The role of polyamine oxidase in antitumor drug response

多胺氧化酶在抗肿瘤药物反应中的作用

• 批准号: 7076829
• 负责人: Robert A. Casero
• 金额: $ 31.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076829
• 关键词: DNA binding protein; RNase protection assay; amine oxidoreductase; antineoplastics; cell cycle; cell line; chemosensitizing agent; cytotoxicity; enzyme activity; enzyme induction /repression; enzyme mechanism; genetic regulatory element; hydrogen peroxide; molecular cloning; neoplasm /cancer pharmacology; neoplastic cell; oxidation; phenotype; polyamines; transcription factor; transfection /expression vector; yeast two hybrid system

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.

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性活性有关。因此，该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的假设，并且该酶可以被操纵以获得治疗优势。先前认为PAO是由其底物乙酰化多胺的可用性调节的组成型酶。我们最近对人类PAO的克隆和初始表征清楚地表明，在几种重要的人类癌症中并非如此，并且可能代表了以前未知的多胺分解代谢途径。 PAO对多胺的分解代谢产生的产品之一是H2O2。已提出H2O2在确定对各种药物（尤其是抗肿瘤多胺类似物）的肿瘤反应方面起着重要的机械作用。 H2O2产生的控制机制和H2O2在肿瘤药物反应性中的贡献尚未得到适当研究，因为密钥酶的功能克隆（PAO）缺乏功能克隆。因此，该提案的具体目的旨在扩大我们的初始发现，证明PAO在特定的人类肿瘤中是高度诱导的。 PAO活性在确定对抗肿瘤多胺类似物的细胞反应中的直接作用将被研究。初步结果表明，PAO的诱导是细胞类型和肿瘤类型特异性事件。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，以更好地理解抗肿瘤剂可以有效和专门针对的方法。总而言之，从拟议的研究中得出的信息对于理解PAO在确定抗癌药物敏感性的作用方面将非常宝贵，并应深刻地增强靶向多胺代谢途径作为抗肿瘤策略的能力。