GENETIC ANALYSIS OF MULTIDRUG RESISTANCE GENES

虽然大量的肿瘤可以在最初成功地治疗 对于化疗，对药物产生抗药性是一个主要原因。 限制。在治疗后耐药的肿瘤通常 对多种药物产生抗药性。这种多药耐药性(MDR)， 在某些情况下，至少是由于P-的过度表达 糖蛋白/MDR基因。MDR基因的功能类似于三磷酸腺苷 (ATP)依赖型泵，可挤出多种疏水性物质 细胞中的化合物。尽管MDR基因的正常功能是 未知的是，它们是膜结合运输超家族的一部分。 分子，三磷酸腺苷结合盒(ABC)超家族。使用分子 我们已经确定了几个MDR相关基因的克隆技术 简单的真核物种和细菌。一个完整的序列 对果蝇黑腹果蝇基因(Mdr50)进行了测定，并对该基因进行了鉴定。 被定位到2号染色体，50号带。有两个基因的特征来自于 酵母，酿酒酵母。这些基因已经被放置在 获得了基因的遗传图谱和基因突变。 目前我们正在测试一些化疗药物，看看是否 抵抗力或敏感度的增加是由这些基因控制的。一个MDR- 大肠埃希氏菌的相关基因已完成测序。这 基因，mdl，是迄今为止这个超家族中最大的基因 在细菌中鉴定出来的。该基因的突变不会影响 细菌的生存能力以及该基因在药物中的潜在作用 抵抗力正在接受检查。如果这些基因编码的蛋白质能够 被展示为运输毒品，他们可能会提供更好的 了解多药耐药基因的功能和多药耐药的发展。 对DNA序列数据库的搜索揭示了at的存在 人类中至少有15个ABC超家族的未特定化成员 基因组。来自其中两个基因的探针表明，它们是 以组织特有的方式表达，并且它们映射到不同的 染色体。这些基因的遗传特征可能揭示出一些 可能参与运输的重要功能分子 细胞对物质的反应。

Although a large number of tumors can be successfully treated initially with chemotherapy, the development of resistance to drugs is a major limitation. Tumors that are resistant following treatment are often resistant to more than one drug. This multidrug resistance (MDR), at least in some cases, is due to the overexpression of the P- glycoprotein/MDR genes. The MDR genes function as adenosine triphosphate (ATP)-dependent pumps that can extrude a wide variety of hydrophobic compounds from the cell. Although the normal function of the MDR genes is not known, they are part of a superfamily of membrane-bound transport molecules, the ATP-binding cassette (ABC) superfamily. Using molecular cloning techniques we have characterized several MDR-related genes from simple eukaryotic species and bacteria. The complete sequence of a Drosophila melanogaster gene (Mdr50) was determined and the gene was mapped to chromosome 2, band 50. Two genes have been characterized from the yeast, Saccromyces cerevisiae. These genes have been placed onto the genetic map and genetic disruptions of the genes have been obtained. Currently we are testing a number of chemotherapy drugs to see whether increased resistance or sensitivity is controlled by these genes. A MDR- related gene from Escherichia coli has been completely sequenced. This gene, mdl, is the largest gene of this superfamily to date that has been identified in bacteria. Mutations in the gene fail to affect the viability of bacteria, and the potential role of this gene in drug resistance is being examined. If the proteins encoded by these genes can be demonstrated to transport drugs, they may provide a better understanding of the function of MDR genes and the development of MDR. Searches of the DNA sequence data bases have revealed the presence of at least 15 uncharacterized members of the ABC superfamily in the human genome. Probes from two of these genes demonstrate that they are expressed in a tissue-specific manner, and that they map to different chromosomes. Genetic characterization of these genes may reveal a number of functionally important molecules that may be involved in the transport of substances by cells.