Effects of fish oil supplementation on eicosanoid production in patients at higher risk for colorectal cancer.

Fish oil supplementation may represent a potential chemopreventive agent for reducing colorectal cancer risk. The mechanism of action of fish oil is unknown but presumed to be related to eicosanoid modification. The purpose of this study was to evaluate the effects of fish oil supplementation on the levels of urinary and rectal eicosanoids. We conducted a randomized, double-blind, controlled trial of 2.5 g of fish oil per day compared with olive oil supplementation over a 6-month period. Study participants had a history of colorectal adenomas. Randomization was stratified based on the gene variant rs174535 in the fatty acid desaturase 1 enzyme (FADS1), which affects tissue levels of arachidonic acid. A total of 141 participants were randomized. Urinary prostaglandin E2 metabolite (PGE-M) was measured at baseline, 3, and 6 months and rectal prostaglandin E2 (PGE2) at baseline and 6 months. Repeated-measures linear regression was used to determine the effect of the intervention on each outcome measure. Overall, fish oil supplementation was found to reduce urinary PGE-M production compared with olive oil (P=0.03). Fish oil did not reduce rectal PGE2 overall; however, it did significantly reduce PGE2 in the subgroup of participants not using aspirin or NSAIDs (P=0.04). FADS1 genotype did not seem to modify effects of fish oil on PGE2 production. We conclude that fish oil supplementation has a modest but beneficial effect on eicosanoids associated with colorectal carcinogenesis, particularly in those not taking aspirin or NSAIDs.

The effects of nutritional interventions on recurrence in survivors of colorectal adenomas and cancer: a systematic review of randomised controlled trials.

BACKGROUND/OBJECTIVES: Nutrition and dietary supplementation may modulate outcomes in colorectal cancer (CRC) survivors. However, no recent systematic review has focused on randomised controlled trials (RCTs). The aim of this systematic review was to examine the effects of nutritional RCTs in survivors of colorectal adenomas and cancer. SUBJECTS/METHODS: Medline, Embase, Scopus, Web of Science and the Cochrane Library were searched to identify research between April 2006 and January 2014. The primary outcomes were colorectal adenoma and cancer recurrence. Each included study was assessed for risk of bias. A meta-analysis using a random-effects model was performed, in which two or more RCTs investigated the same dietary intervention. RESULTS: Eight completed RCTs, all in colorectal adenoma survivors, were identified, with four investigating the effect of folic acid. A meta-analysis of the four folic acid RCTs showed no statistically significant effect of folic acid on colorectal adenoma recurrence (relative risks=0.93; 95% confidence interval: 0.69, 1.25). The impact of the remaining completed RCTs, investigating antioxidant supplementation, green tea extract, prebiotic fibre and phytooestrogens/insoluble fibre, could not be reliably estimated because of the limited number and heterogeneity of the interventions. In addition, three heterogeneous ongoing RCTs were identified, investigating green tea (n=1) and eicosapentaenoic acid (n=1) in colorectal adenoma survivors and dietary modifications (n=1) in CRC survivors in remission. CONCLUSIONS: Overall, this systematic review highlights the need for further research, especially in CRC survivors, as we identified no completed and only one ongoing RCT in this population.

Black raspberries suppress colonic adenoma development in ApcMin/+ mice: relation to metabolite profiles.

Freeze-dried black raspberries (BRBs) have demonstrated chemopreventive effects in a dietary intervention trial with human colorectal cancer patients. The aim of this study was to investigate BRB-caused metabolite changes using the Apc(Min/+) mouse as a model of human colorectal cancer. Wild-type (WT) mice were fed control diet, and Apc(Min/+) mice were fed either control diet or control diet supplemented with 5% BRBs for 8 weeks. Colonic and intestinal polyp size and number were measured. A non-targeted metabolomic analysis was conducted on colonic mucosa, liver and fecal specimens. Eight weeks of BRB treatment significantly decreased intestinal and colonic polyp number and size in Apc(Min/+) mice. The apc gene mutation significantly changed 52 metabolites in colonic mucosa associated with increased amino acid and decreased lipid metabolites, as well as 39 liver and 8 fecal metabolites. BRBs significantly reversed 23 apc-regulated metabolites, including 13 colonic mucosa, 8 liver and 2 fecal metabolites that were involved in amino acid, glutathione, lipid and nucleotide metabolism. Of these, changes in eight metabolites were linearly correlated with decreased colonic polyp number and size in BRB-treated Apc(Min/+) mice. Elevated levels of putrescine and linolenate in Apc(Min/+) mice were significantly decreased by BRBs. Ornithine decarboxylase expression, the key enzyme in putrescine generation, was fully suppressed by BRBs. These results suggest that BRBs produced beneficial effects against colonic adenoma development in Apc(Min/+) mice and modulated multiple metabolic pathways. The metabolite changes produced by BRBs might potentially reflect the BRB-mediated chemopreventive effects in colorectal cancer patients.

Interleukin-6 as a potential indicator for prevention of high-risk adenoma recurrence by dietary flavonols in the polyp prevention trial.

Serum interleukin-6 (IL-6), a proinflammatory cytokine, is considered an indicator of inflammation and may be an indicator of colorectal carcinogenesis given that inflammation can promote carcinogenesis. Flavonols, which can be found in fruits and vegetables, may inhibit colorectal carcinogenesis partly by inhibiting inflammation. We estimated odds ratios and 95% confidence intervals (95% CI) to determine whether serum IL-6 was associated with colorectal adenoma recurrence and flavonol intake and thus may serve as a risk indicator and as a response indicator to dietary flavonols. Serum IL-6 concentrations at baseline, year 1, and year 3 were measured in 872 participants from the intervention arm of the Polyp Prevention Trial, a 4-year trial that examined the effectiveness of a low-fat, high-fiber, high-fruit and vegetable diet on adenoma recurrence. Intake of flavonols, especially of isorhamnetin, kaempferol, and quercetin, was inversely associated with serum IL-6 concentrations (highest versus lowest flavonol intake quartile, 1.80 versus 2.20 pg/mL) and high-risk (OR, 0.51; 95% CI, 0.26-0.98) and advanced adenoma recurrence (OR, 0.17; 95% CI, 0.06-0.50). A decrease in IL-6 concentration during the trial was inversely associated with high-risk (OR, 0.44; 95% CI, 0.23-0.84) and advanced adenoma recurrence (OR, 0.47; 95% CI, 0.19-1.18). Individuals with above median flavonol intake and equal or below median IL-6 change after baseline had the lowest risk of recurrence of high-risk and advanced adenoma. Our results suggest that serum IL-6 may serve as a risk indicator and as a response indicator to dietary flavonols for colorectal cancer prevention.

Vitamin C intake and apoptosis in normal rectal epithelium.

Apoptosis, or programmed cell death, may lower the risk of neoplasia by removing genetically damaged or mutated cells. A high rate of apoptosis has been linked to a reduced risk of colorectal adenomas; therefore, it is important to understand factors that impact apoptosis. Antioxidants (e.g., vitamin C) protect cells from harmful oxidation processes but may interfere with apoptosis by protecting genetically damaged cells from reactive oxygen species-dependent cell death. The objective of this study was to evaluate the association between vitamin C intake and apoptosis in normal rectal mucosa. Study participants were part of a large, cross-sectional study, the Diet and Health Study III. Participants were recruited from consecutive, consenting patients who underwent colonoscopy at University of North Carolina Hospitals between August 1, 1998 and March 4, 2000. Vitamin C intake, obtained from a food frequency questionnaire, included both dietary sources and vitamin supplements. Apoptosis was measured by morphological evaluation of H&E-stained sections obtained from pinch biopsy samples of normal rectal mucosa in consenting participants (n = 503). The relationship between vitamin C and apoptosis varied by adenoma status. Among individuals with adenomas, there was an inverse linear association between apoptosis and total vitamin C intake. Similarly, individuals with adenomas in the highest quintile of total vitamin C intake were substantially less likely than those in the lowest quintile to have increased colonic apoptosis (odds ratio, 0.05; 95% confidence interval, 0.01-0.46). Vitamin C was not significantly associated with apoptosis in adenoma-free patients. High vitamin C intake was associated with reduced colorectal apoptosis among individuals with adenomas in this study population. Given that high apoptosis may lower colorectal cancer risk, vitamin C supplements may be contraindicated for patients with a history of adenomas.

Calcium or resistant starch does not affect colonic epithelial cell proliferation throughout the colon in adenoma patients: a randomized controlled trial.

Patients with a history of sporadic adenomas have increased epithelial cell proliferative activity, an intermediate risk marker for colorectal cancer. Reduction of proliferation by dietary intervention may reflect a decreased colorectal cancer risk. To evaluate whether calcium or resistant starch could reduce proliferative activity throughout the colon, we performed a randomized controlled trial in 111 sporadic adenoma patients. Patients received two placebos, 1 g of calcium + placebo, or 30 g of amylomaize (19 g of resistant starch) + placebo. After 2 mo, biopsies were collected from the cecum, transverse and sigmoid colon, and rectum during colonoscopy. Epithelial cell proliferation was determined by dividing the number of 5-bromo-2-deoxyuridine-labeled nuclei by the total number of nuclei x 100 (labeling index, LI). LI of luminal, mid, and basal compartments was determined. Twenty-five patients dropped out. In the remaining 86 patients (28 treated with placebo, 30 with calcium + placebo, and 28 with resistant starch + placebo), no difference was observed in total LI, the LI of the three compartments, or the crypt length in the four areas of the colorectum. Colonic epithelial cell proliferative activity throughout the colon of sporadic adenoma patients is not affected by supplementation with 1 g of calcium or 19 g of resistant starch.

Intake of supplemental and total fiber and risk of colorectal adenoma recurrence in the wheat bran fiber trial.

The Wheat Bran Fiber (WBF) trial was a double-blind Phase III clinical trial in which participants were randomized to a cereal fiber supplement of either 13.5 or 2.0 g/day. No protective effect for adenoma recurrence was observed for those randomized to the high-fiber group as compared with those in the low-fiber group. However, the high-fiber group had significantly lower adherence to the supplement as assessed by cereal box counts. The aim of this study was to determine whether reported supplemental and total fiber intake affected colorectal adenoma recurrence in the WBF trial population, regardless of treatment group assignment. A total of 1208 participants who completed the WBF trial had a colonoscopy before the date of the last cereal box count and/or at least one colonoscopy within 90 days after it and, thus, were eligible for the current analyses. Statistical analyses were done using multivariate logistic regression models that included potentially confounding variables. Compared with individuals consuming less than 1.8 g/day of supplemental fiber, the adjusted odds ratio (95% confidence interval) for adenoma recurrence for those consuming greater than 11.0 g/day was 0.94 (0.66-1.33). The odds ratio (95% confidence interval) for participants whose total fiber intake was greater than 30.3 g/day was 0.98 (0.68-1.42) compared with those whose intake was less than 17.9 g/day. The results of this study show that neither fiber intake from a wheat bran supplement nor total fiber intake affects the recurrence of colorectal adenomas, thus lending further evidence to the body of literature indicating that consumption of a high-fiber diet, especially one rich in cereal fiber, does not reduce the risk of colorectal adenoma recurrence.

Chemoprevention of metachronous adenomas of the large bowel: design and interim results of a randomized trial of calcium and fibre. ECP Colon Group.

A European multicentric intervention study, led by the colon group of the European Cancer Prevention Organization, is under way. The main aim of the study is to test the efficacy of oral calcium supplementation with 2 g calcium per day and oral dietary supplementation with mucilaginous substances (as 3.8 g of ispaghula husk) on adenoma recurrence. Secondary aims are the study of treatment efficacy on colonic cell proliferation and on stool bile acid and sterol concentration. Serum and plasma samples are also collected. To better interpret the effect of the intervention, a diet history questionnaire and an aspirin and anti-inflammatory drug questionnaire are administered. The aim will be achieved through a randomized placebo-controlled clinical trial using a parallel design in patients aged 35 to 75 at entry with a complete colonoscopy and a clean colon. Overall, 655 subjects have been included. All randomized patients are followed up every six months for 3 years. If one of the evaluated interventions proves efficient, the benefits of a simple, safe and inexpensive prophylaxy for a very common cancer will be clear.

Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis by compounds derived from cruciferous vegetables and green tea.

We have shown that PEITC and I3C, both of cruciferous origin, inhibited lung tumor formation induced by the tobacco-specific nitrosamine NNK. The inhibition by PEITC is due largely to its inhibitory effect on the enzymes of NNK metabolism, whereas; the inhibition by I3C may be attributed to its ability to induce hepatic enzyme activity of NNK metabolism, which resulted in decreased availability of NNK to the lung. On a molar basis, PEITC is considerably more effective than I3C. PEITC was released upon consumption of watercress. The N-acetylcysteine conjugate of PEITC is a promising urinary marker for quantitating uptake of this dietary anticarcinogen in humans. These studies also showed that green tea polyphenol EGCG inhibited the NNK-induced lung tumorigenesis, probably due to its antioxidant property. These studies provide for the first time evidence for the involvement of free radicals in nitrosamine tumorigenesis. The mechanism by which free radicals are generated by NNK treatment is not yet known. The reduced levels of oxidative lesions in lung as a result of EGCG treatment may be related to its ability to reduce reactive oxygen species and/or to chelate iron ion resulting in a decreased production of hydroxyl radicals. Overall, these studies have identified ingredients in cruciferous vegetables and green tea that are inhibitory against lung tumorigenesis induced by NNK in rodents.