Kodama M, Kodama T
Gan. 1982 Aug;73(4):661-6.
The purpose of this investigation was to clarify the relation between the therapeutic efficacy of cyclophosphamide and the activity of the endogenous and exogenous corticosteroid hormones using ICR female mice with ascitic Ehrlich tumor. A single ip injection of the drug, 3 mg/mouse, was given to each mouse 36 hr after tumor inoculation (1 X 10(6) tumor cells, ip), and the drug effect was assessed in terms of the number of 1-month survivors with and without tumor. The clock time of drug administration which produced minimal therapeutic efficacy chronologically coincided with the dark period (8 PM approximately 8 AM) and/or with a stage of increased plasma corticosterone in mice. In support of this, concomitant administration of corticosterone (hydrocortisone or corticosterone) significantly depressed the anti-tumor effect of the drug. Evidence is presented to indicate that the adverse effect of corticosteroids is related to an accelerated metabolism of cyclophosphamide within the host. The drug effect for a given total dose was improved by the use of hourly partitioned injections in place of a single injection. It was concluded that the therapeutic efficacy of cyclophosphamide is dependent on the time of exposure to drug action on the scale of hours, but not days, and that the anti-tumor effect of the drug can be suppressed by increased activity of endogenous and exogenous corticosteroid hormones through acceleration of the drug metabolism.
本研究的目的是利用患有腹水型艾氏瘤的ICR雌性小鼠，阐明环磷酰胺的治疗效果与内源性和外源性皮质类固醇激素活性之间的关系。在接种肿瘤（1×10⁶个肿瘤细胞，腹腔注射）36小时后，给每只小鼠腹腔注射一次药物，剂量为3mg/小鼠，根据有肿瘤和无肿瘤的1个月存活小鼠数量评估药物效果。按时间顺序产生最小治疗效果的给药时钟时间与黑暗期（晚上8点至早上8点左右）和/或小鼠血浆皮质酮水平升高阶段一致。支持这一点的是，同时给予皮质酮（氢化可的松或皮质酮）会显著降低药物的抗肿瘤效果。有证据表明，皮质类固醇的不良反应与宿主内环磷酰胺代谢加速有关。通过采用每小时分次注射代替单次注射，给定总剂量的药物效果得到了改善。得出的结论是，环磷酰胺的治疗效果取决于数小时而非数天的药物作用暴露时间，并且内源性和外源性皮质类固醇激素活性的增加会通过加速药物代谢来抑制药物的抗肿瘤效果。
