Folate and its preventive potential in colorectal carcinogenesis.: How strong is the biological and epidemiological evidence?

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Abstract

Based on a 15-year old hypothesis, it is believed that an adequate ingestion of folate vitamins decreases, whereas a nutritional depletion of folate increases the risk of colorectal cancer. The present article reviews the efforts to provide biochemical and epidemiological evidence for folate as a chemopreventive agent against colorectal carcinogenesis.

Biological evidence:

Tetrahydrofolates govern the intracellular one-carbon metabolism and account for proper DNA biosynthesis and macromolecular modification. Numerous experimental studies traced different molecular pathways and tried to link folate depletion with DNA instability and/or mutagenesis. However, none of the proposed underlying molecular mechanisms appear clearly defined.

Epidemiological evidence:

Numerous case–control and prospective studies have been conducted on folate and colorectal cancer, which all together miss a clinical bottom line. The recommendation of folate intake to prevent colorectal cancer is therefore not evidence-based.

Introduction

The therapeutic effect of the water soluble B-Vitamin folic acid (Vitamin B9; [1], [2], [3]) has been mainly attributed to megaloblastic anemia [4], [5] and to the prevention of malformancies during embryonic development of the neural tube [6], [7], [8], [9], [10], [11], [12], [13], [14]. That restricted view appears to be outdated when considering preventive effects of folate in hyperhomocysteinemia as atherosclerotic risk factor [15], [16], [17] or in Alzheimer's disease [18], [19], [20], [21], [22], [23], [24]. A third preventive potential of folate is suggested in carcinogenesis, namely in that of colorectal cancer, and is the topic of the present article; based on the biochemical knowledge, the review will outline the contemporary molecular understanding of colorectal tumorigenesis in terms of a diminished folate supply. Reviewing the current knowledge from nutritional studies, it will also assess the impact of dietary folate intake in terms of colorectal carcinoma.

Section snippets

Chemical structure of folates

Chemically, folates form a complex family [25] with standardized recommendations on nomenclature [26]; the parent compound of folates is the pteroic acid abbreviated by the three-letter symbol Pte (see Fig. 1A). Folic acid is pteroylmonoglutamic acid (abbreviated by PteGlu(1)) and is generated by the conjugation of the terminal carboxyl group of Pte with the α-amino group of a l-glutamic acid residue (see Fig. 1B). In pteroylpolyglutamates (PteGlun, n > 1) pteroic acid is attached to more than

Dietary folate intake in man—nutritional basis

Mammals are not able to generate pteroic acid [Pte] as they have lost the ability to conjugate pteridine and 4-amino-benzoic acid enzymatically (see Fig. 1). The individual folate status therefore depends on the dietary intake and on the duodenal/jejunal absorption. Dietary folate occurs as a mixture of different polyglutamate vitamins. Folates are most present in green leafy vegetables (spinach, Brussels sprouts), brewer's yeast, cereals (wheat germ) and in offal (liver, kidney) [125], [126],

Conclusion

Greatest efforts have been made to corroborate an epidemiological inverse association between daily folate intake and colorectal cancer. Unfortunately, the present results are inconsistent and equivocal. They cannot provide convincing evidence for (at least a partial) chemopreventive effect of folate on (proximal) colon or rectal cancer and do therefore not contribute to a differentiated clinical recommendation. It can be conceded that folate somehow appears to be related to colorectal cancer,

Reviewers

Dr. Marie-Christine Boutron-Ruault, Registre Bourguignon des Cancers Digestifs, Faculte de Medecine, F-21033 Dijon, France.

Young-In Kim, M.D., FRCP(C), Associate Professor of Medicine & Nutritional Sciences, University of Toronto, Room 7258, Medical Sciences Building, 1 King's College Circle, Toronto, Ont., Canada M5S 1A8.

L. Cornelius Bollheimer received his medical degree from the University of Heidelberg in 1995. Following a postdoctoral fellowship at the Joslin Diabetes Center/Boston and at the University of Texas, Southwestern Medical School/Dallas, he joined the Department of Internal Medicine of the University of Regensburg, Germany in 1997. His research interests are focused on metabolic and preventive aspects of nutritional medicine.

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    L. Cornelius Bollheimer received his medical degree from the University of Heidelberg in 1995. Following a postdoctoral fellowship at the Joslin Diabetes Center/Boston and at the University of Texas, Southwestern Medical School/Dallas, he joined the Department of Internal Medicine of the University of Regensburg, Germany in 1997. His research interests are focused on metabolic and preventive aspects of nutritional medicine.

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