Antiproliferative Potential of Polyamine Catabolism

多胺分解代谢的抗增殖潜力

• 批准号: 7031629
• 负责人: CARL W PORTER
• 金额: $ 38.63万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031629
• 关键词: acyltransferase; antineoplastics; biotransformation; enzyme activity; enzyme induction /repression; enzyme linked immunosorbent assay; genetically modified animals; high performance liquid chromatography; laboratory mouse; neoplasm /cancer chemotherapy; neoplastic growth; nonhuman therapy evaluation; pharmacokinetics; polyamines; polymerase chain reaction; spermidine; spermine

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：临床前功效研究和近期几种药物进入临床试验的进展表明，多胺定向药物能够实现有意义的和选择性的抗肿瘤活性。将多胺生物合成与细胞周期和细胞凋亡的致癌失调联系起来的基本发现有助于理解这些发展。作为针对多胺生物合成的策略的替代方案，我们认为激活参与多胺分解代谢或输出到细胞外的途径将产生有用的抗增殖后果。这一论断基于以下事实：多胺乙酰化酶、亚精胺/精胺N1-乙酰转移酶(SSAT)的条件性过度表达会耗尽细胞内多胺池并抑制细胞生长。最近发现的一种新型哺乳动物精胺氧化酶（SMO）也具有类似的潜力。由于现在已知这两种酶都是可诱导的，因此可以设计策略来利用它们通过多胺分解代谢和 SSAT 通过促进多胺从细胞中输出来差异性地促进多胺池耗尽的能力。以下目标将从遗传学和药理学角度评估这种方法的治疗潜力。目标 1 将完成 SMO 的生化表征，并检查另一种最近发现的多胺氧化酶 (PAO) 的底物特异性、细胞内功能和类似物诱导性。目标 2 将检查条件性 SMO 或 PAO 过度表达对多胺稳态和细胞生长的影响。目标 3 将培育出系统性过度表达 SMO 和 PAO 的转基因小鼠，以确定这些基因的生理和药理学意义。目标 4 将通过将 SMO 和 SSAT 转基因小鼠与易患肠道肿瘤 (APCmin) 的小鼠杂交，从基因角度评估活化多胺分解代谢的抗肿瘤和/或肿瘤预防潜力。在目标 4 的研究结果的指导下，目标 5 将发现和开发多胺分解代谢酶的小分子调节剂作为潜在的抗癌药物。除了评估一种新型抗癌方法之外，拟议的研究还对改善现有多胺导向疗法的使用以及了解 Dolvamine 稳态及其对药理学扰动的反应具有重要意义。