ROLE OF CELL CHOLESTEROL IN MODULATING VINCRISTINE UPTAKE AND RESISTANCE

The relationship between cell-membrane permeability to vincristine and cholesterol/phospholipid levels was studied in L5178Y murine leukemic lymphoblasts and in 2 multidrug-resistant cell sublines, VCR/P60 and VCR/P200, which expressed increasing levels of vincristine resistance. The uptake of H-3-vincristine was measured in all cell lines and in c holesterol-depleted and -reloaded L5178Y and VCR/P200 cells. The initi al rate of drug entry in resistant cells was lower than that measured in the parental cell line and it decreased as the relative resistance increased. An increment of cholesterol content, characterized in resis tant cells, was directly proportional to the relative resistance to vi ncristine. Cholesterol depletion in both sensitive and resistant cells resulted in an increase in the rate of vincristine uptake, which reve rted to the respective basal levels when each cell line was cholestero l-reloaded. The rate of drug uptake was inversely correlated with the molar ratio of cholesterol to phospholipids. Although both VCR/P cell sublines, but not the sensitive parental cells, expressed the P-glycop rotein in their plasma membrane, there were no differences in drug eff lux and retention between resistant and parental cells. These results indicate that cholesterol modulates the permeation of vincristine thro ugh the plasma membrane and strongly suggest that increased levels of cholesterol/phospholipid account for the lower drug accumulation and g reater resistance in these multidrug-resistant cells. (C) 1993 Wiley-L iss, Inc.