See W A, Crist S A, Williams R D
Department of Urology, University of Iowa, Iowa City 52242.
Cancer Res. 1991 Mar 1;51(5):1378-83.
Previous studies demonstrated that single doses of systemic cyclophosphamide (CY) as low as 0.5 mg/kg are effective in preventing bladder tumor implantation in a rat model. In an effort to determine if the urinary bladder represents a unique site of CY activity, a series of experiments were performed to define the mechanism by which low-dose CY prevents bladder tumor implantation. Potential sites for CY antitumor activity include direct tumor cytotoxicity resulting from serum delivery of drug to the tumor; tumor cytotoxicity resulting from tissue drug levels at the site of implantation; altered tumor cell adherence to the urothelial injury site; nonspecific urothelial cytotoxicity resulting from urinary excretion of the CY metabolites; tumor cell-specific cytotoxicity resulting from urinary excretion of the CY metabolite acrolein; and second-pass cytotoxicity resulting from urinary excretion of the active form of CY. Experiments were performed to determine if a single predominant site of activity could be defined. Cyclophosphamide levels at the site of tumor implantation appeared to be the most important determinant of antiimplantation activity. Only tumor recipients pretreated with CY had a significant decrease in bladder tumor implantation. In vivo and in vitro assays measuring the effect of blood-borne drug delivery directly to the tumor failed to demonstrate cytotoxic activity. Tumor cell adherence assays measuring in vitro adherence of CY-treated tumor cells and in vivo adherence of tumor cells in CY-treated recipients showed no difference in comparison to control groups. Interval histological comparison of CY-treated and control bladders failed to demonstrate any difference. Urinary levels of acrolein did not contribute to antiimplantation activity. Preimplantation CY doses prevented tumor development in a s.c. implantation model, thereby excluding a second-pass effect resulting from urinary drug excretion. These data suggest that the bladder is not unique in its response to systemic low-dose CY administered for the prevention of implantation-mediated tumor recurrence. Low-dose, perioperative chemoprophylaxis may be applicable to other tumor systems in which intraoperative tumor dissemination is felt to contribute to recurrence risk.
先前的研究表明，单剂量低至0.5mg/kg的全身环磷酰胺（CY）可有效预防大鼠模型中的膀胱肿瘤种植。为了确定膀胱是否是CY活性的独特部位，进行了一系列实验以明确低剂量CY预防膀胱肿瘤种植的机制。CY抗肿瘤活性的潜在部位包括：药物经血清传递至肿瘤导致的直接肿瘤细胞毒性；植入部位组织药物水平导致的肿瘤细胞毒性；肿瘤细胞对尿路上皮损伤部位黏附性的改变；CY代谢产物经尿液排泄导致的非特异性尿路上皮细胞毒性；CY代谢产物丙烯醛经尿液排泄导致的肿瘤细胞特异性细胞毒性；以及CY活性形式经尿液排泄导致的二次通过细胞毒性。进行实验以确定是否能明确单一的主要活性部位。肿瘤植入部位的环磷酰胺水平似乎是抗种植活性的最重要决定因素。只有用CY预处理的肿瘤受体的膀胱肿瘤种植有显著减少。测量血源药物直接传递至肿瘤的体内和体外试验未能证明细胞毒性活性。测量经CY处理的肿瘤细胞的体外黏附性以及经CY处理的受体中肿瘤细胞的体内黏附性的肿瘤细胞黏附试验显示，与对照组相比没有差异。对经CY处理和对照的膀胱进行间隔组织学比较未发现任何差异。尿液中丙烯醛水平对抗种植活性没有贡献。植入前给予CY剂量可预防皮下种植模型中的肿瘤发展，从而排除了尿液药物排泄导致的二次通过效应。这些数据表明，膀胱对用于预防植入介导的肿瘤复发的全身低剂量CY的反应并非独特。低剂量围手术期化学预防可能适用于其他术中肿瘤播散被认为会增加复发风险的肿瘤系统。
