| Tumor cells often display a multidrug resistance phenotype whereby selection with one chemotherapeutic agent leads to a broad spectrum of resistance to other unrelated compounds. The MCF7 human breast carcinoma cell line exemplifies this phenomenon; cells selected in the presence of mitoxantrone (MCF7/MX) are highly resistant to the selective agent, but also display an unusual cross-resistance to the antifolate methotrexate (MTX). This cross-resistance has been characterized as a drug accumulation defect due to an ATP-dependent enhanced efflux. This phenotype does not correlate with any of the known mechanisms of MTX resistance involving alterations in uptake, target, and/or metabolism of this drug and thus, may represent a novel form of drug resistance. Here, we have positively correlated expression of the breast cancer resistance protein (BCRP), particularly the wild-type form (arginine 482), with MTX resistance. Further studies in vitro have supported this association; BCRP was demonstrated to transport MTX as well as MTX-polyglutamates. These studies revealed a novel role for BCRP as a mediator of MTX-transport and resistance, and have shown for the first time that MTX-polyglutamates can be effluxed from the cell. Together this work has expanded the field of multidrug resistance and may provide insight into a novel clinical mechanism of MTX resistance. |
