Rouse K, Nwokedi E, Woodliff J E, Epstein J, Klimberg V S
University of Arkansas for Medical Sciences, Little Rock, USA.
Ann Surg. 1995 Apr;221(4):420-6. doi: 10.1097/00000658-199504000-00014.
Chemotherapy 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.
Thirty-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, kidney and gut glutaminase activity, and glutathione content (tumor, gut, heart, liver, muscle, kidney, and lung).
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 susceptibility to chemotherapy. Significantly decreased glutathione content in tumor cells in the GLN+MTX group correlated with enhanced tumor volume loss (-0.8 +/- 1.0 mL in GLN+MTX vs. +9.5 +/- 2.0 mL in GLY+MTX, p < 0.05).
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 treatment-related injury.
化疗剂量受正常组织毒性的限制。静脉注射谷氨酰胺可通过增加细胞内谷胱甘肽（GSH）含量来保护肝细胞免受氧化损伤。作者推测，补充口服谷氨酰胺（GLN）可通过改变谷胱甘肽代谢来提高宿主耐受性，从而提高甲氨蝶呤（MTX）的治疗指数。作者研究了口服谷氨酰胺对肿瘤和宿主谷胱甘肽代谢以及对甲氨蝶呤反应的影响。
将36只300 g的Fischer 344大鼠植入纤维肉瘤。植入后第21天，将大鼠随机分为通过灌胃接受含1 g/kg/天谷氨酰胺或甘氨酸（GLY）的等氮等热量饮食的组。在预喂养2天后的第23天，将大鼠随机分为以下四组之一，接受腹腔注射甲氨蝶呤（20 mg/kg）或生理盐水（CON）：GLN+MTX、GLY+MTX、GLN-CON或GLY-CON。在第24天，处死大鼠并研究其动脉谷氨酰胺浓度、肿瘤体积、肾脏和肠道谷氨酰胺酶活性以及谷胱甘肽含量（肿瘤、肠道、心脏、肝脏、肌肉、肾脏和肺）。
给接受MTX的大鼠提供富含谷氨酰胺的饮食会降低肿瘤谷胱甘肽水平（GLN+MTX组为2.38±0.17，而GLY+MTX组为2.92±0.20，p<0.05），而增加或维持宿主谷胱甘肽储备（在肠道中，GLN+MTX组为2.60±0.28，而GLY+MTX组为1.93±0.18，p<0.05）。肿瘤细胞中谷胱甘肽水平降低会增加对化疗的敏感性。GLN+MTX组肿瘤细胞中谷胱甘肽含量显著降低与肿瘤体积损失增加相关（GLN+MTX组为-0.8±1.0 mL，而GLY+MTX组为+9.5±2.0 mL，p<0.05）。
这些数据表明，口服补充谷氨酰胺可通过保护正常组织免受化疗相关损伤并可能使肿瘤细胞对化疗敏感，从而提高抗肿瘤药物的选择性。
