MECHANISMS REGULATING CELL RESISTANCE TO ADRIAMYCIN

已有证据表明中国仓鼠对阿霉素耐药 肺细胞由质膜的磷酸化调节 糖蛋白（P-180）。 我们已经发现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，当P-180被过度磷酸化时， 蛋白质变得无生物活性， 将所述抗性细胞转化为药物敏感表型。 了解这种反应的细节应该会提供相当多的信息 深入了解阿霉素耐药的基础。 在本研究中，我们 将详细分析参与调控的分子事件， P-180磷酸化。 将进行详细的研究，分析 P-180的磷酸化位点以及这些位点 在超磷酸化反应中被调节。 我们还将 确定在超磷酸化过程中是否存在拓扑 P-180在质膜上的重排。 其他研究将 进行鉴定和表征蛋白激酶活性 参与P-180的磷酸化。 可能调节 还将检测这些酶的活性。 还将进行研究，以确定是否超磷酸化的 P-180可作为检测少量 在耐药和敏感的异质群体中的耐药细胞 细胞 调节人肿瘤细胞阿霉素耐药性的机制将是 详细研究

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.