Effect of duration of exposure to S9788, cyclosporin A or verapamil on sensitivity of multidrug resistant cells to vincristine or doxorubicin.

In order to explain the high potency of S9788, a new multidrug resistance modifier currently in clinical development, we investigated its accumulation and retention in sensitive and resistant cells. Our results show that S9788 is 13-fold more accumulated and 23-fold more retained than VRP in the resistant S1/tMDR cell line. We also studied the effect of duration of incubation on the ability of S9788, verapamil and cyclosporin A to overcome the resistance of S1/tMDR and KB-A1 cells to a short exposure of doxorubicin or vincristine. Compared to a single co-incubation of 4 h, a 24 h post-incubation with 5 microM S9788 markedly increased the reversal of S1/tMDR resistance to VCR (fold reversal 4 h = 123; fold reversal 24 h = 4739), while it moderately increased S1/tMDR sensitivity to DOX (fold reversal 4 h = 1.9; fold reversal 24 h = 2.9). Similar results were obtained on KB-A1 resistance to VCR (fold reversal 4 h = 41, fold reversal 24 h = 21819) and KB-A1 resistance to DOX (fold reversal 4 h = 89; fold reversal 24 h = 160). This phenomenon also occurred with verapamil and cyclosporin A. These results clearly show that the effect of duration of exposure on the modulating activity of S9788 and of the 2 other modulators depends on the cytotoxic drug. Although the direct transposition of these results to a clinical situation is difficult, they suggest that a continuous infusion of S9788, starting simultaneously with the administration of the cytotoxic drug and ending 24 h later, might be a more effective schedule for clinical administration than a bolus administration.