Dexverapamil to modulate vinblastine resistance in metastatic renal cell carcinoma

Abstract

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.