STRUCTURE/FUNCTION AND REGULATION OF MRP

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Cellular resistance to cytotoxic drugs is a major obstacle to the successful treatment of disseminated malignancies. The emergence of resistant cells after repeated courses of chemotherapy is exacerbated by multidrug resistance (MDR), in which surviving cells exposed to one natural product drug become simultaneously resistant to a spectrum of other natural product drugs. We have now demonstrated that mrp, a recently described member of the ABC superfamily of transporters, is capable of conferring multidrug resistance. This activity was previously thought to be associated only with MDR1. Although the topology of mrp is similar to that of mDR1, consisting of two hydrophilic ATP binding domains appended to amino terminal hydrophobic domaines, our experiments indicate that mrp confers a distinct pattern of multidrug resistance. Like MDRI, mrp confers resistance to a variety of lipophilic agents, including, doxorubicin, daunorubicin, VP-16, vincristine, actinomycin D, and mitoxantrone. In contrast however, it has little or no activity for the natural products taxol and vinblastine. Our studies have further shown that the mrp is located in cytoplasmic membranes, and that its distinct mechanism of action involves facilitating drug accumulation in cytoplasmic organelles, thereby protecting vital nuclear and cellular targets, and leading to reduced cellular drug levels. We have detected mrp expression in each of 15 normal human tissues, as well as in 54 of 55 tumor cell lines, including breast, colon, lung, sarcoma, gastric, melanoma and astrocytoma. Together these data suggest that mrp may play an important role in the inherent, and possibly acquired, cytotoxic drug resistance mechanisms of many common solid tumors. In view of its activity for bulky lipophilic compounds it may also play a role in protection from carcinogenic xenobiotics. This proposal contains cellular and molecular biological experiments to elucidate the mrp mechanism of action, its structure function relationships and the agents and mechanism that influence its expression. This information will contribute to our understanding of the molecular framework of drug resistance, which is necessary for the rationale design of improved cancer treatments.