GLUTAMINE ENHANCES SELECTIVITY OF CHEMOTHERAPY THROUGH CHANGES IN GLUTATHIONE METABOLISM

Objective Chemotherapy doses are limited by toxicity to normal tissues . Intravenous glutamine protects liver cells from oxidant injury by in creasing intracellular glutathione (GSH) content, The authors hypothes ized that supplemental oral glutamine (GLN) would increase the therape utic index of methotrexate (MTX) by improving host tolerance through c hanges in glutathione metabolism. The authors examined the effects of oral glutamine on tumor and host glutathione metabolism and response t o methotrexate. Methods Thirty-six 300-g Fischer 344 rats were implant ed with fibrosarcomas. On day 21 after implantation, rats were randomi zed to receive isonitrogenous isocaloric diets containing 1 g/kg/day g lutamine or glycine (GLY) by gavage. On day 23 after 2 days of prefeed ing, rats were randomized to one of the following four groups receivin g an intraperitoneal injection of methotrexate (20 mg/kg) or saline (C ON): GLN + MTX, GLY + MTX, GLN-CON, or GLY-CON. On day 24, rats were k illed and studied for arterial glutamine concentration, tumor volume, tumor, kidney and gut glutaminase activity, and glutathione content (t umor, gut, heart, liver, muscle, kidney, and lung). Results Provision of the glutamine-enriched diets to rats receiving MTX decreased tumor glutathione (2.38+/-0.17 in GLN + MTX vs. 2.92+/-0.20 in GLY + MTX, p < 0.05), whereas increasing or maintaining host glutathione stores (in gut, 2.60+/-0.28 in GLN + MTX vs. 1.93 + 0.18; in GLY + MTX, p < 0.05 ). Depressed glutathione levels in tumor cells increases susceptibilit y to chemotherapy. Significantly decreased glutathione content in tumo r cells in the GLN + MTX group correlated with enhanced tumor volume l oss (-0.8+/-1.0 mL in GLN + MTX vs. +9.5+/-2.0 mL in GLY + MTX, p < 0. 05). Conclusion These data suggest that oral glutamine supplementation will enhance the selectivity of antitumor drugs by protecting normal tissues from and possibly sensitizing tumor cells to chemotherapy trea tment-related injury.