Studies on Reversing Effect of Multidrug Resistance by Dipyridamole. I. Modulation of Epirubicin-Induced Effects on Cell Proliferation and Cell Cycle by Dipyridamole

Abstract

Dipyridamole, a nucleoside membrane transport inhibitor, enhanced the cytotoxicity of epirubicin for mouse leukemia P388 cells by a factor of 1.8-fold and that for 30-fold doxorubicin-resistant sublines of P388 cells (P388/DOX) by a factor of 6.5-fold. This interaction was shown to be truly synergistic by DNA histogram and median effect analysis. The dipyridamole enhancement of the cytotoxicity of epirubicin was a dose-dependent effect ; it was greatest when cells were exposed to dipyridamole before treatment with epirubicin. In cell cycle experiments, 1-5μM dipyridamole increased the accumulation of G₂+M phase produced by the treatment with 0.5-1μM epirubicin. Dipyridamole, however, did not appear to alter the patterns of DNA histogram in sensitive cells. These results suggest that the increase of the accumulation of G₂+M phase in resistant cells is an important factor for the interaction between epirubicin and dipyridamole.