A. Venne et al., HYPERSENSITIZING EFFECT OF PLURONIC L61 ON CYTOTOXIC ACTIVITY, TRANSPORT, AND SUBCELLULAR-DISTRIBUTION OF DOXORUBICIN IN MULTIPLE DRUG-RESISTANT CELLS, Cancer research, 56(16), 1996, pp. 3626-3629
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.