The role of polyamine oxidase in antitumor drug response

描述(由申请人提供)： 多胺分解代谢的诱导与几种新的抗肿瘤多胺类似物的细胞毒活性有因果关系。因此，这项提案的总体目标是检验多胺分解代谢酶、多胺氧化酶(PAO)活性与药物反应直接相关以及该酶可被操纵以获得治疗优势的假设。此前，PAO被认为是一种结构性表达的酶，受其底物乙酰化多胺的可用性调节。我们最近对人类PAO的克隆和初步鉴定清楚地表明，在几种重要的人类癌症中并非如此，可能代表了一种以前未知的多胺分解代谢途径。PAO分解多胺产生的产物之一是过氧化氢。H_2O_2被认为在决定肿瘤对多种药物，特别是抗肿瘤多胺类似物的反应中起着重要的机制作用。由于缺乏关键酶PAO的功能克隆，对过氧化氢产生的调控机制以及过氧化氢产生在肿瘤药物反应中的贡献还没有得到很好的研究。因此，这项提案的具体目的是为了扩大我们的初步发现，即证明PAO在特定的人类肿瘤中具有高度的诱导性。PAO活性在确定细胞对抗肿瘤多胺类似物的反应中的直接作用将被研究。初步结果表明，PAO的诱导是一种细胞类型和肿瘤类型特异的事件。因此，我们将确定调节正常细胞和肿瘤细胞中PAO表达的分子事件，以更好地了解它可能被抗肿瘤药物有效和特异性靶向的方式。总之，从拟议的研究中获得的信息对于理解PAO在确定抗癌药物敏感性中的作用将是非常有价值的，并应该深刻地增强将多胺代谢途径作为抗肿瘤策略的能力。

DESCRIPTION (provided by applicant): 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.