The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2)

Mechanisms of drug resistance other than P-glycoprotein are of increasing i nterest as the list of newly identified members of the ABC transport family has grown, We sought to characterize the phenotype of the newly discovered ABC transporter encoded by the mitoxantrone resistance gene, MXR, also kno wn as ABCP1 or BCRP, The pharmacodynamics of mitoxantrone and 12 other fluo rescent drugs were evaluated by confocal microscopy in four multidrug-resis tant human colon (S1) and breast (MCF-7) cancer cell lines, We utilized two sublines, MCF-7 AdVp3000 and S1-M1-80, and detected overexpression of MXR by PCR, immunoblot assay and immunohistochemistry. These MXR overexpressing sublines were compared to cell lines with P-glycoprotein and MRP-mediated resistance. High levels of cross-resistance were observed for mitoxantrone, the anthracyclines, bisantrene and topotecan. Reduced levels of mitoxantro ne, daunorubicin, bisantrene, topotecan, rhodamine 123 and prazosin were ob served in the two sublines with high MXR expression, Neither the P-glycopro tein substrates vinblastine, paclitaxel, verapamil and calcein-AM, nor the MRP substrate calcein, were extruded from MCF-7 AdVp3000 and S1-M1-80 cells , Thus, the multidrug-resistant phenotype due to MXR expression is overlapp ing with, but distinct from, that due to P-glycoprotein. Further, cells tha t overexpress the MXR protein seem to be more resistant to mitoxantrone and topotecan than cells with P-glyeoprotein-mediated multidrug resistance, Ou r studies suggest that the ABC half-transporter, MXR, is a potent, new mech anism for conferring multiple drug resistance, Definition of its mechanism of transport and its role in clinical oncology is required.