HYPERSENSITIZING EFFECT OF PLURONIC L61 ON CYTOTOXIC ACTIVITY, TRANSPORT, AND SUBCELLULAR-DISTRIBUTION OF DOXORUBICIN IN MULTIPLE DRUG-RESISTANT CELLS

The present study demonstrated that poly(oxypropylene) and poly(oxyeth ylene) block copolymer pluronic L61 (L61)-hypersensitized multidrug-re sistant CH(R)C5 Chinese hamster ovary cells and MCF-7/ADR human breast carcinoma cells to the cytotoxic action of doxorubicin (Dox), CH(R)C5 and MCF-7/ADR cells manifested 290- and 700-fold increases, respectiv ely, in their sensitivity to Dox/L61 formulation compared with free Do x. Their sensitive counterparts Aux-B1 and MCF-7 displayed only margin al or no increase at all in their response to Dox/L61 The study of the drug transport performed by flow cytometry showed that L61 enhanced t he drug uptake and reduced the P-glycoprotein-mediated drug efflux, Vi sualization of Dox subcellular distribution in CH(R)C5 cells by fluore scent microscopy revealed that Dot was sequestered in cytoplasmic vesi cles, whereas incubation of the cells with Dox/L61 altered the drug co mpartmentalization by releasing the drug from these vesicles and shift ing it to the nucleus. These findings suggested that the hypersensitiv e response of multidrug-resistant cells to the action of Dox/L61 was c aused by an increase in the drug accumulation and changes in its subce llular distribution.