MECHANISMS REGULATING CELL RESISTANCE TO ADRIAMYCIN

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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.