Risk reduction through polyamine inhibition among colorectal carcinoma patients

在2007年期间，估计有150，000例新的结直肠癌（CRC）病例在美国被诊断出来。 美国，使其成为美国男性和女性中第三大常见癌症。即使在潜在的治疗之后 尽管如此，CRC患者仍然处于继发性肿瘤的高风险中。广泛的调查 表明多胺调节在细胞增殖和癌发生中是重要的。我们 初步实验和流行病学分析表明，非甾体抗炎药和限制精氨酸有益 对结肠癌发生和生存的影响，从而为组织多胺减少作为一种策略提供了理论基础。 用于结肠癌患者的三级化学预防。我们提出的IIa期的主要终点是 临床生物标志物试验（目标1）将减少直肠组织中的多胺腐胺水平，在12- 每日阿司匹林和饮食精氨酸限制对24例经最佳治疗的局部晚期 结肠癌患者。 在本提案的目标2中，我们将描述与以下相关的潜在有效基因-环境相互作用 大肠癌患者精氨酸和多胺代谢的多胺调节基因分析 鸟氨酸脱羧酶-1（Odc 1，参与多胺合成）和精脒精胺 乙酰转移酶（Ssat，参与多胺细胞输出）。携带Odd G315 A minor-A等位基因的患者 与携带主要G等位基因的患者相比， Ode A等位基因加阿司匹林的使用与结肠息肉复发的减少有关。使用 来自基于人群的UC Irvine CRC基因环境中723例CRC病例的现有血液标本 研究（1994-1996年），我们将确定与对照组相比， 主要G等位基因的人随后，我们将确定这些遗传效应是如何受到 饮食精氨酸/肉类摄入量影响存活率。Odc 1和Ssat中的其他多态性将 以类似的方式进行研究，以表征相关的遗传效应和基因-环境影响 与饮食精氨酸/肉类摄入量对CRC特异性存活率的影响有关。 相关性（参见说明）： 多胺是天然存在的物质，来源于精氨酸，过量，促进结肠肿瘤 阵在临床试验中，我们的目标是减少结肠癌患者的结肠多胺， 阿司匹林和限制性精氨酸（即，低肉）饮食。我们还将评估基因的遗传变异 负责多胺调节，使用来自一项大型人群CRC研究的血液标本， 确定这些基因变异如何与饮食精氨酸/肉类摄入量相互作用，以影响生存。

During the year 2007 an estimated 150,000 new cases of colorectal cancer (CRC) were diagnosed in the U.S., making it the third most common cancer among U.S. males and females. Even after potentially curative treatment, CRC patients remain at high risk for secondary tumors. Extensive investigations have demonstrated that polyamine regulation is important in cellular proliferation and carcinogenesis. Our preliminary experimental and epidemiologic analyses suggest a benefit from NSAIDs and arginine-restriction on colon carcinogenesis and survival, thus providing a rationale for tissue polyamine reduction as a strategy for tertiary chemoprevention among colon cancer patients. The primary endpoint of our proposed phase lla clinical biomarker trial (Aim 1) will be reduction in rectal tissue levels of the polyamine putrescine, after a 12- week intervention of daily aspirin and dietary arginine restriction in 24 optimally-treated locally advanced colon cancer patients. In Aim 2 of this proposal, we will describe potentially operative gene-environment interactions related to arginine and polyamine metabolism among CRC cases through analysis of the polyamine-regulatory genes ornithine decarboxylase-1(Odc1, involved in polyamine synthesis) and spermidine spermine acetyltransferase (Ssat, involved in polyamine cellular export). Patients with the Odd G315A minor-A allele have been shown to have decreased risk of adenoma recurrence compared to those with the major G-allele. The Ode A-allele plus aspirin usage has been associated with reduction in colon polyp recurrence. Using existing blood specimens from 723 CRC cases in the population-based UC Irvine CRC gene-environment study (1994-1996), we will determine if survival is improved for cases with the Ode minor-A allele compared to those with the major G-allele. Subsequently we will determine how these genetic effects are influenced by dietary arginine/meat intake to influence survival. Additional polymorphisms in Odc1 and Ssat will investigated in a similar manner, to characterize relevant genetic effects, and gene-environment influences related to dietary arginine/meat intake on CRC specific survival. RELEVANCE (See instructions): Polyamines are naturally occurring substances derived from arginine that, in excess, promote colon tumor formation. In a clinical trial, our goal is to decrease colonic polyamines in colon cancer patients using daily aspirin and a restricted arginine (i.e., low-meat) diet. We will also evaluate genetic variants of genes responsible for polyamine regulation, using blood specimens from a large population-based CRC study, and determine how these gene variants interact with dietary arginine/meat intake to influence survival.