The induction of polyamine catabolism has been causally linked to the cytotoxic activity of several new antitumor polyamine analogues. Therefore the overall objectives of this proposal are to test the hypotheses that the polyamine catabolic enzyme, polyamine oxidase (PAO) activity is directly linked to drug response and this enzyme can be manipulated for therapeutic advantage. PAO was previously thought to be a constitutively expressed enzyme regulated by the availability of its substrate, the acetylated polyamines. Our very recent cloning and initial characterization of a human PAO clearly demonstrates that this is not the case in several important human cancers and may represent a previously unrecognized pathway for polyamine catabolism. One of the products generated by the catabolism of polyamines by PAO is H2O2. H2O2 has been proposed to play an important mechanistic role in determining tumor responsiveness to various agents, particularly the antitumor polyamine analogues. The controlling mechanisms of H2O2 production and the contribution of H2O2 generation in tumor drug responsiveness have not been appropriately studied because of the lack of functional clones of the key enzyme, PAO. Therefore, the specific aims of this proposal are designed to expand our initial findings that demonstrate PAO is highly inducible in specific human tumors. The direct role of PAO activity in determining the cellular response to the antitumor polyamine analogues will be investigated. Preliminary results suggest that the induction of PAO is a cell type-and tumor type-specific event. Consequently, we will determine the molecular events that regulate the expression of PAO in normal and tumor cells to better understand ways in which it may be effectively and specifically targeted by antineoplastic agents. In summary, the information derived from the proposed studies will be invaluable in understanding the role of PAO in determining anticancer drug sensitivity and should profoundly enhance the ability to target the polyamine metabolic pathway as an antineoplastic strategy.
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