Risk reduction through polyamine inhibition among colorectal carcinoma patients

描述(申请人提供)：2007年，美国估计新增15万例结直肠癌(CRC)病例，使其在美国男性和女性中排名第三。即使经过潜在的根治治疗，结直肠癌患者仍有发生继发性肿瘤的高风险。广泛的研究表明，多胺调节在细胞增殖和癌症发生中起着重要作用。我们的初步实验和流行病学分析表明，非甾体抗炎药和精氨酸限制对结肠癌的发生和生存有好处，因此提供了组织多胺减少作为结肠癌患者三级化学预防策略的理论基础。我们建议的11a期临床生物标记物试验(AIM 1)的主要终点将是减少直肠组织中多胺腐胺的水平，在24名局部接受最佳治疗的晚期结肠癌患者进行为期12周的每日阿司匹林和饮食精氨酸限制的干预后。在本提案的目标2中，我们将通过分析多胺调节基因鸟氨酸脱羧酶-1(Odc1，参与多胺合成)和亚精胺精胺乙酰转移酶(SSAT，参与多胺细胞输出)，描述与精氨酸和多胺代谢相关的潜在的基因-环境相互作用。携带奇数G315A小A等位基因的患者与携带主要G等位基因的患者相比，腺瘤复发的风险降低。Ode A等位基因加上阿司匹林的使用与结肠息肉复发的减少有关。利用基于人群的UC Irvine CRC基因环境研究(1994-1996)中723例CRC患者的现有血液样本，我们将确定与那些具有主要G等位基因的患者相比，Ode Minor-A等位基因的患者的存活率是否有所提高。随后，我们将确定这些遗传效应是如何通过饮食精氨酸/肉类摄入量来影响生存的。Odc1和SSAT的其他多态将以类似的方式进行研究，以表征相关的遗传效应，以及与饮食精氨酸/肉类摄入量相关的基因环境对结直肠癌特定存活率的影响。

DESCRIPTION (provided by applicant): 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.