THE EFFECT OF CROWN-ETHERS, TETRAALKYLAMMONIUM SALTS, AND POLYOXYETHYLENE AMPHIPHILES ON PIRARUBICIN INCORPORATION IN K562 RESISTANT CELLS

The basic distinguishing feature of all cells expressing functional P- glycoprotein-multidrug resistance (P-gp-MDR) is a decrease in steady-s tate accumulation drug levels as compared to drug-sensitive controls. In an attempt to identify mechanism(s) by which MDR can be circumvente d, we examined the cellular accumulation, in resistant cells, of 4'-O- tetrahydropyranyl-doxorubicin (pirarubicin) alone and in conjunction w ith various molecules belonging to three different classes: the crown ethers, the tetraalkylammonium salts, and the polyoxyethylene amphiphi les. The present study was performed using a spectrofluorometric metho d which enabled us to follow the uptake and release of fluorescent mol ecules by living cells while the cells were being incubated with the d rug. Erythroleukemia K562 cell lines were used. Our data show that the compounds of these three completely different classes were able to in crease the incorporation of pirarubicin provided they had a minimum de gree of lipophilicity. Study of the growth inhibitory activity of thes e compounds revealed that cross-resistance to the tetraalkyl ammonium salt increased with the lipophilicity and was equal to 58 for tetraoct ylammonium salt, the most lipophilic compound of this series. This dem onstrates that neither the presence of a positive charge nor an aromat ic moiety is required for MDR recognition.