The ability of polyamine-directed agents to achieve meaningful and selective antitumor activity is indicated by preclinical efficacy studies and the recent progression of several agents to clinical trial. Fundamental findings linking polyamine biosynthesis to oncogenic dysregulation of the cell cycle and apoptosis lend understanding to these developments. As an alternative to strategies targeting polyamine biosynthesis, we submit that activation of pathways involved in polyamine catabolism or export out of the cell will have useful antiproliferative consequences. This assertion is predicated on the fact that conditional overexpression of the polyamine-acetylating enzyme, spermidine/spermine Nl-acetyltransferase (SSAT), depletes intracellular polyamine pools and inhibits cell growth. A recently identified novel mammalian spermine oxidase (SMO) has similar potential. Since both enzymes are now known to be inducible, strategies can be devised to exploit their ability to differentially contribute to polyamine pool depletion--SMO, by polyamine catabolism and SSAT, by facilitating polyamine export out of cells. The following Aims will genetically and pharmacologically evaluate the therapeutic potential of this approach.
Aim 1 will complete biochemical characterization of SMO and examine another recently discovered polyamine oxidase (PAO) with respect to substrate specificity, intracellular function and analog inducibility.
Aim 2 will examine the effects of conditional SMO or PAO over-expression on polyamine homeostasis and cell growth.
Aim 3 will develop transgenic mice that systemically overexpress SMO and PAO to determine the physiological and pharmacological significance of these genes.
Aim 4 will genetically evaluate the antitumor and/or tumor preventive potential of activated polyamine catabolism by cross-breeding SMO and SSAT transgenics with mice that are predisposed to intestinal neoplasia (APCmin). Guided by findings in Aim 4, Aim 5 will discover and develop small molecule modulators of polyamine catabolic enzymes as potential anticancer agents. In addition to evaluating a novel anticancer approach, the proposed studies have implications for improving the use of existing polyamine-directed therapies and for understanding Dolvamine homeostasis and its response to pharmacological perturbations. ? ?
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