REVERSION OF THE P-GLYCOPROTEIN-MEDIATED MULTIDRUG RESISTANCE OF CANCER-CELLS BY FK-506 DERIVATIVES

FK-506 is a resistance-modulating agent (RMA) for tumor cells whose mu ltidrug resistance (MDR) involves a P-glycoprotein (Pgp)-mediated anti -cancer drug efflux. The family of FK-506 relatives and derivatives in cludes analogs which display a whole range of chemosensitizing strengt hs, from no detectable RMA activity to a complete reversion of the MDR phenotype. Similarly, FK-506 analogs display a whole range of immunos uppressive activities, including inactive ones. FK-506 was compared fo r RMA activity with 11 FK-506 analogs which were at least 20-fold less active than FK-506 for the inhibition of the bi-directional mixed lym phocyte reaction displayed the whole range of RMA activity. One such s trong RMA derivative of FK-506 (SDZ 280-629) was further shown able to restore completely daunomycin retention by highly resistant MDR P388 tumor cells.