The central hypothesis of this proposal is that polyamines play key, albeit diverse, roles in cellular responses to physical and chemical stresses, including ionizing radiation, heat shock and certain anticancer chemotherapies. The specific hypothesis to be tested is that polyamines, or polyamine modifications resulting from catabolism, alter specific gene expression and that this altered pattern of gene expression affects cellular responses to stress.
The Specific Aims of this proposal are to: 1. Determine the physiological consequences of polyamine catabolism in human cells by selectively expressing/suppressing polyamine catabolic enzymes in cells deficient in this pathway. 2. Determine the mechanism(s) by which the polyamines, or their acetyl derivatives, affect the expression of specific genes, including the spermidine/spermine N1-acetyltransferase (N1-SAT), the first enzyme in polyamine catabolism, and the growth associated gene c-myc. The long term objective of this proposal is to understand the basic biochemical mechanisms of cellular stress responses. With this information, it will be possible determine if these mechanisms are altered in neoplastic cells and, if so, devise specific anti-cancer strategies, which selectively kill or prevent the growth of cancer cells and have limited toxicities against normal tissues. Additionally, a greater understanding of basic mechanisms of cellular stress responses will allow clinicians to more precisely design treatments which enhance the antitumor effects of conventional or novel cancer therapies.
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