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 cell line, a subline of the MCF-7 human breast carcinoma cell line which is resistant to cis-diamminedichloroplatinum(II), is also resistant to carboplatin, D-tetraplatin and to a lesser degree to melphalan, thiotepa and BCNU compared with the MCF-7 parental cell line. This resistance persists both under normally oxygenated conditions and after 2 h of exposure to hypoxic conditions prior to exposure to the antitumor alkylating agents under normally oxygenated conditions. When the MCF-7 parental cells and MCF-7/CDDP cells were treated with SR-4233 (20 μM) or etanidazole (5 mM) for 2 h prior to and during exposure to the antitumor alkylating agents there was no change in the sensitivity and resistance patterns of the cell lines. However, if the MCF-7 parental cells and the MCF-7/CDDP cells were exposed to SR-4233 (20 μM) or etanidazole (5 mM) for 2 h under hypoxic conditions followed by release of the hypoxia and exposure to the antitumor alkylating agents for 1 h under normally oxygenated conditions the resistance of the MCF-7/CDDP was reversed so that both the MCF-7 parental and MCF-7/CDDP cell lines were essentially equally sensitive to the six antitumor alkylating agents. These results indicate that non-cytotoxic concentrations of modulators such as SR- 4233 or etanidazole may be useful in reversing resistance to the antitumor alkylating agents in solid tumors with significant hypoxic fractions.