CELLULAR PHARMACOLOGY OF LIPOPHILIC ANTHRACYCLINES IN HUMAN TUMOR-CELLS IN CULTURE SELECTED FOR RESISTANCE TO DOXORUBICIN

We have studied the cytotoxicity and intracellular accumulation of two lipophilic anthracyclines, pirarubicin and idarubicin, as compared to doxorubicin, in two human tumor cell lines, MCF7 and K562, and in the ir doxorubicin-resistant counterparts, presenting the multidrug-resist ant (MDR) phenotype. The new lipophilic anthracyclines were found to p resent a higher cytotoxicity and accumulation than the reference anthr acycline, doxorubicin, and there was a significant inverse correlation between drug accumulation and IC50 in both cell types. With the aim o f identifying the reasons for the higher cytotoxicity and accumulation of lipophilic anthracyclines, we used and compared the efficiency of three MDR modulators, verapamil, quinine and S-9788. We showed that al l three were able to sensitize the resistant cells to the three anthra cyclines, but with different efficiencies, S-9788 being the most activ e reverter and quinine the least active at equimolar doses. We also ob served that there was no correlation between the abilities of a modula tor to reverse resistance and to restore drug accumulation. In view of the sustained activity of the modulators to increase pirarubicin and idarubicin cytotoxicity and accumulation, as they do for doxorubicin, we conclude that the better efficiency of lipophilic anthracyclines is likely to be due to their high uptake rate rather than to a decreased activity of P-glycoprotein on these drug substrates.