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: 3796491
• 负责人: I PASTAN
• 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/3796491
• 关键词: P glycoprotein; adenosinetriphosphatase; bone marrow; gene expression; genetic transduction; human tissue; intracellular transport; laboratory mouse; liposomes; membrane permeability; molecular cloning; multidrug resistance; mutant; neoplasm /cancer chemotherapy; neoplastic cell; protein purification; tissue /cell culture; 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 MDR1 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 drug-dependent ATPase activity in artificial liposomes.

人类癌症的化疗耐药性已被研究 建立模拟发育的体外和体内遗传系统 的耐药性。 人类多重耐药的主要机制 癌症是我们已克隆并测序的 MDR1 基因的表达。 逆转录病毒载体携带的MDR1基因的表达可用于 转导细胞产生多药耐药性并已被用于赋予 体外和体内对小鼠骨髓细胞的抵抗力。 机械论 P-糖蛋白的研究表明它参与药物的清除 直接来自质膜。 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-糖蛋白的变化和药物依赖性 ATP 酶活性的重建 人工脂质体。