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Effects of Calcium Antagonists in Multidrug Resistant Primary Human Renal Cell Carcinomas

Department of Urology, Mannheim Hospital, University of Heidelberg, D-6800 Mannheim [G. H. M., J. K., R. K. T., P. M. A.], and Department of Oncology and Immunology, Knoll AG, D-6700 Ludwigshafen, Federal Republic of Germany [G. K., E. S.]

Human renal cell carcinomas display a characteristically high degree of intrinsic chemoresistance to a multitude of chemotherapeutic agents. It was suggested previously, that P-170 glycoprotein contributes to this phenomenon in renal cell carcinoma indicated by elevated MDR-1 gene mRNA levels and by the expression of this specific resistance characteristic. The P-170-related efflux mechanism can be inactivated by certain calcium antagonists.

P-170 was traced immunohistochemically using monoclonal antibody C 219. Concomitantly, we studied the enhancement of vinblastine cytotoxicity with 4 major classes of calcium-blocking agents in a microculture tetrazolium assay. Seven different calcium antagonists were selected: verapamil (VPM, racemic form), its R-stereoisomer (R-VPM), diltiazem, flunarizine, nifedipine, and its derivatives nimodipine and nitrendipine.

Verapamil or R-verapamil causes a significant decrease of viable tumor cells as compared to vinblastine alone (P < 0.001). Similar effects were found with diltiazem, nifedipine, and its derivatives reaching approximately 70% of the VPM/R-VPM activity. Flunarizine showed only minor enhancement of cytotoxicity. P-170 expression was demonstrated in 18 of 32 tumors, and a relation to chemoresistance was evident. None of the chemoresponders, but 18 of 25 (72%) of the highly resistant tumors, revealed this resistance factor. It was concluded that certain calcium antagonists in combination with chemotherapy may well offer therapeutic options in renal cell carcinoma as they apparently inactivate the underlying mechanism conferring resistance. The new stereoisomer R-VPM, in particular, may be used in clinical trials since it combines strong enhancement of vinblastine drug responsiveness with a 10-fold lower cardiovascular activity as compared to racemic VPM, thus allowing higher concentrations to be applied.

¹ To whom requests for reprints should be addressed, at Laboratory of Molecular Biology, Bldg. 37, Rm., 2D 27, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Received 4/18/89. Revised 3/12/90.

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