SDZ 280-125 - A CYCLOPEPTOLIDE ENDOWED WITH AN IN-VITRO CYCLOSPORINE A-LIKE PROFILE OF ACTIVITY FOR THE REVERSION OF THE P-GLYCOPROTEIN-MEDIATED MULTIDRUG-RESISTANCE OF TUMOR-CELLS

Tumor cells whose multidrug resistance is caused by the P-glycoprotein (Pgp) mediated anti-cancer drug (ACD) efflux can be chemosensitized b y cyclosporins, whose derivatives were found to display a whole range of resistance-modulating activities. Similarly, derivatives of the non -immunosuppressive natural fungus cyclic peptolide SDZ 90-215 were rec ently shown to display a broad range of chemosensitizing activities. W ith highly resistant cells expressing high levels of Pgp, one such com pound (SDZ 280-125) was shown here to restore both a normal sensitivit y to the growth-inhibitory effects of ACD and a normal retention of an anthracycline antibiotic. With both read-outs, SDZ 280-125 activity w as about 3-fold that of cyclosporin A (CsA). SDZ 280-125 also displaye d the same profile of chemosensitization as CsA for different ACD clas ses.