The role of polyamine oxidase in antitumor drug response

描述（由申请人提供）： 多胺催化剂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，本提案的总体目标是测试多胺分解代谢酶、多胺氧化酶（PAO）活性与药物反应直接相关并且该酶可被操纵以获得治疗优势的假设。PAO以前被认为是一种组成型表达的酶，受其底物乙酰化多胺的可用性调节。我们最近克隆和初步鉴定的人PAO清楚地表明，这是不是在几个重要的人类癌症的情况下，并可能代表了一个以前未被认识的途径，多胺催化剂。通过PAO催化多胺生成的产物之一是H2O2。H2O2已被提出在确定肿瘤对各种药剂，特别是抗肿瘤多胺类似物的反应性中发挥重要的机制作用。由于缺乏关键酶PAO的功能性克隆，H2O2产生的控制机制以及H2O2产生在肿瘤药物反应中的贡献尚未得到适当的研究。因此，该提案的具体目标旨在扩展我们的初步发现，即PAO在特定的人类肿瘤中具有高度诱导性。将研究PAO活性在确定抗肿瘤多胺类似物的细胞反应中的直接作用。初步结果表明，PAO的诱导是一种细胞类型和肿瘤类型特异性事件。因此，我们将确定调节PAO在正常和肿瘤细胞中表达的分子事件，以更好地理解PAO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将是非常宝贵的，在了解的作用，PAO在确定抗癌药物的敏感性，并应深刻提高能力，以多胺代谢途径为目标的抗肿瘤策略。

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.