Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line

Topotecan- or mitoxantrone-selected cell lines (T8 and MX3, respectively), derived from the human IGROV1 ovarian cancer cell line, were resistant to t he topoisomerase I inhibitors topotecan, SN-38 (the active metabolite of ir inotecan), and 9-aminocamptothecin, as well as to the topoisomerase IT drug mitoxantrone. In both resistant cell lines, decreased accumulation of topo tecan and mitoxantrone was observed, caused by enhanced energy-dependent ef flux of the drugs involved, Zn both cell lines, we found that the breast ca ncer resistance protein/mitoxantrone resistance/ placenta-specific ATP bind ing cassette (BCRP/MXR/ABCP) gene was overexpressed. Furthermore, BCRP/MXR/ ABCP expression levels in various partially revertant T8 cells correlated w ith the levels of resistance to topotecan, SN-38, and mitoxantrone, strongl y suggesting BCRP/MXR/ ABCP to be the transporter responsible for the enhan ced efflux, Pharmacodynamic analysis demonstrated that BCRP/MXR/ABCP is a v ery efficient transporter of topotecan; in vitro, 70% of the intracellular topotecan pool was transported out of the T8 or MX3 cells within 30 s, In c onclusion, we report for the first time that BCRP/MXR/ABCP can also be upre gulated upon exposure of tumor cells to the clinically important drug topot ecan, and that BCRP-mediated efflux of topotecan is very efficient. This hi ghly efficient efflux of topotecan by BCRP/MXR/ABCP may have clinical relev ance for patients being treated with topotecan.