Schilsky R L, Janisch L, Berezin F, Mick R, Vogelzang N J, Ratain M J
Department of Medicine, University of Chicago, Illinois 60637.
Cancer Res. 1993 Mar 15;53(6):1293-6.
Studies previously performed in our laboratory demonstrated synergistic cytotoxicity and DNA strand break formation in human tumor cells following exposure to a combination of bromodeoxyuridine and bleomycin. Synergy was evident when bromodeoxyuridine was administered prior to or simultaneously with bleomycin and occurred over a wide range of concentration ratios. We therefore undertook a phase I clinical trial of the combination of iododeoxyuridine (IdUrd) and bleomycin to determine the maximally tolerated dose of IdUrd that could be administered with a standard dose of bleomycin and to determine the toxicities of the combination. Eligible patients were those with advanced cancer refractory to standard therapy who had a performance status of 0-2, measurable or evaluable disease, and adequate organ function. IdUrd was administered as a 5-day continuous i.v. infusion beginning at a dose of 250 mg/m2/day with escalation in cohorts of 3-6 patients according to a modified Fibonacci scheme. Bleomycin was administered at a dose of 15 mg/m2/day as a continuous i.v. infusion during the last 3 days of the IdUrd infusion. Cycles of therapy were repeated every 28 days. Plasma levels of IdUrd and iodouracil were determined by high performance liquid chromatography. Thirty patients received a total of 79 cycles of IdUrd/bleomycin. Dose-limiting toxicity was bone marrow suppression. At the maximally tolerated IdUrd dose of 2780 mg/m2/day, the median neutrophil nadir after the first cycle of therapy was 805/microliters and the median platelet nadir was 48,000/microliters. Other toxic effects included mucositis, fatigue, nausea, diarrhea, fever, and skin toxicity. Plasma steady-state concentrations of IdUrd increased proportionally to administered IdUrd dose. IdUrd clearance varied from 0.253 liters/min/m2 to 0.503 liters/min/m2 and did not correlate with IdUrd dose. IdUrd dose and concentration correlated significantly with granulocyte and platelet nadirs, and a pharmacodynamic model for white blood cell count nadir could be defined by pretreatment white blood cell count, IdUrd dose, and gender. The recommended IdUrd dose for phase II testing of this combination is 2140 mg/m2/day. Phase II studies will be of particular interest in those diseases, such as carcinomas of the head, neck, and esophagus, where bleomycin has documented activity as a single agent.
我们实验室之前进行的研究表明，人肿瘤细胞在暴露于溴脱氧尿苷和博来霉素的组合后会出现协同细胞毒性和DNA链断裂。当溴脱氧尿苷在博来霉素之前或同时给药时，协同作用很明显，并且在很宽的浓度比范围内都存在。因此，我们开展了一项碘脱氧尿苷（IdUrd）与博来霉素联合使用的I期临床试验，以确定可与标准剂量博来霉素联合使用的IdUrd的最大耐受剂量，并确定该联合用药的毒性。符合条件的患者为那些对标准治疗难治的晚期癌症患者，其体能状态为0 - 2，疾病可测量或可评估，且器官功能良好。IdUrd以250 mg/m²/天的剂量进行为期5天的持续静脉输注，根据改良的斐波那契方案，每3 - 6名患者一组逐步增加剂量。博来霉素在IdUrd输注的最后3天以15 mg/m²/天的剂量进行持续静脉输注。治疗周期每28天重复一次。通过高效液相色谱法测定血浆中IdUrd和碘尿嘧啶的水平。30名患者共接受了79个周期的IdUrd/博来霉素治疗。剂量限制性毒性为骨髓抑制。在IdUrd的最大耐受剂量2780 mg/m²/天时，第一个治疗周期后的中性粒细胞计数最低点中位数为805/微升，血小板计数最低点中位数为48,000/微升。其他毒性作用包括粘膜炎、疲劳、恶心、腹泻、发热和皮肤毒性。IdUrd的血浆稳态浓度与给药的IdUrd剂量成比例增加。IdUrd清除率在0.253升/分钟/平方米至0.503升/分钟/平方米之间变化，且与IdUrd剂量无关。IdUrd剂量和浓度与粒细胞和血小板最低点显著相关，并且白细胞计数最低点的药效学模型可以通过治疗前白细胞计数、IdUrd剂量和性别来定义。该联合用药II期试验推荐的IdUrd剂量为2140 mg/m²/天。II期研究对于那些疾病，如头颈部和食管癌，将特别有意义，在这些疾病中博来霉素作为单一药物已证明有活性。
