-dose methotrexate therapy for lymphoblastic leukemia or malignant tumor. Impairment of biopterin metabolism leading to decreased availability of monoamine neurotransmitters has been suggested to explain methotrexate neurotoxicity. To investigate such a mechanism, we have measured prospectively by HPLC the concentrations of total biopterin, homovanillic acid, and 5-hydroxyindolacetic acid in cerebrospinal fluid of 57 children with acute lymphoblastic leukemia. A sequential analysis of cerebrospinal fluid was performed for each patient: cerebrospinal fluid samples were obtained before therapy and after each of the four high-dose methotrexate infusions during the CNS prophylaxis phase. A significant increase of total biopterin concentrations in cerebrospinal fluid was observed after high-dose methotrexate therapy compared with the pretreatment values. No cumulative effect was noted. In contrast, no significant variation of the homovanillic acid and 5-hydroxyindolacetic acid levels was observed in cerebrospinal fluid. However, individual analysis revealed a transient decrease of homovanillic acid and 5-hydroxyindolacetic acid concentrations in cerebrospinal fluid of six children. The increase of total biopterin mimicking that observed in inherited dihydropteridine reductase deficiencies suggests that methotrexate inhibits the regenerating system of biopterin in the brain of patients undergoing high-dose methotrexate therapy.