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.
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.
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|Zell, Jason A; Ziogas, Argyrios; Bernstein, Leslie et al. (2010) Meat consumption, nonsteroidal anti-inflammatory drug use, and mortality among colorectal cancer patients in the California Teachers Study. Cancer Prev Res (Phila) 3:865-75|
|Zell, Jason A; Ziogas, Argyrios; Ignatenko, Natalia et al. (2009) Associations of a polymorphism in the ornithine decarboxylase gene with colorectal cancer survival. Clin Cancer Res 15:6208-16|