GENETIC ANALYSIS OF MULTIDRUG RESISTANCE GENES

肿瘤对几种药物的耐药性(多药耐药，MDR)是 癌症化疗的一个主要限制。在一些肿瘤中，多药耐药是 与P-糖蛋白/(Pgp)多药耐药基因的过度表达有关 多药耐药相关蛋白(MRP)。PGP和MRP是成员 三磷酸腺苷(ATP)依赖的转运蛋白家族的成员 已被证明会导致多种化合物的外流 从牢房里出来的。该基因家族被称为三磷酸腺苷结合盒 (ABC)家族，其成员运输多种不同的化合物 穿过细胞和组织的膜。人类的ABC基因是 参与了包括囊性纤维化在内的多种疾病， 肾上腺皮质营养不良与家族性持续性高胰岛素血症 低血糖症。寻找与多药耐药相关的新基因 我们已经鉴定了21个新的人类ABC基因。的遗传定位 这些基因中的每一个以及它们的表达模式 下定决心。其中一个基因MRP3主要在 肝脏。这种基因在一组细胞中的表达 已经对4万个潜在的化疗家庭进行了筛查 评估过了。这些数据提供了有关分子性质的信息 由MRP3运输。我们已经克隆了一个秀丽线虫的同源物 并测定了人MRP基因MRP-1的表达 在这种线虫的细胞里。MRP-1基因在几个组织中表达 动物中的分泌细胞，符合基因发挥的作用 在去除有毒化合物方面。MRP-1基因突变的研究 基因证明它对镉的去除是必不可少的，一种 人类MRP基因的功能。MRP功能的动物模型 应有助于进一步了解其作用机制。 这种药物和重金属转运体。

Resistance of tumors to several drugs (Multidrug Resistance, MDR) is a major limitation of cancer chemotherapy. In some tumors MDR is due to the overexpression of the P-glycoprotein/(PGP)MDR gene, or the multidrug resistance-related protein (MRP). PGP and MRP are members of a family of adenosine triphosphate (ATP)-dependent transporters and have been shown to cause the efflux of a large variety of compounds from the cell. The gene family is known as the ATP-binding cassette (ABC) family, and its members transport multiple diverse compounds across the membranes of cells and tissues. Human ABC genes are involved in a number of diseases including cystic fibrosis, adrenoleuko-dystrophy, and familial persistent hyperinsulinemic hypoglycemia. To identify new genes involved in multidrug resistance we have characterized 21 new human ABC genes. The genetic location of each of these genes as well as their expression pattern has been determined. One of these genes, MRP3, is expressed predominantly in the liver. The expression of this gene in a panel of cells used for the screening of 40,000 potential chemotherapeutic families has been assessed. This data provides information on the nature of molecules transported by MRP3. We have cloned a Caenorhabditis elegans homolog of the human MRP gene mrp-1 and determined the expression of the gene in the cells of this nematode. The mrp-1 gene is expressed in several secretory cells in the animal, consistent with the gene playing a role in the removal of toxic compounds. Genetic disruption of the mrp-1 gene demonstrates that it is essential for removal of cadmium, a function of the human MRP gene. This animal model of MRP function should be useful in further understanding the mechanism of action of this drug and heavy metal transporters.