title: Risk and risk reduction involving arginine intake and meat consumption in colorectal tumorigenesis and survival.
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.
authors.affiliation: Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA 92697-7550, USA. jzell@uci.edu
authors.forename: Jason A
authors.initials: JA
authors.lastname: Zell
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Ignatenko
authors.forename: Hagit F
authors.initials: HF
authors.lastname: Yerushalmi
authors.forename: Argyrios
authors.initials: A
authors.lastname: Ziogas
authors.forename: David G
authors.initials: DG
authors.lastname: Besselsen
authors.forename: Eugene W
authors.initials: EW
authors.lastname: Gerner
authors.forename: Hoda
authors.initials: H
authors.lastname: Anton-Culver
mesh_terms: D000123:Acetyltransferases / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001120:Arginine / Q000008:administration & dosage* / Q000378:metabolism; D000068579:Celecoxib; D003110:Colonic Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000503:physiopathology; D004435:Eating / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D008460:Meat / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000235:genetics; D011073:Polyamines / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D012307:Risk Factors; D013449:Sulfonamides / Q000494:pharmacology; D016019:Survival Analysis; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001120:Arginine; D000068579:Celecoxib; D052247:Nitric Oxide Synthase Type II; D009955:Ornithine Decarboxylase; D011073:Polyamines; D011720:Pyrazoles; D013449:Sulfonamides; D000099228:Diamine N-Acetyltransferase; C496317:Nos2 protein, mouse