High dietary niacin may increase prostaglandin formation but does not increase tumor formation in ApcMin/+ mice

High doses of niacin (nicotinic acid) used to treat dyslipidemias cause flushing, due to high levels of prostaglandin D(2) (PGD(2)). GPR109A, a G-protein coupled receptor, triggers the flushing in the skin. In addition to boosting PGD(2), niacin binding to GPR109A activates the entire prostanoid cascade. We found that GPR109A occurs throughout the gastrointestinal tract. Mice that alternated between a 1% niacin diet and a control diet had higher urinary prostaglandin E(2) (PGE(2)) metabolite levels when on niacin (2.8-fold increase; 95% confidence interval, 1.8-3.9). PGE(2) promotes tumors in the intestines, whereas PGD(2) may have an opposite effect, on the basis of our report showing that transgenic hematopoietic prostaglandin D synthase suppresses intestinal adenomas in Apc(Min/+) mice. To determine if either tumor growth or tumor suppression prevails, we fed Apc(Min/+) mice a 1% niacin diet and assessed tumor development. A 1% niacin diet did not affect the number of tumors scored histologically in Apc(Min/+) mice at 14 wk (33 mice on niacin, 33 controls). Although niacin stimulates production of various prostaglandins, our results support an interpretation that very high intakes of niacin are safe in relation to intestinal tumors in this model.     

Adiposity-Related Protection of Intestinal Tumorigenesis: Interaction With Dietary Calcium

Although high-calcium diets have been reported to reduce the risk of colorectal cancer, our preliminary data with the adenomatous polyposis coli (Apc) Min mutation (Min/+;Apc^Min/+) mouse shows a paradoxical increase in intestinal tumor loads (> 65%) with high calcium diets. Since we previously demonstrated that increasing dietary calcium reduces adiposity, and Apc^Min/+ mice on high calcium diets exhibited profound loss of adipose tissue, we hypothesized that loss of an adipose tissue-derived tumor suppressor factor(s) resulted in increased tumor susceptibility in animals on the high calcium diet. Accordingly, tumor prone Apc^Min/+ mice were crossed with obesity prone lethal yellow agouti (A ^y /a) mice to generate obese A^y/Apc^Min/+ mice. Low (0.2%), normal (0.5%), and high (1.2%) calcium diets were fed to both A^y/Apc ^Min/+ mice and Apc^Min/+ mice from 35–40 days until 90 days of age (n = 21/strain, n = 7/diet group). The high calcium diet reduced weight gain in both strains (P < 0.01) and reduced fat pad mass by 46–57% in A ^y /Apc^Min/+(P < 0.004) and by 65–82% in Apc^Min/+(P < 0.03).Apc^Min/+ mice on the high calcium diet exhibited an increase in tumor number (76 vs. 29, P = 0.009), but this effect was not seen in the A^y/Apc^Min/+ mice.β-Catenin and cyclin D1 gene expression were significantly induced with high calcium diet in intestinal tumor tissue of Apc^Min/+ mice but not in A^y/Apc^Min/+ mice. We conclude that the differential effect of dietary calcium on intestinal tumorigenesis in lean vs. obese Apc^Min/+ may result from the loss of adipose-derived protective factor(s) due to the substantial loss of body fat in Apc^Min/+ mice fed a high calcium dairy diet, increasingβ-catenin and cyclin D1 in tumors.     

Quercetin's Effects on Intestinal Polyp Multiplicity and Macrophage Number in the Apc Min/+ Mouse

Numerous in vitro studies argue for quercetin's chemopreventive potential in colon cancer; however, experimental studies in rodents are limited. Macrophages play a role in tumorigenesis, but the effects of quercetin on macrophage infiltration in colon cancer is unknown. We examined the effects of quercetin on intestinal polyp multiplicity and macrophage number in Apc ^Min/+ mice. Apc ^Min/+ mice were assigned to placebo or quercetin (n = 8/group) groups. Mice were given a placebo or quercetin (0.02%) diet from 4–20 wk of age, after which intestines were analyzed for polyp number and size in the small intestine (Sections 1–4) and colon (Section 5) and for macrophage number in the small intestine (Sections 1 and 3). Spleen weight was determined as a marker of systemic inflammation. Quercetin decreased total intestinal polyps by 67% (P < 0.05). Specifically, quercetin reduced intestinal polyps in categories >2 mm (69%) and 1–2 mm (79%; P < 0.05), and in Sections 2 (75%), 3 (80%), and 4 (79%; P < 0.05). Quercetin also decreased macrophage number in Sections 1 (57%) and 3 (81%), and spleen weight (P < 0.05). These data suggest that quercetin can reduce polyp number and size distribution in the Apc ^Min/+ mouse and that these effects may be related to a reduction in macrophage infiltration.     

Inhibitory effects of calcium against intestinal cancer in human colon cancer cells and ApcMin/+ mice

The aim of the study was to investigate the inhibitory effects of calcium against intestinal cancer in vitro and in vivo. We first investigated the effects of calcium treatment in HCT116 and HT29 human colon cancer cells. At the concentration range of 0.8-2.4 mM, calcium significantly inhibited cell growth (by 9-29%), attachment (by 12-26%), invasion (by 15-31%), and migration (by 19-61%). An immunofluorescence microscope analysis showed that the treatment with calcium (1.6 mM) for 24 h increased plasma membrane β-catenin but decreased nuclear β-catenin levels in HT29 cells. We then investigated the effect of dietary calcium on intestinal tumorigenesis in Apc^Min/+ mice. Mice received dietary treatment starting at 6 weeks of age for the consecutive 8 weeks. The basal control diet contained high-fat (20% mixed lipids by weight) and low-calcium (1.4 mg/g diet) to mimic the average Western diet, while the treatment diet contained an enriched level of calcium (5.2 mg calcium/g diet). The dietary calcium treatment decreased the total number of small intestinal tumors (by 31.4%; P < 0.05). The largest decrease was in tumors which were ≥ 2 mm in diameter, showing a 75.6% inhibition in the small intestinal tumor multiplicity (P < 0.001). Immunohistochemical analysis showed significantly reduced nuclear staining of β-catenin (expressed as nuclear positivity), but increased plasma membrane staining of β-catenin, in the adenomas from the calcium-treated groups in comparison to those from the control group (P < 0.001). These results demonstrate intestinal cancer inhibitory effects of calcium both in human colon cancer cells and Apc^Min/+ mice. The decreased β-catenin nuclear localization caused by the calcium treatment may contribute to the inhibitory action.     

Involvement of the Niacin Receptor GPR109a in the Local Control of Glucose Uptake in Small Intestine of Type 2 Diabetic Mice

Niacin is a popular nutritional supplement known to reduce the risk of cardiovascular diseases by enhancing high-density lipoprotein levels. Despite such health benefits, niacin impairs fasting blood glucose. In type 2 diabetes (T2DM), an increase in jejunal glucose transport has been well documented; however, this is intriguingly decreased during niacin deficient state. In this regard, the role of the niacin receptor GPR109a in T2DM jejunal glucose transport remains unknown. Therefore, the effects of diabetes and high-glucose conditions on GPR109a expression were studied using jejunal enterocytes of 10-week-old m+/db and db/db mice, as well as Caco-2 cells cultured in 5.6 or 25.2 mM glucose concentrations. Expression of the target genes and proteins were quantified using real-time polymerase chain reaction (RT-PCR) and Western blotting. Glucose uptake in Caco-2 cells and everted mouse jejunum was measured using liquid scintillation counting. 10-week T2DM increased mRNA and protein expression levels of GPR109a in jejunum by 195.0% and 75.9%, respectively, as compared with the respective m+/db control; high-glucose concentrations increased mRNA and protein expression of GPR109a in Caco-2 cells by 130.2% and 69.0%, respectively, which was also confirmed by immunohistochemistry. In conclusion, the enhanced GPR109a expression in jejunal enterocytes of T2DM mice and high-glucose treated Caco-2 cells suggests that GPR109a is involved in elevating intestinal glucose transport observed in diabetes.     

Adiposity-related protection of intestinal tumorigenesis: interaction with dietary calcium

Although high-calcium diets have been reported to reduce the risk of colorectal cancer, our preliminary data with the adenomatous polyposis coli (Apc) Min mutation (Min/+;Apc(Min/+)) mouse shows a paradoxical increase in intestinal tumor loads (> 65%) with high calcium diets. Since we previously demonstrated that increasing dietary calcium reduces adiposity, and Apc(Min/+) mice on high calcium diets exhibited profound loss of adipose tissue, we hypothesized that loss of an adipose tissue-derived tumor suppressor factor(s) resulted in increased tumor susceptibility in animals on the high calcium diet. Accordingly, tumor prone Apc(Min/+) mice were crossed with obesity prone lethal yellow agouti (A(y)/a) mice to generate obese A(y)/Apc(Min/+) mice. Low (0.2%), normal (0.5%), and high (1.2%) calcium diets were fed to both A(y)/Apc(Min/+) mice and Apc(Min/+) mice from 35-40 days until 90 days of age (n=21/strain, n=7/diet group). The high calcium diet reduced weight gain in both strains (P < 0.01) and reduced fat pad mass by 46-57% in A(y)/Apc(Min/+)(P < 0.004) and by 65-82% in Apc(Min/+)(P < 0.03).Apc(Min/+) mice on the high calcium diet exhibited an increase in tumor number (76 vs. 29, P=0.009), but this effect was not seen in the A(y)/Apc(Min/+) mice. beta-Catenin and cyclin D1 gene expression were significantly induced with high calcium diet in intestinal tumor tissue of Apc(Min/+) mice but not in A(y)/Apc(Min/+) mice. We conclude that the differential effect of dietary calcium on intestinal tumorigenesis in lean vs. obese Apc(Min/+) may result from the loss of adipose-derived protective factor(s) due to the substantial loss of body fat in Apc(Min/+) mice fed a high calcium dairy diet, increasing beta-catenin and cyclin D1 in tumors.     

Inhibition of Intestinal Tumorigenesis in Apc Min/+ Mice by Green Tea Polyphenols (Polyphenon E) and Individual Catechins

In this work, we compared the cancer preventive activities of Polyphenon E (PPE), a standardized green tea polyphenol preparation given in diet versus drinking fluid as well as the activities of PPE versus individual catechins. We treated Apc^Min/+ mice for 9 wk with 0.08% (-)-epigallocatechin-3-gallate (EGCG), 0.08% (-)-epicatechin-3-gallate, or 0.12% PPE in drinking fluid or diet. Only 0.12% dietary PPE and 0.08% EGCG in drinking fluid significantly decreased tumor multiplicity (70% and 51%, respectively). Compared to PPE in drinking fluid, dietary PPE delivered twofold more EGCG to the small intestine. Immunohistochemistry showed that adenomas in groups treated with PPE and EGCG had decreased cell proliferation, β -catenin nuclear expression, and phospho-Akt levels; higher cleaved caspase-3 levels, and partially restored retinoid X receptor α expression. The results suggest that these molecular events contribute to the cancer prevention activity of EGCG and PPE. Furthermore, diet appears to be a better route of administration for PPE than drinking fluid.     

Chemopreventive effects of orange peel extract (OPE). I: OPE inhibits intestinal tumor growth in ApcMin/+ mice

Orange peel is a rich source of flavonoids with polymethoxyflavones as major constituents, compounds associated with potential antioxidant, anti-inflammatory, and antitumor activities. We studied the effect of an orange peel extract (OPE) on intestinal tumor growth in Apc(Min/+) mice, a mouse model for human familial adenomatous polyposis (FAP). The OPE contained 30% polymethoxyflavones, a mixture that included tangeretin (19.0%), heptamethoxyflavone (15.24%), tetramethoxyflavone (13.6%), nobiletin (12.49%), hexamethoxyflavone (11.06%), and sinensitin (9.16%). Apc(Min/+) mice were fed one of four diets: (1) AIN-76A control diet; (2) a new Western-style diet (NWD), i.e., AIN-76A diet modified with decreased calcium, vitamin D, and methyl-donor nutrients and increased lipid content); (3) NWD with 0.25% OPE; and (4) NWD with 0.5% OPE, with all additives premixed in the diet. After 9 weeks of feeding NWD to the Apc(Min/+) mice, tumors increased mainly in the colon, with tumor multiplicity increasing 5.3-fold and tumor volume increasing 6.7-fold. After feeding 0.5% OPE in NWD, the development of tumors markedly decreased, with multiplicity decreasing 49% in the small intestine and 38% in the colon. NWD also led to increased apoptosis in intestinal tumors, and 0.5% OPE in NWD further increased apoptosis in tumors of the small and large intestine. Findings indicated that OPE inhibited tumorigenesis in this preclinical mouse model of FAP, and increased apoptosis may have contributed to this effect.     

APCmin/+小鼠缺失维生素D受体对肠道肿瘤生长的影响

目的 探讨维生素D受体(VDR)失活对APCmin/+小鼠肠道肿瘤生长的影响及机制.方法 通过构建APCmin/+VDR-/-小鼠模型(n=8),与APCmin/+小鼠比较(n=8),4月龄时观察肠道肿瘤大小及数目情况,肿瘤作HE染色以判断病理类型,免疫组化检测肿瘤相关基因BCL-2、vimentin-1、Stat-1和MSH-2蛋白的表达.结果 4月龄时2组鼠比较,APCmin/+VDR-/-小鼠>3 mm肿瘤明显增多(P<0.01).HE染色显示肠道肿瘤为管状腺瘤.APCmin/+肿瘤的Stat-1表达较强,而MSH-2和vi-mentin-1表达在APCmin/+VDR-/-肿瘤中均更强.结论 维生素D受体缺失促使APCmin/+小鼠肠道肿瘤的发展.     

Dietary resveratrol does not affect intestinal tumorigenesis in Apc(Min/+) mice

To determine its effect on intestinal tumorigenesis and the protumorigenic COX pathway in Apc(Min/+) mice, resveratrol was administered as a powdered admixture in the diet at 0, 4, 20, or 90 mg/kg body weight for 7 wk. In two separate experiments, resveratrol did not affect intestinal tumor load. It was stable in the diet under experimental conditions, circulated in the plasma as the glucuronide-conjugated form and reached the tumors as evidenced by significant decreases in PGE2 levels. However, immunohistochemical staining of intestinal tumors revealed no changes in COX-2 expression. This study demonstrates that resveratrol consumed ad libitum in the diet, does not modify tumorigenesis in Apc(Min/+) mice.     

Chemoprevention of Colorectal Cancer by Targeting Janus Kinase 3 With a Rationally Designed Small Molecule Inhibitor

The effects of the rationally designed JAK3 inhibitor JANEX-1 on the development of intestinal tumors in the APC^min mouse model of familial adenomatous polyposis were examined. At a non-toxic dose level, >4 times lower than its day 30 LD₁₀, JANEX-1 was highly effective in preventing intestinal tumor development in Min mice, resulting in markedly improved survival outcomes. JAK3 inhibitors may, therefore, be useful in the chemoprevention of colorectal cancer. Here, an overview regarding the potential of JANEX-1 as a chemopreventive agent is provided.     

Vitamin D Reduces Colitis- and Inflammation-Associated Colorectal Cancer in Mice Independent of NOD2

Inflammatory bowel disease (IBD) patients are at increased risk of developing colorectal cancer (CRC). Vitamin D (vD) induces NOD2 gene expression, enhancing immunity, while deficiency impairs intestinal epithelial integrity, increasing inflammation. This study investigated the effect of vD on CRC in colitis, and if preventive benefits are mediated via NOD2. Inflammation-associated CRC was induced by treating C57BL/6J and Nod2^?/? mice with azoxymethane (AOM) and dextran sodium sulfate (DSS) cycles (×3). vD-deficient mice displayed more severe colitis compared to vD-supplemented mice, with greater weight loss, higher colitis activity index, increased colonic weight/length ratios, and lower survival rates. Increased histological inflammation score and increased IL-6 were observed in the mucosa of vD-deficient mice. Overall incidence of colonic tumors was not significantly different between vD-deficient and vD-supplemented mice. Higher tumor multiplicity was observed in vD-deficient vs vD-supplemented groups (both mouse strains). After AOM/DSS treatment, decreased plasma 25(OH)D₃ levels and downregulation of vD target genes Cyp24 and Vdr were observed in both mice strains (vD-deficient or vD-supplemented diet), compared to saline-treated controls on the vD-deficient diet. In conclusion, vD supplementation reduced colitis severity and decreased the number of inflammation-associated colorectal tumors in both C57BL/6J and Nod2^?/? mice, independent of NOD2.     

Prostaglandin E2 production in mice is reduced by consumption of range-fed sources of red meat

Many view bison as a healthful alternative to other red meat sources, and as a way to decrease health risks, they associate it with meat consumption. Using mice as a model for immune function, we hypothesized that consumption of meat from range-fed bison would decrease prostaglandin (PG) E₂ and alter prostacyclin (PGI₂) release upon immune challenge when compared with mice fed meat from grain-finished bison, range-fed beef, feedlot steers, free-ranging elk, or chicken breast. After 2 weeks on an experimental diet and inflammatory stimulation, mouse peritoneal macrophage was isolated and analyzed in 12 animals per diet. Peritoneal cell arachidonic acid increased in response to a chicken-based diet (P < .05), which was likely attributable to higher arachidonic acid intake. Release of PGE₂ was lowest in mice consuming meat of range-fed beef, range-fed bison, and elk but was highest with meat of grain-finished beef and intermediate in mice fed chicken (P < .05). Mice fed elk meat had the greatest PGI₂, whereas PGI₂ was decreased in mice fed meat of either range bison, range beef, or chicken (P < .05) and intermediate in mice fed meat of steers or bison finished in a feedlot. We conclude that consumption of meats characteristic of range-fed ruminants or wild ungulates supports reduced PGE₂ and greater PGI₂ synthesis, indicating potentially greater immune health and lower blood clotting potential than meat from grain-finished cattle or bison in this model system.     

Effects of Long-Term Oral Administration of Arachidonic Acid and Docosahexaenoic Acid on the Immune Functions of Young Rats

Natural killer (NK) cells have many functional activities, including cytotoxicity and the capacity to produce cytokines and chemokines. NK cell activity is regulated partly by eicosanoids, which are produced from arachidonic acid (ARA) and eicosapentaenoic (EPA) acid. In this study, we investigated the effects of long-term therapy with ARA or docosahexaenoic acid (DHA) on the cytotoxic effects of the NK cells of young rats, which were fed on a nonfish oil diet for two generations. Control oil, ARA (240 mg/kg BW/day) or DHA (240 mg/kg BW/day) were orally administrated to the rats for 13 weeks before determining the cytotoxic activity of NK cells from the spleen against YAC-1 mouse lymphoma cell line, as well as the plasma levels of docosanoids or eicosanoids and inflammatory cytokines. Long-term ARA administration significantly suppressed the cytotoxic activity of NK cells. Moreover, ARA administration significantly increased the plasma levels of ARA, prostaglandin (PG) E₂, and PGD₂. However, DHA administration did not produce any different effects compared with those in the control rats. Furthermore, the inflammatory cytokine levels were not affected by the administration of ARA or DHA. These results suggest that long-term ARA administration has an inhibitory effect on the tumor cytotoxicity of NK cells in rat spleen lymphocytes owing to the enhanced synthesis of PGE₂ and PGD₂ from ARA because of the elevated plasma ARA levels in young rats.     

No effect on adenoma formation in Min mice after moderate amount of flaxseed

Summary Background & aim The mammalian lignan enterolactone (ENL) produced from plant lignans, e. g. secoisolariciresinol diglycoside (SDG), may protect against various cancers in humans. The present work aims to evaluate the effect of flaxseed on tumour formation in multiple intestinal neoplasia (Min) mice, a model for colon tumorigenesis. Design Male and female Min mice were fed either with a non–fibre control diet or the same diet supplemented with 0.5 % (w/w) defatted flaxseed meal. Conversion of SDG to the mammalian lignans enterodiol (END) and ENL in the gut, and plasma ENL, were measured by HPLC with coulometric electrode array detector (CEAD) and timeresolved fluoroimmunoassay, respectively. Wild–type mice were also fed with the experimental diets in order to see whether lignan metabolism is different in Min and wild–type mice. Results The total number of adenomas or their size in the small intestine was not different in the flaxseed and control groups. The flaxseed group had a tendency for a decreased number of colon adenomas in both genders. Gender and genotype based differences were found in the intestinal ENL levels. When compared to Min females, Min males in the flaxseed group had several fold higher ENL levels in the small intestine (Min males 125 ± 124.5 nmol/g vs. females 22.8 ± 16.0 nmol/g, P = 0.048) and caecum (47.6 ± 31.6 nmol/g vs. females 14.5 ± 6.6 nmol/g, P = 0.001). Presence of adenomas in the gut influences the intestinal lignan metabolism. Min mice had less intestinal END and ENL as compared with the wild–type mice (P < 0.05). Mean plasma ENL increased 7–fold during the flaxseed feeding (7 nmol/L in control vs. 50 nmol/L in flaxseed group) but no differences between gender and genotype were found. The plasma ENL level did not correlate with adenoma number in the small intestine and colon. Conclusion The number of intestinal adenomas in the Min mouse model is not related to ENL level in plasma nor is it associated with the levels of intestinal lignans. A gender difference in ENL lignan metabolism was found in the gut but not in the plasma.     

Effects of Dietary Fat and Endurance Exercise on Plasma Cortisol,Prostaglandin E2, Interferon-γ and Lipid Peroxides in Runners

Objective: Exercise and the neuroendocrine and oxidative stress it elicits on immune function is modulated by dietary fat intake. The effects of increasing dietary fat on endurance exercise-induced alterations (80% of V?O_2max for 2 hours) in the plasma levels of cortisol and prostaglandin E₂ (PGE₂), interferon-γ (IFN-γ) and lipid peroxides were investigated. As higher levels of cortisol, PGE₂ and lipid peroxides could be immunosuppressive, the effects of different levels of dietary fat on these measures in runners were determined.

Methods: Healthy trained runners (males and females) consumed serially 15% fat diet (of daily energy), 30% fat diet and 40% fat diets for four weeks each. In the last week of each diet period the subjects ran to exhaustion at 80% of their V?O_2max and blood was drawn pre- and post-run. Cortisol, IFN-γ, PGE₂ and lipid peroxides were determined using standard techniques.

Results: Pre-exercise levels of plasma cortisol were elevated, IFN-γ was unchanged and PGE₂ and lipid peroxides decreased on the 40%F diet compared to 30%F and 15%F. Post-exercise levels of plasma cortisol (p < 0.004), PGE₂ (p < 0.0057) and lipid peroxide levels increased (p < 0.0001) after endurance exercise on all diets. The rates of increase of plasma cortisol levels during exercise were similar on all three diets. Although absolute cortisol levels were higher in the high fat group, the rate of increase of plasma cortisol level during exercise was similar on each diet. The dietary fat levels did not affect IFN-γ, however, PGE₂ and lipid peroxides decreased with increasing fat at baseline at 40%F level (p < 0.01; 30%F vs. 40%F: p < 0.002; 15%F vs. 40%F: p < 0.007).

Conclusions: Data from the present study suggest that higher levels of fat in the diet, up to 40%, increase endurance running time without adverse effects on plasma cortisol, IFN-γ, and lipid peroxide levels.     

The Adjuvant Effect of Squalene,an Active Ingredient of Functional Foods,on Doxorubicin-Treated Allograft Mice

Many functional foods or physiologically active ingredients derived from plants and animals are actively being investigated for their role in chronic disease prevention. Squalene (SQ) is found as active ingredient in the functional foods predominantly present in olive oil and shark liver oil. It is known that during chemotherapy anticancer drugs induce inflammation. SQ has been thought to prevent and suppress inflammation; however, there is little direct evidence available. We examined the adjuvant effect of SQ on tumor-transplanted mice along with anticancer drug doxorubicin (DOX). SQ significantly suppressed the DOX-induced increase in prostaglandin E₂ (PGE₂) concentration (P?<?0.05) in plasma of tumor-bearing mice. SQ inhibited the numbers of writhing response (P?<?0.05), formalin-induced pain and decreased COX-2 and substance P expression in the tumor tissue compared to control mice and also enhanced the antitumor efficacy of DOX in allograft mice. Thus, SQ reduces inflammation through modulation of PGE₂ production indicating its potential as an adjuvant during chemotherapy in tumor-bearing mice.     

Antagonism of arachidonic acid is linked to the antitumorigenic effect of dietary eicosapentaenoic acid in Apc(Min/+) mice

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.