Dorr R T, Alberts D S
Br J Cancer. 1982 Jan;45(1):35-43. doi: 10.1038/bjc.1982.5.
Male DBA2 mice were given 10(6) P-388 leukaemic cells i.p. and cimetidine (CMT) at 100 mg/kg 1 day for 10 days, or as a single 100 mg/kg injection 30 min before cyclophosphamide (CTX). CMT significantly prolonged the survival of groups of mice receiving 50, 100 and 200 mg/kg of CTX 3 days after tumour inoculation. Median survival increased by 5.5 days (P less than 0.05), 10 days (P less than 0.05) and 13 days (P less than 0.05) respectively. The addition of CMT had the effect of roughly doubling the CTX dose, without increasing the lethality. CMT produced the only long-term survival seen in the study (1-2/10) CMT alone had no apparent antitumour activity. CMT significantly prolonged mean pentobarbital sleep to 28.6-60 min vs only 10 min for phenobarbital treated mice. Both CMT regimens increased the plasma concentration time products for CTX-induced metabolites (NBP) by about 1.3 fold (in contrast to a 33% reduction with phenobarbital). On average the single-dose CMT regimen produced the greatest effect on survival, on pentobarbital sleep duration and on total NBP reactive species. Probable mechanisms for the CMT-CTX interaction include competitive microsomal enzyme inhibition and/or acutely depressed hepatic blood flow. Caution should be used in combining CMT with full doses of CTX and any other highly metabolized antineoplastic agents in man.
给雄性DBA2小鼠腹腔注射10(6)个P - 388白血病细胞，并于第1天给予西咪替丁（CMT），剂量为100 mg/kg，共10天，或在环磷酰胺（CTX）给药前30分钟单次注射100 mg/kg。在接种肿瘤3天后，CMT显著延长了接受50、100和200 mg/kg CTX的小鼠组的存活时间。中位生存期分别增加了5.5天（P < 0.05）、10天（P < 0.05）和13天（P < 0.05）。添加CMT的效果大致相当于将CTX剂量加倍，而不增加致死率。CMT产生了该研究中唯一观察到的长期存活（1 - 2/10），单独使用CMT没有明显的抗肿瘤活性。CMT显著延长了戊巴比妥睡眠时间，从苯巴比妥处理的小鼠仅10分钟延长至28.6 - 60分钟。两种CMT给药方案均使CTX诱导的代谢产物（NBP）的血浆浓度 - 时间乘积增加了约1.3倍（相比之下，苯巴比妥使其降低了33%）。平均而言，单剂量CMT方案对存活、戊巴比妥睡眠时间和总NBP反应性物种的影响最大。CMT与CTX相互作用的可能机制包括竞争性微粒体酶抑制和/或急性肝血流量降低。在人体中，将CMT与全剂量的CTX以及任何其他高度代谢的抗肿瘤药物联合使用时应谨慎。
