MECHANISMS REGULATING CELL RESISTANCE TO ADRIAMYCIN

已有证据表明中国仓鼠对阿霉素具有耐药性 肺细胞受质膜磷酸化的调节 糖蛋白(P-180)。我们发现促进药物摄取的药物 在耐药细胞中诱导平行的P-180过度磷酸化。 多条证据表明，由于P-180被过度磷酸化 蛋白质在生物学上变得不活跃，这导致 耐药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大的帮助 深入了解阿霉素耐药的基础。在目前的研究中，我们 将详细分析参与调控的分子事件 P-180的磷酸化。我们会进行详细研究，以分析 P-180的磷酸化位点及其作用机制 在过度磷酸化反应中被调节。我们还将 确定在过度磷酸化过程中是否存在拓扑 P-180在质膜上的重排。其他研究将包括 进行了蛋白激酶(S)活性的鉴定和表征 参与P-180的磷酸化。可能会调节 这些酶的活性也将被检测。 还将进行研究，以确定是否过度磷酸化 P-180可以作为一种敏感的检测方法来检测少量的 耐药细胞在耐药和敏感的异质群体中 细胞。 调节人类肿瘤细胞对阿霉素耐药性的机制将是 进行了详细的研究。

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.