ENHANCED TOPOISOMERASE-I ACTIVITY AND INCREASED TOPOISOMERASE II-ALPHA CONTENT IN CISPLATIN-RESISTANT CANCER CELL-LINES

Although the combined effects of cisplatin (CDDP) and DNA topoisomeras e (Topo) inhibitors have been described in recent literature, little i s known about the combined effects and their biological basis in CDDP- resistant cells. The aim of the present study was to elucidate the com bined effect of CDDP and Topo inhibitors on CDDP-resistant cells as we ll as to investigate the biological factors involved in the sensitivit y to these anti-cancer agents. We found synergistic actions between CD DP and SN-38 (a Topo I inhibitor) or VP-16 (a Topo II inhibitor) in KF r cells, a CDDP-resistant subline of the KF epithelial ovarian carcino ma cell line, but not in the parent KF cells. We subsequently assayed Topo protein levels and enzymatic activities in two sets of CDDP-sensi tive and -resistant cell lines: KF and KFr, and HeLa and HeLa/CDDP. Th e levels of Topo I protein in the CDDP-resistant cells did not differ from those of their parent cell lines and were unaffected by exposure to CDDP. Topo I enzymatic activity, however, was 2- to 4-fold higher i n the CDDP-resistant cell lines than in their respective parent cell l ines. In contrast, higher levels of Topo II alpha protein were observe d both before and after CDDP exposure in the CDDP-resistant cells than in their controls. However, no difference in Topo II catalytic activi ty was observed between the CDDP-resistant and -sensitive cells.