Ermens A A, Schoester M, Spijkers L J, Lindemans J, Abels J
Institute of Hematology, Erasmus University Rotterdam, The Netherlands.
Cancer Res. 1989 Nov 15;49(22):6337-41.
Several chemotherapeutic protocols for the treatment of malignancies include administration of methotrexate (MTX) during or shortly after total anesthesia. Clinical observations in patients treated for breast carcinoma or childhood cancer have shown unexpected myelosuppression and mucosal damage. This phenomenon may be attributed to the synergistic effects of nitrous oxide, which inactivates the cobalamin coenzyme of methionine synthase, and MTX, which inhibits dihydrofolate reductase, on folate metabolism. However, no quantitative data on dose-effect relationships are available regarding the combined toxicity of MTX and N2O. We investigated the effect of exposure to N2O on the toxicity of MTX. Groups of male Wistar rats were exposed to either 50% N2O/50% O2 or air for 12-48 h. Subsequently, a single i.p. injection of 10, 20, 40, or 80 mg MTX/kg body weight was given. Gastrointestinal toxicity resulted in diarrhea and weight loss in all groups for 5 days after MTX administration. Concomitantly, bone marrow depression with leukocytopenia and thrombocytopenia occurred. Exposure to N2O did not alter the plasma clearance of MTX. No substantial liver or kidney toxicity could be detected, but the 50% lethal dose for MTX was reduced from 60 mg/kg to 10 mg/kg if rats had been exposed to N2O for 48 h; the main causes of death were dehydration and bleeding. The administration of 5-formyl-tetrahydrofolate (4 x 10 mg i.p.) but not 5-methyltetrahydrofolate protected completely against the lethal effect of the drug combination. Altogether, cytotoxic effects of MTX on proliferating cells are potentiated by N2O. Therefore, the use of this anesthetic shortly before or during MTX administration should be avoided.
几种用于治疗恶性肿瘤的化疗方案包括在全身麻醉期间或之后不久给予甲氨蝶呤（MTX）。对乳腺癌或儿童癌症患者的临床观察显示出意外的骨髓抑制和粘膜损伤。这种现象可能归因于一氧化二氮和MTX对叶酸代谢的协同作用，一氧化二氮使甲硫氨酸合酶的钴胺素辅酶失活，MTX则抑制二氢叶酸还原酶。然而，关于MTX和N2O联合毒性的剂量 - 效应关系尚无定量数据。我们研究了暴露于N2O对MTX毒性的影响。将雄性Wistar大鼠分组，使其暴露于50% N2O / 50% O2或空气中12 - 48小时。随后，腹腔注射单次剂量为10、20、40或80 mg MTX / kg体重。MTX给药后5天，所有组均出现胃肠道毒性，表现为腹泻和体重减轻。同时，出现骨髓抑制伴白细胞减少和血小板减少。暴露于N2O并未改变MTX的血浆清除率。未检测到明显的肝脏或肾脏毒性，但如果大鼠暴露于N2O 48小时，MTX的半数致死剂量从60 mg / kg降至10 mg / kg；主要死亡原因是脱水和出血。腹腔注射5 - 甲酰四氢叶酸（4×10 mg）而非5 - 甲基四氢叶酸可完全保护大鼠免受药物组合的致死作用。总之，N2O增强了MTX对增殖细胞的细胞毒性作用。因此，应避免在MTX给药前不久或给药期间使用这种麻醉剂。
