Antiproliferative Potential of Polyamine Catabolism

描述（由申请人提供）：临床前疗效研究和几种药物最近进入临床试验的进展表明，多胺导向药物能够实现有意义的选择性抗肿瘤活性。多胺的生物合成与致癌的细胞周期失调和细胞凋亡之间的联系使人们对这些发展有了更深入的了解。作为靶向多胺生物合成的策略的替代方案，我们认为激活多胺催化剂或出口到细胞外的途径将具有有用的抗增殖后果。这一断言的基础是，多胺乙酰化酶亚精胺/精胺NI-乙酰转移酶（SSAT）的条件性过表达会耗尽细胞内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）具有类似的潜力。由于这两种酶是现在已知的诱导型，策略可以被设计来利用它们的能力，差异有助于多胺池耗尽-SMO，通过多胺catalysts和SSAT，通过促进多胺输出细胞。以下目的将从遗传学和生物学角度评估这种方法的治疗潜力。目的1完成SMO的生化特性研究，并对新近发现的另一种多胺氧化酶（PAO）进行底物特异性、胞内功能和类似物诱导等方面的研究。目的2研究条件性SMO或PAO过表达对多胺稳态和细胞生长的影响。目的3建立系统性过表达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4将通过将SMO和SSAT转基因小鼠与易患肠肿瘤（APCmin）的小鼠杂交来遗传评估活化的多胺催化剂的抗肿瘤和/或肿瘤预防潜力。在目标4发现的指导下，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善现有多胺导向疗法的使用，并有助于了解Dolvamine体内平衡及其对药理学扰动的反应。

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.