BCRP/MXR/ABCP expression in topotecan-resistant human breast carcinoma cells

We have previously described a mitoxantrone-resistant MCF7 cell line that i s cross-resistant to topotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] (CPT-11), and 9-aminocamptothecin, but not to camptothecin. A novel mechani sm that resulted in decreased topotecan accumulation in MCF7/MX cells was p roposed (Yang et al. Cancer Res 55: 4004-4009, 1995). We now have developed a topotecan-resistant cancer cell line from wild-type MCF7 cells. MCF7/TPT 300 cells were 68.9-fold resistant to topotecan, 68.3-fold to 10-hydroxy-7- ethylcamptothecin (SN-38), and 116-fold to mitoxantrone, but only 4.1 fold to camptothecin. Topotecan efflux was increased in MCF7/TPT300 cells compar ed with MCF7/WT cells, and this increase was reversed upon ATP depletion by sodium azide, suggesting an energy-dependent drug efflux mechanism. Howeve r, MCF7/TPT300 cells did not overexpress P-glycoprotein or the multidrug re sistance-associated protein (MRP1). In contrast, overexpression of the brea st cancer resistance protein (BCRP/MXR/ABCP) was observed in MCF7/TPT300 ce lls as well as DNA topoisomerase I down-regulation. Our data suggest that e nhanced topotecan efflux contributes partly to topotecan resistance in MCF7 /TPT300 cells, possibly mediated by BCRP/MXR/ABCP. (C) 2000 Elsevier Scienc e Inc.