CROSS-RESISTANCE TO CAMPTOTHECIN ANALOGS IN A MITOXANTRONE-RESISTANT HUMAN BREAST-CARCINOMA CELL-LINE IS NOT DUE TO DNA TOPOISOMERASE-I ALTERATIONS

We have previously described a mitoxantrone-resistant human breast car cinoma cell line, MCF7/MX, in which resistance was associated with a d efect in the energy-dependent accumulation of mitoxantrone in the abse nce of P-glycoprotein overexpression (M. Nakagawa et al., Cancer Res. 52: 6175-6181, 1992). We now report that this cell line is highly cros s-resistant to the camptothecin analogues topotecan (180-fold), 9-amin ocamptothecin (120-fold), CPT-11 (56-fold), and SN38 (101-fold), but i s only mildly cross-resistant to the parent compound camptothecin (3.2 -fold) and 10,11-methylenedioxy-camptothecin (2.9-fold). Topotecan acc umulation was decreased in MCF7/MX cells compared to parental MCF7/WT cells, and there was a corresponding reduction in topotecan-mediated s timulation of the enzyme/DNA complex formation in MCF7/MX cells compar ed to MCF7/WT cells. No overexpression of the multidrug resistance-ass ociated protein was detected compared to parental MCF7/WT cells. Furth ermore, both sensitive MCF7/WT and mitoxantrone-resistant MCF7/MX cell s contain equal amounts of DNA topoisomerase I protein, and DNA relaxa tion activities were equal in both cell lines and inhibited to the sam e extent by topotecan and camptothecin. Thus, these results suggest a novel mechanism of resistance to topoisomerase I inhibitors in cancer cells.