Abnormalities in the regulation of Iymphocyte senescence and apoptosis are fundamental to the pathogenesis of lymphoproliferative diseases, and also play a role in the progression of autoimmune syndromes. The overall goal of this research grant is to identify these abnormalities, and to exploit the information pharmacologically for the development of better treatments for these disabling and often fatal ailments. Experiments supported by this grant since the last competitive review four years ago: (i) have demonstrated that purine deoxynucleosides with anti lymphocyte activity can directly stimulate Apaf 1 dependent caspase activation; (ii) have synthesized and analyzed novel substantiated indanones that induce apoptosis in chronic lymphocytic leukemia (CLL) cells without harming normal lymphocytes; (iii) have shown that the non steroidal anti inflammatory drug etodolac can depress malignant Iymphocyte counts in CLL patients; and (iv) have revealed that both the R and S enantiomers of etodolac interfere with mitochondrial respiration in CLL cells, cause rapid degradation of the anti apoptotic protein Mcl 1, and activate the nuclear hormone receptor PPARy. Based upon this progress, the specific aims of the renewal application are (1) to study in detail how different purine nucleosides interact with components of the apoptotic machinery in normal and malignant lymphocytes; (2) to clarify the biochemical basis for the selective toxicity of substituted indanones to malignant B cells, emphasizing changes in the cytoskeleton and cell death receptor expression; (3) to analyze the importance of PPARy, Mcl 1, and mitochondria in the regulation of cell survival in Iymphocytes, using R etodolac as a pharmacologic probe; and (4) to test the clinical activity of R etodolac in lymphoproliferative diseases and multiple myeloma. The proposed experiments differ from most other studies of apoptosis regulation because of their focus on quiescent cells, their utilization of lymphocytes taken directly from patients, and their aim to translate results quickly to the clinic. When complete, these experiments should enhance current knowledge of the factors that regulate senescence and apoptosis in non dividing lymphocytes, and could lead to less toxic and more effective therapies for lymphoproliferative and possibly autoimmune diseases.
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