ObjectiveChemotherapy doses are limited by toxicity to normal tissues. Intravenous glutamine protects liver cells from oxidant injury by increasing intracellular glutathione (GSH) content. The authors hypothesized that supplemental oral glutamine (GLN) would increase the therapeutic index of methotrexate (MTX) by improving host tolerance through changes in glutathione metabolism. The authors examined the effects of oral glutamine on tumor and host glutathione metabolism and response to methotrexate.
MethodsThirty-six 300-g Fischer 344 rats were implanted with fibrosarcomas. On day 21 after implantation, rats were randomized to receive isonitrogenous isocaloric diets containing 1 g/kg/day glutamine or glycine (GLY) by gavage. On day 23 after 2 days of prefeeding, rats were randomized to one of the following four groups receiving an intraperitoneal injection of methotrexate (20 mg/kg) or saline (CON): GLN + MTX, GLY + MTX, GLN-CON, or GLY-CON. On day 24, rats were killed and studied for arterial glutamine concentration, tumor volume, tumor, kidney and gut glutaminase activity, and glutathione content (tumor, gut, heart, liver, muscle, kidney, and lung).
ConclusionThese 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 treatment-related injury. jected to alternate 12-hour periods of dark/light cycle and given at least 1 week to acclimate to the animal care facilities. During that time, the rats were allowed ad libitum intake of standard rat chow and water. Animals were randomized during the study period to receive isonitrogenous isocaloric chow diets supplemented with 1 g/kg/day elemental GLN or glycine (GLY) by gavage.Tumor Cell ImplantationAfter 1 week of acclimation to the animal care facility and on day 0 of the study, 36 rats were randomized to flank implantation of a 2 X 2 X 2 mm3 of viable methylcholanthrene-induced fibrosarcoma cells. This tumor model has been used previously by the author7"15-'6'20,2' to study tumor host metabolism interaction. This tumor-cell line is fast-growing and locally aggressive, metastasizes rarely, and never regresses spontaneously.
Study ProcedureOn day 21 after tumor cell implantation, rats were randomized to receive pair-fed chow diets with supplemental GLN or GLY by gavage. On day 23, after 2 days of prefeeding, rats were randomized to one ofthe following four groups receiving an intraperitoneal injection of MTX (20 mg/kg) or saline (CON): GLN + MTX, GLY + MTX, GLN-CON, or GLY-CON. Each group contained nine rats. On day 24, all rats were weighed and anesthesia was obtained with ketamine (7.5 mg/100 g body weight) and acepromazine (0.1 mg/100 g body weight). Under sterile conditions, a mid-line incision was made, and the rat was heparinized. Arterial blood was withdrawn from the aorta using a 25-gauge needle attached to a 1-mL syringe. Blood was processed for arterial GLN content. The jejunum and kidney were removed and processed for glutaminas...
