This study was aimed to characterize the reversing activity of S16209 and S16317, two new dihydropyridines with low affinity for calcium channels. In vivo, S16209 (75 mg/kg) and S16317 (25 mg/kg) potentiate the antitumor activity of vincristine (VCR) in VCR-resistant leukemia bearing mice. In vitro, a complete sensitization to adriamycin (ADR) or VCR is obtained with 2.5 muM of S16209 in S1/tMDR and KB-A1 cells and with 2.5 muM of S16317 in S1/tMDR and P388/ADR-10 cells. These two compounds are also more potent than verapamil and cyclosporin A in increasing actinomycin-D cytotoxicity in DC-3F/AD cells. In the presence of ADR or VCR, a 4 h co-incubation followed by a post-incubation of 20 h with 2.5 muM S16209 is sufficient to completely overcome the resistance of human KB-A1 and S1/tMDR cells to these cytotoxic drugs. S16209 and S16317 increase ADR accumulation in resistant cells, and completely inhibit the photolabeling of P-gp by [H-3]azidopine at 100 and 10 muM, respectively, suggesting that the reversing activity of these two compounds is mainly due to a specific inhibition of the P-gp mediated efflux of cytotoxic drugs.

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