HYPERSENSITIZATION OF MULTIDRUG-RESISTANT HUMAN OVARIAN-CARCINOMA CELLS BY PLURONIC P85 BLOCK-COPOLYMER

The chemosensitizing effects of Pluronic P85 block copolymer were stud ied using two human ovarian carcinoma sublines: the glycoprotein P (P- gp) multidrug resistant (MDR) SKVLB cells and non-MDR SKOV3 cells. The dramatic increase (up to 700 times) in the daunorubicin cytotoxic act ivity was observed in the presence of 0.01% (22 mu M) to 1% (2.2 mM) c opolymer in the case of SKVLB cells. By contrast, the copolymer induce d a less than 3-fold increase in the drug activity in SKOV3 cells. As a result, the MDR subline demonstrated much higher response (''hyperse nsitivity'') to-the daunorubicin/Pluronic compared to that of the non- MDR cells. The copolymer increased the cytotoxic effects of other MDR type drugs (doxorubicin, epirubicin, vinblastine, and mitomycin C) by a factor of 20-1000 and non-MDR type drugs (methotrexate and cisplatin ) by a factor of 2-5.5. The daunorubicin influx in the cytoplasm and n uclei of SKVLB cells was also increased in the presence of the copolym er, while in SKOV3 cells, it remained practically unchanged. However, the hypersensitization of the MDR cells by the copolymer could not be merely explained by the P-gp modulation. Therefore, the possible role of the copolymer in inhibition of non-P-gp drug resistance is hypothes ized, which may also explain the sensitization of MDR cells with respe ct to non-MDR type drugs as well as sensitization of parental cells. T he concentration dependence of the IC50 in MDR cells indicates that ju st the copolymer unimers are responsible for the hypersensitization ef fect. The results obtained suggest that Pluronic P85 can be used as a delivery system to enhance the activity of antineoplastic agents again st MDR tumors.