Reversal of multidrug resistance by new dihydropyridines with lower calcium antagonistic activity

BS compounds, a series of new dihydropyridines, successfully overcame multidrug resistance in P388/ADR cells in vitro. These agents synergistically potentiated the cytotoxicity of Adriamycin to P388/ADR cells at a concentration of 1-2 microM, whereas they showed hardly any synergistic effect in the parental cell line (P388/S) at the same concentration. They inhibited the active drug efflux in P388/ADR cells as well as the binding of [G-3H]-vinblastine to membrane vesicles from P388/ADR, which was increased in resistant P388 cells as compared with parental cells. Besides, unlike the activity of clinically used calcium antagonists, the calcium antagonistic activity associated with BS compounds was very weak: their arterial relaxation activity was less than 21% of that of verapamil. These data suggest that BS compounds specifically overcome multidrug resistance without the serious hypotensive side effects that accompany the use of verapamil or other calcium antagonists.