Glucocorticosteroids are among the most effective agents for the treatment of lymphoid malignancies. However, glucocorticoid resistance frequently develops in malignant cells and limits the efficacy of therapy. The long term goal of this research is to understand the mechanism(s) of glucocorticoid resistance in human lymphoid leukemia and lymphoma cells and to develop a means of predicting which patients with leukemia and lymphoma are likely to become resistant to glucocorticoids during therapy. The immediate goal of this research is to understand the processes involved in glucocorticoid-induced cell lysis and its regulation in lymphoid cells. Studies will focus both on the """"""""receptor step"""""""" and the """"""""postreceptor step"""""""" in glucocorticoid-induced cell lysis The """"""""receptor step"""""""" is necessary for glucocorticoid-induced cell lysis and there evidence that the responsiveness of cells to glucocorticoids may be regulated by the intracellular concentration of glucocorticoid receptors. This research will focus on the postulate that glucocorticoids and antiglucocorticoids autoregulate intracellular receptor levels and thereby regulate glucocorticoid- induced cell lysis. The mechanisms involved in receptor autoregulation will be determined using a pulse-chase labeling technique to measure the effects of glucocorticoids and antiglucocorticoids on the rates of receptor synthesis and degradation in lymphoid cells. Ultimately, receptor upregulation maybe used to overcome glucocorticoid resistance and to improve the therapeutic efficacy of glucocorticoids in lymphoid malignancies. The """"""""postreceptor step"""""""" constitutes the series of events through which glucocorticoid-receptor complexes bring about cell death. This research will focus on the postulate that glucocorticoid induction of an endonuclease is the primary event in glucocorticoid-induced lysis of human lymphoid leukemia and lymphoma cells. Human lymphoid cells will be tested for glucocorticoid-induced DNA fragmentation and the endonuclease responsible for glucocorticoid induced DNA fragmentation will be identified and characterized. Antibodies to the endonuclease will be raised and used to study glucocorticoid-induced expression of the endonuclease in lymphoid leukemia.and lymphoma cells. Ultimately, failure of glucocorticoids to induce the endonuclease may prove to be a mechanism of glucocorticoid resistance in lymphoid malignancies.
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