Risk and risk reduction involving arginine intake and meat consumption in colorectal tumorigenesis and survival

Int J Cancer. 2007 Feb 1;120(3):459-68. doi: 10.1002/ijc.22311.

Abstract

Elevated polyamine and nitric oxide levels (both derived from arginine) promote tumorigenesis, whereas non-steroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal cancer (CRC) incidence in experimental and epidemiologic studies. We investigated dietary arginine-induced intestinal tumorigenesis and NSAID-inhibitory effects in Apc(Min/+) mice differentially expressing nitric oxide synthase-2 (Nos2). We also studied effects of estimated arginine exposures through meat consumption on tumor characteristics and survival in human CRC cases. Dietary arginine increased high-grade colon adenoma incidence in Apc(Min/+)Nos2(+/+) mice, but not in Nos2 knockout mice. Additionally, celecoxib suppressed intestinal steady state ornithine decarboxylase RNA levels (p < 0.001), induced steady state spermidine/spermine N(1)-acetyltransferase RNA levels (p = 0.002), decreased putrescine levels (p = 0.04) and decreased tumor number in the small intestines of Apc(Min/+)Nos2(+/+) mice (p = 0.0003). Five hundred and eleven cases from our NCI-supported CRC gene-environment study were analyzed based on self-reported meat (as a surrogate for arginine) consumption. Familial CRC cases (n = 144) in the highest meat consumption quartile (Q4) had no statistically significant differences in tumor grade compared to cases in Q1-Q3 (p = 0.32); however, they were observed to have decreased overall survival (OS) (10-year OS = 42% vs. 65%; p = 0.017), and increased risk of death in an adjusted analysis (hazards ratio [HR] = 2.24; p = 0.007). No differences in tumor grade, OS or adjusted HR were observed for sporadic CRC cases (n = 367) based on meat consumption. Our results suggest important roles for arginine and meat consumption in CRC pathogenesis, and have implications for CRC prevention.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetyltransferases / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Arginine / administration & dosage*
  • Arginine / metabolism
  • Celecoxib
  • Colonic Neoplasms / etiology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colorectal Neoplasms / etiology*
  • Colorectal Neoplasms / physiopathology
  • Eating / physiology*
  • Female
  • Gene Expression / drug effects
  • Humans
  • Male
  • Meat / adverse effects*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Ornithine Decarboxylase / genetics
  • Polyamines / metabolism
  • Pyrazoles / pharmacology
  • Risk Factors
  • Sulfonamides / pharmacology
  • Survival Analysis

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Polyamines
  • Pyrazoles
  • Sulfonamides
  • Arginine
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Acetyltransferases
  • diamine N-acetyltransferase
  • Ornithine Decarboxylase
  • Celecoxib