title: Antagonism of arachidonic acid is linked to the antitumorigenic effect of dietary eicosapentaenoic acid in Apc(Min/+) mice.
abstract: The multiple intestinal neoplasia (Apc(Min/+)) mouse possesses a germline mutation at codon 850 of the adenomatous polyposis coli (Apc) gene resulting in the formation of a nonfunctional truncated gene product. Following a somatic mutation of the remaining wild-type allele, mice spontaneously develop approximately 40-50 tumors throughout the intestinal tract. This mouse model has been used to study intestinal tumorigenesis because this mutation is analogous to the inherited APC mutation in humans with familial adenomatous polyposis (FAP). These individuals characteristically develop numerous adenomas throughout their intestinal tracts. Only a few studies have evaluated the effects of dietary fatty acids on tumorigenesis in this animal model with varying results, and none have linked these effects to alterations in arachidonic acid (AA) metabolism. This study was designed to evaluate the antitumorigenic effect of dietary (n-3) polyunsaturated fatty acids (PUFA) in the Apc(Min/+) mouse model and to determine whether these effects are related to inhibition of AA metabolism. Male Apc(Min/+)mice were fed diets supplemented with eicosapentaenoic acid (EPA), AA or a combination of AA + EPA. Mean tumor number in the EPA group was 68% lower (P<0.05) compared with the control group, whereas AA supplementation did not significantly alter tumor load. The reduction in tumor load coincided with significant reductions in intestinal AA content and levels of prostaglandins. However, supplementing AA to the EPA diet (AA + EPA) abolished the antitumorigenic effect of EPA, increased tissue AA content fourfold and prostaglandin production two- to fourfold. These results indicate that AA is involved in tumorigenesis and suggest that EPA's ability to reduce tumor load in Apc(Min/+) mice is related to reductions in tissue AA content or its metabolism.
authors.affiliation: Department of Nutrition, College of Human Ecology, University of Tennessee, Knoxville, TN 37996-1900, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Petrik
authors.forename: M F
authors.initials: MF
authors.lastname: McEntee
authors.forename: C H
authors.initials: CH
authors.lastname: Chiu
authors.forename: J
authors.initials: J
authors.lastname: Whelan
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004032:Diet; D004347:Drug Interactions; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000494:pharmacology*; D018095:Germ-Line Mutation; D007413:Intestinal Mucosa / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000235:genetics / Q000517:prevention & control; D007422:Intestines / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011453:Prostaglandins / Q000096:biosynthesis*
chemical_list: D016588:Anticarcinogenic Agents; D005231:Fatty Acids, Unsaturated; D011453:Prostaglandins; D016718:Arachidonic Acid; D015118:Eicosapentaenoic Acid