D-VERAPAMIL DOWN-MODULATES P170-ASSOCIATED RESISTANCE TO DOXORUBICIN,DAUNORUBICIN AND IDARUBICIN

Verapamil (VRP) is an effective modulator of P170-associated multidrug resistance (MDR), but its clinical application is limited by cardiova scular side-effects. The D-isomer of VRP (D-VRP) is 10 times less acti ve than the racemic mixture on the cardiovascular system, but retains a MDR modulating activity. Daunorubicin (DNR) and doxorubicin (DX) are two anthracyclines whose cytotoxicity is strongly related with the ex pression of P170, while their respective lipophylic derivatives idarub icin (IDA) and iododoxorubicin (IDX) are less P170-dependent. We studi ed the effect Of D-VRP on intracellular retention and on the cytotoxic ity of these four anthracyclines in two MDR cell systems (LOVO and CEM ) by flow cytometry and by a microcultured tetrazolium colorimetric as say (MTT). We found that in MDR cells D-VRP increased intracellular an thracycline concentration and increased the cytotoxicity of DNR, IDA a nd DX but not of IDX. The effect of D-VRP was dose-related, but it was already consistent at D-VRP concentrations that can be readily mainta ined in vivo (2-3 muM). These data suggest that at a clinically tolera ble concentration D-VRP can downmodulate the resistance to DNR and DX and can