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

• 批准号: 8103149
• 负责人: Jason Zell
• 金额: $ 17.85万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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/8103149
• 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 Polyps; Colorectal Adenoma; Colorectal Cancer; Data; Data Analyses; Development; Diagnosis; Dietary Intervention; Endoscopy; Environment; Epidemiology; Epithelial; Female; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genotype; 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; high risk; improved; in vivo; male; novel; population based; post intervention; promoter; rectal; tumor progression; urinary

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.

描述（由申请人提供）：2007年，美国估计有15万例结直肠癌（CRC）新病例被诊断出来，使其成为美国男性和女性中第三大常见癌症。即使经过潜在的治愈治疗，结直肠癌患者继发肿瘤的风险仍然很高。广泛的研究表明，多胺调节在细胞增殖和癌变中起重要作用。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益，从而为减少组织多胺作为结肠癌患者三级化学预防策略提供了理论依据。我们提出的i期临床生物标志物试验（Aim 1）的主要终点将是在24例局部晚期结肠癌患者中，经过12周的每日阿司匹林和饮食精氨酸限制干预后，直肠组织中多胺腐胺水平的降低。在本提案的目标2中，我们将通过分析多胺调控基因鸟氨酸脱羧酶-1（Odc1，参与多胺合成）和亚精胺乙酰转移酶（Ssat，参与多胺细胞输出）来描述CRC病例中与精氨酸和多胺代谢相关的潜在有效基因-环境相互作用。与具有主要g等位基因的患者相比，具有奇数G315A小a等位基因的患者具有较低的腺瘤复发风险。a型等位基因加上阿司匹林的使用与结肠息肉复发率的降低有关。利用加州大学欧文分校（UC Irvine）基于人群的结直肠癌基因环境研究（1994-1996）中723例结直肠癌病例的现有血液标本，我们将确定携带小等位基因Ode -a的病例是否比携带大等位基因g的病例生存率更高。随后，我们将确定这些遗传效应如何受到膳食精氨酸/肉类摄入量的影响，从而影响生存。Odc1和Ssat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，以及与饮食精氨酸/肉类摄入量有关的基因环境对结直肠癌特异性生存的影响。