STRUCTURE/FUNCTION AND REGULATION OF MRP

细胞对细胞毒性药物的耐药性是细胞免疫的主要障碍。 成功治疗播散性恶性肿瘤。 的出现 反复化疗后的耐药细胞， 多药耐药（MDR），其中存活的细胞暴露于一种天然的 产品药物变得同时耐一系列其他天然药物， 毒品产品。 我们现在已经证明，MRP，最近描述的 ABC转运蛋白超家族的成员，能够赋予 多药耐药 这一活动此前被认为是 仅与MDR 1相关。 尽管mrp的拓扑结构与 由两个亲水性ATP结合结构域组成， 氨基端疏水结构域，我们的实验表明， 赋予了独特的多药耐药模式。 像MDRI一样，mrp赋予 对多种亲脂性试剂，包括，阿霉素， 柔红霉素、VP-16、长春新碱、放线菌素D和米托蒽醌。 在 相反，它对天然产物几乎没有活性， 紫杉醇和长春碱。 我们的研究进一步表明， 位于细胞质膜，其独特的作用机制 包括促进药物在细胞质细胞器中的积累， 保护重要的核和细胞目标，并导致减少 细胞药物水平。 我们检测了15例正常乳腺组织中MRP的表达， 人组织以及55种肿瘤细胞系中的54种，包括乳腺， 结肠、肺、肉瘤、胃、黑色素瘤和星形细胞瘤。 综合这些 数据表明，MRP可能在固有的， 许多常见的细胞毒性耐药机制可能是获得性的， 实体瘤 鉴于其对大体积亲脂性化合物的活性， 也可能在保护免受致癌性外源性物质的影响方面发挥作用。 这 建议包含细胞和分子生物学实验， 阐明MRP的作用机制、结构与功能的关系 以及影响其表达的因素和机制。 这 这些信息将有助于我们了解分子结构 耐药性，这是必要的合理设计， 癌症治疗

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.