OVERCOMING PGP-RELATED MULTIDRUG-RESISTANCE - THE CYCLOSPORINE DERIVATIVE SDZ PSC-833 CAN ABOLISH THE RESISTANCE TO METHOXY-MORPHOLYNIL-DOXORUBICIN

Background. The results obtained so far in studies designed to neutral ize P glycoprotein (PGP)-related multidrug resistance (MDR) by using M DR reversal agents, have not yet fulfilled the promise of the experime nts which were performed in vitro. In order to improve PGP-related MDR neutralization, we tested in vitro the activity of the cyclosporine d erivative SDZ PSC 833 (PSC) together with doxorubicin (DOX) and with t wo new DOX derivatives named 4' iodo 4' deoxy-doxorubicin (IODODOX) an d methoxy-morpholynil-doxorubicin (MMDOX, FCE 23762) using four differ ent human cell lines and their multi-drug resistant variants. Methods. Anthracycline toxicity was evaluated by using the MTT method after a 7-day culture with continuous exposure to the antitumor drugs with or without the addition of PSC. Results. PSC significantly downmodulated the toxicity of all three anthracyclines in all the four cell systems. However, despite the great increase caused by PSC in the toxicity of DOX and a more modest effect on the toxicity of the two DOX derivative s, this MDR reversal agent could only completely block the PGP mediate d MMDOX resistance whereas DOX refractoriness was only decreased. Conc lusions. The combination of MMDOX or IODODOX with PSC 1.6 mu M is more efficient than the combination of DOX plus PSC for the full reversion of PGP-mediated drug resistance. Careful clinical studies are require d to evaluate if these associations can also effectively and safely ne utralize MDR in vivo.