DECREASED UPTAKE OF CYCLOSPORINE-A BY P-GLYCOPROTEIN (PGP) EXPRESSINGCEM LEUKEMIC-CELLS AND RESTORATION OF NORMAL RETENTION BY PGP BLOCKERS

The P-glycoprotein (Pgp) molecules which are expressed on multidrug re sistant (MDR) tumor cells can efflux a variety of cytostatics. In both normal and tumoral epitheliums, Pgp molecules are selectively express ed on the apical surface of the epithelial cells. Such a distribution seems to be responsible for the transcellular transport of Pgp substra tes, including cyclosporin A (CsA), from the basal to the apical side. Some normal lymphoid cells also express small amounts of Pgp molecule s, for as yet unknown functions. Nevertheless, the sensitivity of thei r mitogen-induced proliferation to cytostatics, including doxorubicin and CsA, could be increased by the Pgp blockers. Using isotopically-la beled CsA and tumoral lymphoid cell lines, we now show a higher CsA re tention in Pgp-lacking parental ('Par') cells than in Pgp-expressing M on cells. The Pgp blockers can restore the CsA retention in the Mon ce lls to its level in the Par cells.