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Effects of calcium antagonists in multidrug resistant primary human renal cell carcinomas
G H Mickisch1, J Kössig, G Keilhauer
1Department of Urology, Mannheim Hospital, University of Heidelberg, Federal Republic of Germany.
Abstract:
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 less than 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.
Insights
Certain calcium antagonists can overcome chemoresistance in human renal cell carcinoma by inhibiting P-170 glycoprotein. The R-verapamil stereoisomer shows promise for clinical trials due to enhanced efficacy and reduced cardiovascular effects.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Human renal cell carcinomas exhibit significant intrinsic chemoresistance.
- P-170 glycoprotein and MDR-1 gene expression are implicated in this resistance via an efflux mechanism.
- Calcium antagonists can potentially inhibit the P-170 efflux pump.
Purpose of the Study:
- To investigate the role of P-170 glycoprotein in renal cell carcinoma chemoresistance.
- To evaluate the efficacy of various calcium antagonists in enhancing vinblastine cytotoxicity.
- To assess the potential of P-170 expression as a marker for chemoresistance.
Main Methods:
- Immunohistochemical detection of P-170 using monoclonal antibody C219.
- Microculture tetrazolium assay to assess vinblastine cytotoxicity enhancement.
- Testing seven calcium antagonists: verapamil (racemic and R-stereoisomer), diltiazem, flunarizine, nifedipine, nimodipine, and nitrendipine.
Main Results:
- P-170 expression was found in 18 of 32 tumors, correlating with chemoresistance.
- Verapamil and R-verapamil significantly enhanced vinblastine cytotoxicity (P < 0.001).
- Diltiazem, nifedipine, and derivatives showed moderate enhancement; flunarizine had minimal effect.
Conclusions:
- Calcium antagonists, particularly R-verapamil, can inactivate P-170 mediated chemoresistance in renal cell carcinoma.
- Combination therapy with calcium antagonists may offer new therapeutic strategies.
- R-verapamil is a candidate for clinical trials due to its potent enhancement of vinblastine response and lower cardiovascular toxicity.