GENETIC ANALYSIS OF THE MULTIDRUG RESISTANCE PHENOTYPE IN TUMOR CELLS

肿瘤细胞多药耐药表型的遗传分析

• 批准号: 3796454
• 负责人: M GOTTESMAN
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3796454
• 关键词: P glycoprotein; Retroviridae; adenosinetriphosphatase; antineoplastics; bone marrow; cis platinum compound; complementary DNA; disease /disorder model; drug metabolism; gastrointestinal drug absorption; gene expression; gene therapy; genetic transduction; genetically modified animals; glycoproteins; human tissue; laboratory mouse; leukopenia; liposomes; membrane transport proteins; messenger RNA; model design /development; molecular cloning; molecular genetics; multidrug resistance; mutant; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplastic cell; nucleic acid sequence; phenotype; protein purification; transfection; transfection /expression vector

Resistance to chemotherapy of human cancers has been studied by establishing in vitro and in vivo genetic systems which mimic development of drug resistance. A major mechanism of multidrug resistance in human cancer is expression of the MDR1 gene which we have cloned and sequenced. Expression of the MDRI gene carried by retroviral vectors can be used to transduce cells to multidrug resistance and has been used to confer resistance to mouse bone marrow cells in vitro and in vivo. Mechanistic studies on P-glycoprotein suggest that it is involved in removing drug directly from the plasma membrane. To study mechanism, we have generated many mutants and initiated biochemical studies including the purification of P-glycoprotein and reconstruction of drugdependent ATPase activity in artificial liposomes.

人类癌症对化疗的抗性已经通过以下方法研究： 建立模拟发育的体外和体内遗传系统 抗药性的证据。人类多药耐药的主要机制 癌症是我们克隆和测序的MDR 1基因的表达。 由逆转录病毒载体携带的MDRI基因的表达可用于 使细胞产生多药耐药性，并已被用于 体外和体内对小鼠骨髓细胞的抗性。机械论 对P-糖蛋白的研究表明，它参与药物的清除， 直接从细胞膜上分离 为了研究机制，我们生成了 许多突变体，并启动了生化研究，包括纯化 P-糖蛋白和药物依赖性ATP酶活性的重建 人工脂质体。