Antiproliferative Potential of Polyamine Catabolism

多胺分解代谢的抗增殖潜力

• 批准号: 6730529
• 负责人: CARL W PORTER
• 金额: $ 38.5万
• 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/6730529
• 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)：临床前疗效研究和几种药物临床试验的最新进展表明，多胺导向的药物具有实现有意义和选择性的抗肿瘤活性的能力。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。作为以多胺生物合成为目标的策略的替代方案，我们提出，激活参与多胺分解代谢或输出到细胞外的途径将具有有用的抗增殖效果。这一断言是基于这样一个事实，即多胺乙酰化酶亚精胺/精胺NL-乙酰转移酶(SSAT)的条件性过表达会耗尽细胞内的多胺库并抑制细胞生长。最近发现的一种新的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，因此可以制定策略，通过促进多胺从细胞外输出来开发它们对多胺池耗竭的不同贡献能力--通过多胺分解代谢和SSAT而导致的SMO。以下目标将从遗传学和药理学上评估这种方法的治疗潜力。目标1将完成SMO的生化特征，并检测另一种新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的诱导性。目标2将研究条件性SMO或PAO过度表达对多胺稳态和细胞生长的影响。目的3将开发系统过表达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。目的通过将SMO和SSAT转基因基因与易患肠道肿瘤的小鼠(APCmin)杂交，从遗传学角度评价活化多胺分解代谢的抗肿瘤和/或肿瘤预防作用。在目标4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。除了评估一种新的抗癌方法外，拟议的研究还有助于改进现有多胺导向疗法的使用，并有助于理解多尔瓦明的稳态及其对药理扰动的反应。