Risk reduction through polyamine inhibition among colorectal carcinoma patients

通过多胺抑制降低结直肠癌患者的风险

基本信息

批准号：
8307547
负责人：
Jason Zell
金额：
$ 17.91万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-20 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307547
关键词：
Adverse effects Affect Aftercare Alleles Arginine Aspirin Biological Markers Biopsy Blood specimen Cancer Patient Cell Proliferation Cells Chemoprevention Clinical Clinical Trials Collection Colon Colon Carcinoma Colonic Neoplasms Colonic Polyps Colorectal Adenoma Colorectal Cancer Data Data Analyses Development Diagnosis Diet Dietary Intervention Endoscopy Environment Epidemiology Epithelial Female Genes Genetic Genetic Polymorphism Genetic Transcription Genetic Variation Genotype Goals Instruction Intake Intervention Investigation Large Intestine Carcinoma Life Malignant Neoplasms Measures Meat Metabolism Minor Modeling Mucous Membrane Neoplasm Metastasis Non-Steroidal Anti-Inflammatory Agents Oncogenes Oral Ornithine Decarboxylase Participant Patients Phase Polyamines Population Principal Investigator Putrescine Records Recurrence Regimen Regulation Regulator Genes Resected Risk Risk Reduction Role Sampling Serum Single Nucleotide Polymorphism Site Spermidine Spermidine/Spermine N1-Acetyltransferase Spermine Staging Study Subject Survival Rate Tissues Urine Variant Venous blood sampling adenoma arginine polyamine carcinogenesis colon carcinogenesis dietary restriction gene environment interaction genetic variant high risk improved in vivo male novel population based post intervention promoter rectal tumor progression urinary

项目摘要

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.

2007 年期间，估计诊断出 150,000 例结直肠癌 (CRC) 新病例美国，使其成为美国男性和女性中第三大常见癌症。即使在可能治愈后治疗后，结直肠癌患者仍面临继发性肿瘤的高风险。广泛的调查已经证明多胺调节在细胞增殖和癌变中很重要。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有益结肠癌发生和存活的影响，从而为减少组织多胺作为一种策略提供了理论依据用于结肠癌患者的三级化学预防。我们提议的 IIa 期的主要终点临床生物标志物试验（目标 1）将在 12 年后降低直肠组织中多胺腐胺的水平。对 24 例经过最佳治疗的局部晚期患者进行每日阿司匹林和饮食精氨酸限制的每周干预结肠癌患者。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：通过分析多胺调节基因分析结直肠癌病例中的精氨酸和多胺代谢鸟氨酸脱羧酶-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）。具有奇数 G315A 小 A 等位基因的患者与具有主要 G 等位基因的患者相比，已显示腺瘤复发的风险降低。 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。使用来自加州大学欧文分校 CRC 基因环境中 723 例 CRC 病例的现有血液样本研究（1994-1996），我们将确定与 Ode 小 A 等位基因病例相比，生存是否有所改善对于那些具有主要 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影响的膳食精氨酸/肉类摄入量影响生存。 Odc1 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膳食精氨酸/肉类摄入量对结直肠癌特异性生存率的影响。相关性（参见说明）：多胺是源自精氨酸的天然物质，过量会促进结肠肿瘤形成。在临床试验中，我们的目标是减少结肠癌患者每天使用的结肠多胺阿司匹林和限制精氨酸（即低肉）饮食。我们还将评估基因的遗传变异负责多胺调节，使用来自大规模人群的 CRC 研究的血液样本，以及确定这些基因变异如何与饮食精氨酸/肉类摄入相互作用以影响生存。