The objective of this project is to understand how human myeloma cells become resistant to the killing effects of the glucocorticoid dexamethasone (Dex). Three human myeloma cell lines have been established and characterized. One line ARH-77 is growth inhibited by Dex but not killed. Growth of ARH-77DR is completely unaffected by Dex. ARP-1 is killed by Dex by an apoptosis mechanism but can be made resistant by co-incubation with IL-6. The objective of this proposal will be to understand the mechanism of glucocorticoid resistance, particularly as mediated by IL-6. To this end the Specific Aims are to: fully characterize these cells growth response to Dex and IL-6; establish conditions for the effective use of molecular techniques such as transient expression of transfected genes and antisense suppression of expression; use short, defined regulatory sequences that are differentially expressed in the lines to determine differences in binding of trans-acting factors to known cis elements such as the GRE, AP-1, etc.; and, determine whether IL-6 produces Dex-resistance through alteration of fos/jun expression. The specific studies contained in this proposal will take advantage of cultured cell models with well- defined differences in Dex sensitivity. The investigators are experienced in the methodology and in the field of steroid hormone action. Upon completion, these studies will provide a better understanding of the development of hormone resistance which could lead to improved clinical approaches to the treatment of multiple myeloma.
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