STUDIES ON REVERSING EFFECT OF MULTIDRUG- RESISTANCE BY DIPYRIDAMOLE .2. INHIBITION OF EPIRUBICIN EFFLUX FROM RESISTANT CELLS BY DIPYRIDAMOLE AND ITS PHARMACOLOGICAL EFFECT

We have previously reported that dipyridamole increases the cytotoxici ty of epirubicin and alters the cell cycle in doxorubicin-resistant (P 388/DOX) cells, increasing the accumulation of G(2)/M phase by blockin g the cell cycle. In cultured cells, dipyridamole increased dose-depen dently the intracellular accumulation of epirubicin in the resistant c ells. Simultaneous exposure of the resistant cells to epirubicin and 1 00 mu M dipyridamole resulted in a 4.2-fold increase in proportion to the control level of epirubicin after 60 min. Dipyridamole inhibited t he enhanced efflux of epirubicin in doxorubicin-resistant cells. Howev er, dipyridamole had no effect on both the influx and efflux of epirub icin in doxorubicin-sensitive cells. In mice, lethal and bone marrow t oxicity induced by epirubicin were potentiated by administration of hi gh-dose of dipyridamole. In addition, in vivo results also demonstrate d that dipyridamole in combination with epirubicin produced a signific ant reversal of the in vivo antitumor activity of epirubicin in mice b earing P388/DOX cells. These data imply the enhancement effects of dip yridamole on the efficacy and toxicity of epirubicin.