MECHANISMS REGULATING CELL RESISTANCE TO ADRIAMYCIN

调节细胞对阿霉素耐药的机制

• 批准号: 3175362
• 负责人: MELVIN S CENTER
• 金额: $ 6.61万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1987-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3175362
• 关键词: cell membrane; doxorubicin; drug resistance; gel electrophoresis; gene expression; neoplasm /cancer chemotherapy; pharmacokinetics; phosphorylation; protein kinase; cell membrane; doxorubicin; drug resistance; gel electrophoresis; gene expression; neoplasm /cancer chemotherapy; pharmacokinetics; phosphorylation; protein kinase

Evidence has been obtained that adriamycin resistance in Chinese hamster lung cells is regulated by phosphorylation of a plasma membrane glycoprotein (P-180). We have found that agents which enhance drug uptake in resistant cells induce a parallel superphosphorylation of P-180. Several lines of evidence indicates that as P-180 is superphosphorylated the protein becomes biologically inactive and this results in the conversion of the resistant cell to a drug sensitive phenotype. Understanding the details of this reaction should provide considerable insight into the basis of adriamycin resistance. In the present study we will analyze in detail the molecular events involved in the regulation of P-180 phosphorylation. Detailed studies will be carried out to analyze the sites of phosphorylation of P-180 and the mechanism by which these sites are modulated during the superphosphorylation reaction. We will also determine if during superphosphorylation there is a topological rearrangement of P-180 in the plasma membrane. Additional studies will be carried out to identify and characterize the protein kinase(s) activity involved in the phosphorylation of P-180. Factors which may regulate the activity of these enzymes will also be examined. Studies will also be conducted to determine if the superphosphorylation of P-180 could serve as a sensitive assay for detecting a small number of resistant cells in a heterogeneous population of resistant and sensitive cells. Mechanisms regulating adriamycin resistance in human tumor cells will be studied in detail.

已经有证据表明中国仓鼠中的阿霉素抗性 肺细胞受质膜的磷酸化调节 糖蛋白（P-180）。 我们发现可以增强药物吸收的药物 在抗性细胞中诱导P-180的平行超磷酸化。 几条证据表明，由于P-180被超磷酸化 该蛋白质在生物学上无活性，这导致 将抗性细胞转换为药物敏感表型。 了解该反应的细节应提供相当大的 深入了解阿霉素抗性的基础。 在本研究中，我们 将详细分析与调节有关的分子事件 P-180磷酸化。 将进行详细的研究以分析 P-180的磷酸化位点和这些位点的机制 在超磷酸化反应期间进行调节。 我们也会 确定在超磷酸化期间是否有拓扑 质膜中P-180的重排。 其他研究将是 进行识别和表征蛋白激酶的活性 参与P-180的磷酸化。 可能调节的因素 这些酶的活性也将被检查。 还将进行研究以确定是否的超磷酸化是否 P-180可以用作检测少数的敏感测定法 抗性和敏感的异质种群中的抗性细胞 细胞。 调节人类肿瘤细胞中adrimycin抗性的机制将是 详细研究。