EFFECT OF GLUTAMINE ON METHOTREXATE EFFICACY AND TOXICITY

Objective To examine the effect of oral glutamine (GLN) on the efficac y and toxicity of methotrexate (MTX). Summary Background Data The use of high-dose chemotherapy regimens is limited by the severity of their toxicities. Oral GLN has been shown to decrease the gut toxicity seen with MTX treatment while enhancing its tumoricidal effect. Methods an d Results Studies were done in laboratory rats and in breast cancer ou t-patients. Fischer 344 rats were randomized to 48 hours of prefeeding with GLN (1 g/kg/day) or an isonitrogenous amount of glycine. Rats we re killed 24 hours after receiving a 20-mg/kg intraperitoneal dose of MTX. In the GLN group, there was a threefold increase in total MTX in the tumor as compared with the control group, and this increase was in both the diglutamated and pentaglutamated MTX. inversely, there was a significant decrease in the total polyglutamated MTX in the gut in th e GLN group. Given the results of this preclinical study, the authors performed a phase I trial. Nine patients diagnosed with inflammatory b reast cancer received GLN (0.5 g/kg/day) during MTX neoadjuvant therap y, escalating from doses of 40 mg/m(2) to 100 mg/m(2) weekly for 3 wee ks, followed by a doxorubicin-based regimen. No toxicity of oral GLN w as detected. No patient showed any sign of chemotherapy-related toxici ty. One patient had a grade I mucositis. Except for one, ail patients responded to the chemotherapy regimen. Median survival was 35 months.C onclusions These studies suggest that GLN supplementation is safe in i ts administration to the tumor-bearing host receiving MTX. By preferen tially increasing tumor retention of MTX over that of normal host tiss ue, GLN may serve to increase the therapeutic window of this chemother apeutic age.