CYTOTOXICITY OF ANTITUMOR PLATINUM COMPLEXES WITH L-BUTHIONINE-(R,S)-SULFOXIMINE AND OR ETANIDAZOLE IN HUMAN CARCINOMA CELL-LINES SENSITIVEAND RESISTANT TO CISPLATIN/

Human 2008 ovarian carcinoma cells and the C13 CDDP-resistant subline and human MCF-7 breast carcinoma cells and the MCF-7/CDDP CDDP-resista nt subline were exposed to L-buthionine(S, R)-sulfoximine (50 mu M) fo r 48 h prior to and during exposure for 1 h to the antitumor platinum complexes, cis-diamminedichloroplatinum(II), carboplatin or D,L-tetrap latin and/or to etanidazole (1 mM) for 2 h prior to and during exposur e for 1 to the antitumor platinum complexes. These modulators alone di d not significantly alter the cytotoxicity of CDDP toward either paren tal line. A twofold enhancement in cytotoxicity was observed with carb oplatin in the 2008 cells and with D,L-tetraplatin in both parental li nes with the single modulators. The modulator combination (buthionine sulfoximine/etanidazole) was very effective along with D,L-tetraplatin in both the MCF-7 parent and MCF-7/CDDP cell lines where at the highe r platinum complex concentrations there was 1.5 to 3 logs increased ki lling of cells by the drug plus the modulators compared with the drug alone. Similarly, when C13 cells were exposed to CDDP (100 mu M) or D, L-tetraplatin (100 mu M) along with buthionine sulfoximine and etanida zole there was a 2-log increase in cell killing compared with exposure to the platinum complex alone. Treatment of each of the four cell lin es with buthionine sulfoximine decreased both the non-protein and tota l sulfhydryl content of the cells. Treatment with the combination of m odulators did not produce a further decrease in cellular sulfhydryl co ntent compared with buthionine sulfoximine alone. The total sulfhydryl content in MCF-7 cells and 2008 cells exposed to buthionine sulfoximi ne and etanidazole was 58% and 31% of normal and the total sulfhydryl content of MCF-7/CDDP cells and C13 cells treated the same way was 54% and 23% of normal, respectively. DNA alkaline elution was used to ass ess the impact of exposure to the modulators, buthionine sulfoximine a nd etanidazole, alone and in combination on the cross linking of DNA b y the antitumor platinum complexes in the MCF-7 and MCF-7/CDDP cell li nes. Overall, the increases in DNA cross linking factors were greater in the MCF-7 cells than in the MCF-7/CDDP cells. These results indicat e a possible clinical potential for this modulator combination.