Kroes A C, Lindemans J, Schoester M, Abels J
Cancer Chemother Pharmacol. 1986;17(2):114-20. doi: 10.1007/BF00306738.
Exposure to nitrous oxide interferes selectively with the coenzyme function of vitamin B12 and causes inactivation of methionine synthetase, with subsequent impairment of folate metabolism and reduction of cellular proliferation. In a rat leukemia model (BNML) we investigated the combined administration of nitrous oxide, inactivating vitamin B12, and methotrexate (MTX), a folate antagonist inhibiting the enzyme dihydrofolate reductase. Through different mechanisms, both agents decrease the availability of tetrahydrofolate, and subsequently of other reduced folates, with increased impairment of folate-dependent synthesis of thymidylate. Effects on leukemic growth and on hematological values in rats demonstrated enhancement of the therapeutic effect of MTX by exposure to nitrous oxide. With several treatment schedules, the results of combined treatment were seen to be better than additive when compared with the effects of single agents. In particular, pretreatment of leukemic rats with nitrous oxide for 3 days before administration of MTX appeared effective. With higher doses of MTX, concomitant exposure to nitrous oxide even resulted in toxic effects. These findings were in accordance with the results of some metabolic studies performed in leukemic rats.(ABSTRACT TRUNCATED AT 250 WORDS)
接触一氧化二氮会选择性干扰维生素B12的辅酶功能，导致甲硫氨酸合成酶失活，进而损害叶酸代谢并减少细胞增殖。在大鼠白血病模型（BNML）中，我们研究了使维生素B12失活的一氧化二氮与作为叶酸拮抗剂抑制二氢叶酸还原酶的甲氨蝶呤（MTX）的联合给药情况。通过不同机制，这两种药物都会降低四氢叶酸以及随后其他还原型叶酸的可用性，从而增加对胸苷酸叶酸依赖性合成的损害。对大鼠白血病生长和血液学指标的影响表明，接触一氧化二氮可增强MTX的治疗效果。采用多种治疗方案时，与单一药物的效果相比，联合治疗的结果显示出优于相加效应。特别是，在给予MTX前3天用一氧化二氮预处理白血病大鼠似乎有效。使用更高剂量的MTX时，同时接触一氧化二氮甚至会产生毒性作用。这些发现与在白血病大鼠中进行的一些代谢研究结果一致。（摘要截短于250字）
