Mickisch G H, Noordzij M A, vd Gaast A, Gebreamlack P, Köhrmann K U, Mogler-Drautz E, Kupper H, Schröder F H
Department of Urology, AZR-Dijkzigt, Erasmus University, Rotterdam, The Netherlands.
J Cancer Res Clin Oncol. 1995;121 Suppl 3(Suppl 3):R11-6. doi: 10.1007/BF02351065.
Multidrug resistance (MDR) in a variety of human tumours such as renal cell carcinoma (RCC) is thought to be caused by expression of the MDR1 gene and may be reversed by applying modern chemosensitisers such as dexverapamil, which inhibit the MDR1 gene product P-glycoprotein. This preliminary report gives information on a clinical study complying with good clinical practice regulations in patients with advanced RCC. The final evaluation is pending. Vinblastine, if anything the most effective chemotherapeutic agent (5-day continuous regimen), was combined with oral dexverapamil (6 times per day) as a chemosensitiser and dexamethasone to increase dexverapamil tolerance. All patients had histologically proven RCC, which was metastatic and progressive at study entry. The statistical design featured a pre-study regimen of two cycles of vinblastine alone followed by evaluation. If no response was documented, with all patients thus serving as their own control, dexverapamil and dexamethasone were added for three cycles of combination therapy. Having obtained institutional permission from the ethical review committee, we enrolled patients of whom 25 qualified for the combined-treatment arm; 13 patients finished the study, 5 patients failed to complete all treatment cycles (1 because of treatment-related toxicity, 3 for personal reasons, not related to treatment, 1 for tumour-related reasons) and 7 patients were at too early a stage for evaluation. Altogether, 61% of all patients tolerated a dose of dexverapamil of at least 2400 mg/day with peak serum levels reaching, in some cases, approximately 8 microM (the sum of dexverapamil plus nordexverapamil levels). WHO grade 3 and 4 toxicities were mainly myelosuppression (5/18). The combination of 1.4 mg m-2 day-1 vinblastine plus dexverapamil was generally felt to be safe and well tolerated. One partial response and 7 stable diseases were noted in this heavily pretreated study population. Four-hourly administration of dexverapamil in combination with dexamethasone plus escalation to the individually tolerated doses have permitted increases in serum levels of dexverapamil.
多种人类肿瘤（如肾细胞癌，RCC）中的多药耐药性（MDR）被认为是由MDR1基因的表达引起的，应用现代化学增敏剂（如右维拉帕米）可能会逆转这种耐药性，右维拉帕米可抑制MDR1基因产物P-糖蛋白。本初步报告提供了一项针对晚期肾细胞癌患者的符合良好临床实践规范的临床研究信息。最终评估尚待完成。长春碱（如果说它是最有效的化疗药物的话，采用5天连续给药方案）与作为化学增敏剂的口服右维拉帕米（每日6次）以及地塞米松联合使用，以提高对右维拉帕米的耐受性。所有患者经组织学证实患有肾细胞癌，在研究开始时已发生转移且病情进展。统计设计的特点是先进行两个周期单独使用长春碱的预研究方案，然后进行评估。如果未记录到反应，由于所有患者均作为自身对照，随后添加右维拉帕米和地塞米松进行三个周期的联合治疗。在获得伦理审查委员会的机构许可后，我们招募了患者，其中25名符合联合治疗组的条件；13名患者完成了研究，5名患者未能完成所有治疗周期（1名因治疗相关毒性，3名因个人原因而非治疗相关，1名因肿瘤相关原因），7名患者处于评估过早阶段。总体而言，所有患者中有61%耐受至少2400毫克/天的右维拉帕米剂量，血清峰值水平在某些情况下达到约8微摩尔（右维拉帕米加去甲右维拉帕米水平之和）。世界卫生组织3级和4级毒性主要为骨髓抑制（5/18）。1.4毫克/平方米/天的长春碱加右维拉帕米的联合用药总体上被认为是安全且耐受性良好的。在这个经过大量预处理的研究人群中，观察到1例部分缓解和7例病情稳定。每4小时给予右维拉帕米联合地塞米松并逐步增加至个体耐受剂量，使得右维拉帕米的血清水平得以提高。
