Dietary folate protects against the development of macroscopic colonic neoplasia in a dose responsive manner in rats.

Kim, Y I; Salomon, Robert N.; Graeme‐Cook, Fiona; Choi, Sang‐Woon; Smith, Donald E.; Dallal, Gerard E.; Mason, Joel B.

doi:10.1136/gut.39.5.732

Cited by 171 publications

(157 citation statements)

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“…25 However, high levels of folate supplementation do not appear to provide additional protection, and in some cases may enhance carcinogenesis. [26][27][28] Kim 24 further noted that progression of established neoplasia is quite likely with supplemental folate. Although caution when extrapolating animal data to humans is warranted, our data on multivitamin use support the notion that additional folate or multivitamins in an environment of adequate folate confers no added protection.…”

Section: Discussionmentioning

confidence: 99%

Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence

Martı́nez

Giovannucci

Jiang

et al. 2006

Intl Journal of Cancer

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In 1996, the US Food and Drug Administration mandated the fortification of grain products with folic acid, a nutrient that has been associated with lower risk of colorectal neoplasia. We assessed the relation of plasma folate and homocysteine and colorectal adenoma recurrence separately in 2 studies: the first involved an intervention of a cereal supplement that contained folic acid, wheat bran fiber (WBF), and the second was conducted primarily during postfortification of the food supply using ursodeoxycholic acid (UDCA). Analyses were stratified for multivitamin use. Results show that plasma folate and homocysteine concentrations were associated with adenoma recurrence among nonusers of multivitamins only. Among nonmultivitamin users, the odds ratio [OR] (95% confidence interval [CI]) for those in the highest versus the lowest folate quartile was 0.65 (0.40-1.06) for the WBF study and 0.56 (0.31-1.02) for the UDCA; likewise, individuals in the highest versus the lowest quartile of homocysteine had higher odds of adenoma recurrence, in both the WBF (OR 5 2.25; 95% CI 5 1.38-3.66) and UDCA (OR 5 1.93; 95% CI 5 1.07-3.49) populations. Analyses comparing multivitamin users to different plasma folate concentrations among nonusers show that odds of recurrence for supplement users was lower only when compared to nonusers who had lower concentrations. Our results show that higher plasma folate or lower homocysteine levels are associated with lower odds of recurrence among nonusers of multivitamins in both studies. Our finding, suggesting that multivitamins or supplemental folate only benefit individuals with lower plasma folate concentrations, should be taken into consideration when designing and interpreting results of intervention studies. ' 2006 Wiley-Liss, Inc.Key words: colorectal adenoma; folate; homocysteine Colorectal cancer is thought to be the result of a multistep evolutionary process that involves a precursor lesion, the adenomatous polyp. Among individuals who undergo removal of their adenoma(s), recurrence of these lesions at surveillance colonoscopy is common, making adenoma recurrence an important endpoint to study in relation to lifestyle and other risk factors.Folate is a water soluble B-vitamin that functions as a coenzyme in single-carbon transfer in nucleic and amino acid metabolism. Folic acid is the fully oxidized monoglutamyl form of folate that is used in supplements and fortified foods. A recent meta analysis showed a significant 20-25% lower risk of developing colorectal cancer among individuals in the highest compared to those in the lowest category of dietary folate 1 ; inverse associations between blood folate and colorectal neoplasia (i.e., cancer and adenoma) have also been shown. [2][3][4] Mechanisms responsible for the inverse association of folate on risk of colorectal cancer are not entirely understood and may involve disturbances in DNA synthesis, methylation and repair, 5-7 albeit alternate mechanisms have been proposed. 8 Homocysteine, a biochemical marker of folate status, is an...

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Section: Discussionmentioning

confidence: 99%

Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence

Martı́nez

Giovannucci

Jiang

et al. 2006

Intl Journal of Cancer

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“…Low folate status can result in increased chromosome instability, DNA damage, impaired repair, aberrant DNA methylation and point mutations (Cravo et al, 1994;Fenech et al, 1997;Kim, 1999). These initiate colon carcinogenesis Folic acid (Kim et al, 1996;Newmark et al, 2001;Konings et al, 2002) (2) Insulin resistance/plasma insulin, free fatty acids and triacylglycerol (McKeown-Eyssen, 1994;Giovannucci, 1995;Kim, 1998) Dietary factors including a hypercaloric diet with refined sugars, increased saturated fat, and reduced n-3 fatty acids, together with reduced energy expenditure, increase the accumulation of energy substrates in the body and lead to insulin resistance (Storlien et al, 1991;Tran et al, 1996Tran et al, , 2003Koohestani et al, 1998;Bruce et al, 2000;Kaaks et al, 2000). Insulin resistance is a state of decreased insulin action that is usually accompanied by increased concentrations of: insulin (due to compensatory hypersecretion of insulin), free fatty acid (FFA, due to the impaired antilipolytic action of insulin) and triacylglycerols (TG, derived from the released FFA) (DeFronzo and Ferrannini, 1991).…”

Section: Study Protocolmentioning

confidence: 99%

A pilot randomised controlled trial to reduce colorectal cancer risk markers associated with B-vitamin deficiency, insulin resistance and colonic inflammation

Cirocco

Giacca

et al. 2005

Br J Cancer

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Colorectal cancer risk is associated with biochemical markers for B-vitamin deficiency, insulin resistance and colonic inflammation, suggesting that these three conditions are each involved in colon carcinogenesis. We expected that dietary supplements of folic acid, n-3 fatty acids and calcium would reduce the markers and thus possibly cancer risk. We therefore randomised 98 participants, with previous colonic polyps or intramucosal carcinomas, to a combined treatment of supplementary folic acid, fish oil and calcium carbonate, or placebos for 28 days. Blood and faecal samples were obtained prior to and at the conclusion of the intervention and analysed for plasma folate, homocysteine, insulin, free fatty acids, triglycerides and faecal calprotectin. In addition, plasma vitamin B 12 , thiamin, glucose and C-reactive protein were assessed. Our supplemental strategy modestly affected some of the biomarkers associated with folate metabolism and insulin resistance, but had no effect on those associated with colonic inflammation. This pilot study demonstrates the feasibility and practicality of clinical trials aimed at reducing diet-related biochemical risk markers for colon cancer. We suggest that long-term intervention studies with tumour-related end points should be undertaken when the intervention agents used are found effective in short-term biochemical risk marker trials.

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“…A moderate folate deficiency also enhanced the incidence of colonic dysplasia and neoplasia in rats treated with dimethylhydrazine (Cravo et al, 1992), which was preceded by alterations in the levels of S-adenosylmethionine and in the activity of specific methyl transferase enzymes (Halline et al, 1988). Folate supplementation led to a progressive reduction in the evolution of macroscopic colonic neoplasia from microscopic foci in a rat model (Kim et al, 1996).…”

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confidence: 99%

Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study

et al. 1999

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Summary Accumulating evidence suggests that folate, which is plentiful in vegetables and fruits, may be protective against colorectal cancer. The authors have studied the relationship of baseline levels of serum folate and homocysteine to the subsequent risk of colorectal cancer in a nested case-control study including 105 cases and 523 matched controls from the New York University Women's Health Study cohort. In univariate analyses, the cases had lower serum folate and higher serum homocysteine levels than controls. The difference was more significant for folate (P < 0.001) than for homocysteine (P = 0.04). After adjusting for potential confounders, the risk of colorectal cancer in the subjects in the highest quartile of serum folate was half that of those in the lowest quartile (odds ratio, OR = 0.52, 95% confidence interval, CI = 0.27-0.97, P-value for trend = 0.04). The OR for the highest quartile of homocysteine, relative to the lowest quartile, was 1.72 (95% CI = 0.83-3.65, P-value for trend = 0.09). In addition, the risk of colorectal cancer was almost twice as high in subjects with belowmedian serum folate and above-median total alcohol intake compared with those with above-median serum folate and below-median alcohol consumption (OR = 1.99, 95% CI = 0.92-4.29). The potentially protective effects of folate need to be confirmed in clinical trials.

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Dietary folate protects against the development of macroscopic colonic neoplasia in a dose responsive manner in rats.

Abstract: (Gut 1996; 39: 732-740)

Cited by 171 publications

References 51 publications

Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence

Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence

A pilot randomised controlled trial to reduce colorectal cancer risk markers associated with B-vitamin deficiency, insulin resistance and colonic inflammation

Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study

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