Interactions between calcium antagonists, calcium fluxes and anthracycline transport.

The calcium antagonists verapamil and nifedipine promote responsiveness to anthracyclines in certain drug-resistant cell lines. Their mode of action involves inhibition of anthracycline exodus, leading to promotion of intracellular drug retention. We examined the relationship between calcium fluxes and anthracycline responsiveness in the P388 murine leukemia, and in a drug-resistant sub-line, P388/ADR. Verapamil and nifedipine promoted daunorubicin accumulation by P388/ADR cells, but this occurred regardless of extracellular calcium concentration and did not involve perturbation of calcium transport. We conclude that these agents promote drug retention via mechanisms not related to calcium ion fluxes.