REVERSAL OF DRUG-RESISTANCE BY EXPOSURE OF MCF-7 OR MCF-7 CDDP HUMAN BREAST-CARCINOMA CELLS TO SR-4233 OR ETANIDAZOLE UNDER HYPOXIC CONDITIONS

Drug resistance is a major problem in cancer therapy. The MCF-7/CDDP c ell line, a subline of the MCF-7 human breast carcinoma cell line whic h is resistant to cis-diamminedichloroplatinum(II), is also resistant to carboplatin, D-tetraplatin and to a lesser degree to melphalan, thi otepa and BCNU compared with the MCF-7 parental cell line. This resist ance persists both under normally oxygenated conditions and after 2 h of exposure to hypoxic conditions prior to exposure to the antitumor a lkylating agents under normally oxygenated conditions. When the MCF-7 parental cells and MCF-7/CDDP cells were treated with SR-4233 (20 muM) or etanidazole (5 mM) for 2 h prior to and during exposure to the ant itumor alkylating agents there was no change in the sensitivity and re sistance patterns of the cell lines. However, if the MCF-7 parental ce lls and the MCF-7/CDDP cells were exposed to SR-4233 (20 muM) or etani dazole (5 mM) for 2 h under hypoxic conditions followed by release of the hypoxia and exposure to the antitumor alkylating agents for 1 h un der normally oxygenated conditions the resistance of the MCF-7/CDDP wa s reversed so that both the MCF-7 parental and MCF-7/CDDP cell lines w ere essentially equally sensitive to the six antitumor alkylating agen ts. These results indicate that non-cytotoxic concentrations of modula tors such as SR-4233 or etanidazole may be useful in reversing resista nce to the