Folsäure in der Prävention des kolorektalen Karzinoms

Zusammenfassung

Kostformen, die einen hohen Anteil an Obst und Gemüse aufweisen, haben sich hinsichtlich des kolorektalen Karzinoms als protektiv erwiesen. Dieser Effekt beruht möglicherweise auf ihrem Gehalt an Folsäure. Die biologisch aktive Form des Vitamins fungiert als Koenzym bei der Übertragung von C1-Substituenten im Stoffwechsel der Aminosäuren, Purine und Pyrimidine. Damit kommt ihr eine Schlüsselstellung bei der DNA-Synthese und der Regulation der Genexpression zu. Gegenwärtig werden 3 unterschiedliche Mechanismen diskutiert, über die Folsäure in die Kanzerogenese eingreifen soll. Diese betreffen die DNA-Methylierung, die Funktion des Rezeptors für den epidermalen Wachstumsfaktor (EGFR) und die Thymidilatsynthese. Ein Folsäuremangel wird mit Veränderungen im Methylierungsmuster des Genoms bzw. bestimmter Protoonkogene und Tumorsuppressorgene in Verbindung gebracht, wie sie für transformierte Zellen typisch sind. Darüber hinaus ist die Thymidilatsynthese im Folsäuremangel eingeschränkt, was den fehlerhaften Einbau von Nukleotiden und DNA-Strangbrüche zur Folge hat. Beobachtungsstudien untermauern die Vermutung, dass eine unzureichende Folsäureversorgung die Entstehung kolorektaler Tumoren begünstigt, wenngleich die Studienergebnisse widersprüchlich sind. Das Risiko kolorektaler Karzinome wird auch durch einen Polymorphismus des MTHFR-Gens beeinflusst. So sind insbesondere Träger des TT-Genotyps bei schlechter Folatversorgung einem erhöhten Krankheitsrisiko ausgesetzt. Um den präventiven Nutzen einer erhöhten Folsäurezufuhr zu belegen, bedarf es weiterer Studien.

Abstract

Several epidemiological studies suggest that plant based diets protect against colorectal cancer. This effect may result from their high levels of folic acid. The mechanisms by which folate might protect against cancer may relate to its role in DNA synthesis, DNA methylation and regulation of gene expression. Folic acid deficiency has been associated with site- and gene specific DNA hypo- and hypermethylation both of which are associated with genomic instability and therefore may be involved in colorectal carcinogenesis. Furthermore thymidylate synthesis is restricted by folic acid deficiency which causes misincorporation of nucleotides and DNA strand breaks. Epidemiological evidence supports the hypothesis that insufficient folic acid supply favors the development of colorectal tumors. In particular prospective studies have supported this connection. The data from case-control studies are less consistent. Functional polymorphisms in folate-metabolizing genes, especially the methylenetetrahydrofolate reductase (MTHFR) could be linked with the risk of colorectal cancer. Observational studies show that individuals with the homozygote genotype for the MTHFR (677C→T) polymorphism are at higher risk when folic acid supply is low. Currently there are only few human intervention trials which show that folic acid can modify and inhibit the development of colorectal tumors. Additional studies are required in order to determine whether folic acid will be a useful agent in colorectal cancer prevention.

Folsäure - kolorektales Adenom - kolorektales Karzinom - DNA-Methylierung - Thymidilatsynthese - EGFR - MTHFR-Polymorphismus - Multivitaminpräparate

Folic acid - colorectal adenomas - colorectal cancer - DNA methylation - EGFR - thymidilate synthesis - MTHFR polymorphism - multivitamin use

Literatur

• 1 Key T J, Schatzkin A, Willett W C, Allen N E, Spencer E A, Travis R C. Diet, nutrition and the prevention of cancer.  Public Health Nutr. 2004;  7 187-200
• 2 Bingham S A. Diet and colorectal cancer prevention.  Biochem Soc Trans. 2000;  28 12-16
• 3 Gatof D, Ahnen D. Primary prevention of colorectal cancer: diet and drugs.  Gastroenterol Clin North Am. 2002;  31 587-623
• 4 Parkin D M, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden. Globocan 2000.  Int J Cancer. 2001;  94 153-156
• 5 Calvert P M, Frucht H. The genetics of colorectal cancer.  Ann Intern Med. 2002;  137 603-612
• 6 Eichholzer M, Luthy J, Moser U, Fowler B. Folate and the risk of colorectal, breast and cervix cancer: the epidemiological evidence.  Swiss Med Wkly. 2001;  131 39-49
• 7 Giovannucci E. Epidemiologic studies of folate and colorectal neoplasia: a review.  J Nutr. 2002;  132 (8 Suppl) 2350S-2355S
• 8 Sharp L, Little J. Polymorphisms in Genes Involved in Folate Metabolism and Colorectal Neoplasia: A HuGE Review.  Am J Epidemiol. 2004;  159 423-443
• 9 Choi S W, Mason J B. Folate status: effects on pathways of colorectal carcinogenesis.  J Nutr. 2002;  132 (8 Suppl) 2413S-2418S
• 10 Kim Y I. Role of folate in colon cancer development and progression.  J Nutr. 2003;  133 (11 Suppl 1) 3731S-3739S
• 11 Kim Y I. Folate and DNA methylation: a mechanistic link between folate deficiency and colorectal cancer?.  Cancer Epidemiol Biomarkers Prev. 2004;  13 511-519
• 12 Lucock M. Folic acid: nutritional biochemistry, molecular biology, and role in disease processes.  Mol Genet Metab. 2000;  71 121-138
• 13 Deutsche Gesellschaft für Ernährung, Österreichische Gesellschaft für Ernährung, Schweizerische Gesellschaft für Ernährungsforschung, Schweizerische Vereinigung für Ernährung, ed .Referenzwerte für die Nährstoffzufuhr. Frankfurt a. M.; Umschau Braus 2000: 117-122
• 14 Schmutte C, Jones P A. Involvement of DNA methylation in human carcinogenesis.  Biol Chem. 1998;  379 377-388
• 15 Feinberg A P, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts.  Nature. 1983;  301 89-92
• 16 Fruhwald M C, Plass C. Global and gene-specific methylation patterns in cancer: aspects of tumor biology and clinical potential.  Mol Genet Metab. 2002;  75 1-16
• 17 Bariol C, Suter C, Cheong K, Ku S L, Meagher A, Hawkins N, Ward R. The relationship between hypomethylation and CpG island methylation in colorectal neoplasia.  Am J Pathol. 2003;  162 1361-1371
• 18 Chen J, Giovannucci E, Hankinson S E, Ma J, Willett W C, Spiegelman D, Kelsey K T, Hunter D J. A prospective study of methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms, and risk of colorectal adenoma.  Carcinogenesis. 1998;  19 2129-2132
• 19 Lengauer C, Kinzler K W, Vogelstein B. DNA methylation and genetic instability in colorectal cancer cells.  Proc Natl Acad Sci U S A. 1997;  94 2545-2550
• 20 Feinberg A P, Vogelstein B. Hypomethylation of ras oncogenes in primary human cancers.  Biochem Biophys Res Commun. 1983;  111 47-54
• 21 Wainfan E, Dizik M, Stender M, Christman J K. Rapid appearance of hypomethylated DNA in livers of rats fed cancer-promoting, methyl-deficient diets.  Cancer Res. 1989;  49 4094-4097
• 22 Dizik M, Christman J K, Wainfan E. Alterations in expression and methylation of specific genes in livers of rats fed a cancer promoting methyl-deficient diet.  Carcinogenesis. 1991;  12 1307-1312
• 23 Balaghi M, Wagner C. DNA methylation in folate deficiency: use of CpG methylase.  Biochem Biophys Res Commun. 1993;  193 1184-1190
• 24 Kim Y I, Christman J K, Fleet J C, Cravo M L, Salomon R N, Smith D, Ordovas J, Selhub J, Mason J B. Moderate folate deficiency does not cause global hypomethylation of hepatic and colonic DNA or c-myc-specific hypomethylation of colonic DNA in rats.  Am J Clin Nutr. 1995;  61 1083-1090
• 25 Jacob R A, Gretz D M, Taylor P C, James S J, Pogribny I P, Miller B J, Henning S M, Swendseid M E. Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women.  J Nutr. 1998;  128 1204-1212
• 26 Rampersaud G C, Kauwell G P, Hutson A D, Cerda J J, Bailey L B. Genomic DNA methylation decreases in response to moderate folate depletion in elderly women.  Am J Clin Nutr. 2000;  72 998-1003
• 27 Pufulete M, Al-Ghnaniem R, Leather A J, Appleby P, Gout S, Terry C, Emery P W, Sanders T A. Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study.  Gastroenterology. 2003;  124 1240-1248
• 28 Kim Y I, Pogribny I P, Basnakian A G, Miller J W, Selhub J, James S J, Mason J B. Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene.  Am J Clin Nutr. 1997;  65 46-52
• 29 Engeland M van, Weijenberg M P, Roemen G M, Brink M, Bruine A P de, Goldbohm R A, Brandt P A van den, Baylin S B, Goeij A F de, Herman J G. Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer.  Cancer Res. 2003;  63 3133-3137
• 30 Herbst R S, Shin D M. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy.  Cancer. 2002;  94 1593-1611
• 31 Barnard J A, Beauchamp R D, Russell W E, Dubois R N, Coffey R J. Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology.  Gastroenterology. 1995;  108 564-580
• 32 Salomon D S, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies.  Crit Rev Oncol Hematol. 1995;  19 183-232
• 33 Pavelic K, Banjac Z, Pavelic J, Spaventi S. Evidence for a role of EGF receptor in the progression of human lung carcinoma.  Anticancer Res. 1993;  13 1133-1137
• 34 Brandt R, Eisenbrandt R, Leenders F, Zschiesche W, Binas B, Juergensen C, Theuring F. Mammary gland specific hEGF receptor transgene expression induces neoplasia and inhibits differentiation.  Oncogene. 2000;  19 2129-2137
• 35 Lage A, Crombet T, Gonzalez G. Targeting epidermal growth factor receptor signaling: early results and future trends in oncology.  Ann Med. 2003;  35 327-336
• 36 Jaszewski R, Khan A, Sarkar F H, Kucuk O, Tobi M, Zagnoon A, Dhar R, Kinzie J, Majumdar A P. Folic acid inhibition of EGFR-mediated proliferation in human colon cancer cell lines.  Am J Physiol. 1999;  277 C1142-1148
• 37 Nagothu K K, Rishi A K, Jaszewski R, Kucuk O, Majumdar A P. Folic acid mediated inhibition of serum-induced activation of EGFR promoter in colon cancer cells.  Am J Physiol Gastrointest Liver Physiol. 2004;  287 G541-546
• 38 Nensey Y M, Arlow F L, Majumdar A P. Aging. Increased responsiveness of colorectal mucosa to carcinogen stimulation and protective role of folic acid.  Dig Dis Sci. 1995;  40 396-401
• 39 Duthie S J, Hawdon A. DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro.  FASEB J. 1998;  12 1491-1497
• 40 Duthie S J, Narayanan S, Blum S, Pirie L, Brand G M. Folate deficiency in vitro induces uracil misincorporation and DNA hypomethylation and inhibits DNA excision repair in immortalized normal human colon epithelial cells.  Nutr Cancer. 2000;  37 245-251
• 41 Christmann M, Tomicic M T, Roos W P, Kaina B. Mechanisms of human DNA repair: an update.  Toxicology. 2003;  193 3-34
• 42 Choi S W, Kim Y I, Weitzel J N, Mason J B. Folate depletion impairs DNA excision repair in the colon of the rat.  Gut. 1998;  43 93-99
• 43 Giovannucci E, Stampfer M J, Colditz G A, Rimm E B, Trichopoulos D, Rosner B A, Speizer F E, Willett W C. Folate, methionine, and alcohol intake and risk of colorectal adenoma.  J Natl Cancer Inst. 1993;  85 875-884
• 44 Benito E, Cabeza E, Moreno V, Obrador A, Bosch F X. Diet and colorectal adenomas: a case-control study in Majorca.  Int J Cancer. 1993;  55 213-219
• 45 Boutron-Ruault M C, Senesse P, Faivre J, Couillault C, Belghiti C. Folate and alcohol intakes: related or independent roles in the adenoma-carcinoma sequence?.  Nutr Cancer. 1996;  26 337-346
• 46 Tseng M, Murray S C, Kupper L L, Sandler R S. Micronutrients and the risk of colorectal adenomas.  Am J Epidemiol. 1996;  144 1005-1014
• 47 Martinez M E, Henning S M, Alberts D S. Folate and colorectal neoplasia: relation between plasma and dietary markers of folate and adenoma recurrence.  Am J Clin Nutr. 2004;  79 691-697
• 48 Paspatis G A, Kalafatis E, Oros L, Xourgias V, Koutsioumpa P, Karamanolis D G. Folate status and adenomatous colonic polyps. A colonoscopically controlled study.  Dis Colon Rectum. 1995;  38 64-67
• 49 Bird C L, Swendseid M E, Witte J S, Shikany J M, Hunt I F, Frankl H D, Lee E R, Longnecker M P, Haile R W. Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps.  Cancer Epidemiol Biomarkers Prev. 1995;  4 709-714
• 50 Fujimori S, Kishida T, Mitsui K, Seo T, Yonezawa M, Shibata Y, Shinozawa I, Tanaka S, Tatsuguchi A, Sato J, Yoshida Y, Yokoi K, Tanaka N, Ohaki Y, Sakamoto C, Kobayashi M. Mean corpuscular volume (MCV) and the risk of colorectal adenoma in menopausal women.  Hepatogastroenterology. 2003;  50 392-395
• 51 Wolters M, Strohle A, Hahn A. Age-associated changes in the metabolism of vitamin B(12) and folic acid: Prevalence, aetiopathogenesis and pathophysiological consequences.  Z Gerontol Geriatr. 2004;  37 109-135
• 52 Baron J A, Sandler R S, Haile R W, Mandel J S, Mott L A, Greenberg E R. Folate intake, alcohol consumption, cigarette smoking, and risk of colorectal adenomas.  J Natl Cancer Inst. 1998;  90 57-62
• 53 Ulrich C M, Kampman E, Bigler J, Schwartz S M, Chen C, Bostick R, Fosdick L, Beresford S A, Yasui Y, Potter J D. Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene-environment interaction?.  Cancer Epidemiol Biomarkers Prev. 1999;  8 659-668
• 54 Giovannucci E, Rimm E B, Ascherio A, Stampfer M J, Colditz G A, Willett W C. Alcohol, low-methionine-low-folate diets, and risk of colon cancer in men.  J Natl Cancer Inst. 1995;  87 265-273
• 55 Giovannucci E, Stampfer M J, Colditz G A, Hunter D J, Fuchs C, Rosner B A, Speizer F E, Willett W C. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study.  Ann Intern Med. 1998;  129 517-524
• 56 Jacobs E J, Connell C J, Patel A V, Chao A, Rodriguez C, Seymour J, McCullough M L, Calle E E, Thun M J. Multivitamin use and colon cancer mortality in the Cancer Prevention Study II cohort (United States).  Cancer Causes Control. 2001;  12 927-934
• 57 Fuchs C S, Willett W C, Colditz G A, Hunter D J, Stampfer M J, Speizer F E, Giovannucci E L. The influence of folate and multivitamin use on the familial risk of colon cancer in women.  Cancer Epidemiol Biomarkers Prev. 2002;  11 227-234
• 58 Jacobs E J, Connell C J, Chao A, McCullough M L, Rodriguez C, Thun M J, Calle E E. Multivitamin use and colorectal cancer incidence in a US cohort: does timing matter?.  Am J Epidemiol. 2003;  158 621-628
• 59 Wei E K, Giovannucci E, Wu K, Rosner B, Fuchs C S, Willett W C, Colditz G A. Comparison of risk factors for colon and rectal cancer.  Int J Cancer. 2004;  108 433-442
• 60 Flood A, Caprario L, Chaterjee N, Lacey Jr J V, Schairer C, Schatzkin A. Folate, methionine, alcohol, and colorectal cancer in a prospective study of women in the United States.  Cancer Causes Control. 2002;  13 551-561
• 61 Harnack L, Jacobs Jr D R, Nicodemus K, Lazovich D, Anderson K, Folsom A R. Relationship of folate, vitamin B-6, vitamin B-12, and methionine intake to incidence of colorectal cancers.  Nutr Cancer. 2002;  43 152-158
• 62 Freudenheim J L, Graham S, Marshall J R, Haughey B P, Cholewinski S, Wilkinson G. Folate intake and carcinogenesis of the colon and rectum.  Int J Epidemiol. 1991;  20 368-374
• 63 Ferraroni M, Vecchia C La, D'Avanzo B, Negri E, Franceschi S, Decarli A. Selected micronutrient intake and the risk of colorectal cancer.  Br J Cancer. 1994;  70 1150-1155
• 64 Kato I, Dnistrian A M, Schwartz M, Toniolo P, Koenig K, Shore R E, Akhmedkhanov A, Zeleniuch-Jacquotte A, Riboli E. Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study.  Br J Cancer. 1999;  79 1917-1922
• 65 Terry P, Jain M, Miller A B, Howe G R, Rohan T E. Dietary intake of folic acid and colorectal cancer risk in a cohort of women.  Int J Cancer. 2002;  97 864-867
• 66 Glynn S A, Albanes D, Pietinen P, Brown C C, Rautalahti M, Tangrea J A, Gunter E W, Barrett M J, Virtamo J, Taylor P R. Colorectal cancer and folate status: a nested case-control study among male smokers.  Cancer Epidemiol Biomarkers Prev. 1996;  5 487-494
• 67 Slattery M L, Schaffer D, Edwards S L, Ma K N, Potter J D. Are dietary factors involved in DNA methylation associated with colon cancer?.  Nutr Cancer. 1997;  28 52-62
• 68 Frosst P, Blom H J, Milos R, Goyette P, Sheppard C A, Matthews R G, Boers G J, Heijer M den, Kluijtmans L A, Heuvel L P van den. et al . A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.  Nat Genet. 1995;  10 111-113
• 69 Yamada K, Chen Z, Rozen R, Matthews R G. Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase.  Proc Natl Acad Sci U S A. 2001;  98 14853-14858
• 70 Jacques P F, Bostom A G, Williams R R, Ellison R C, Eckfeldt J H, Rosenberg I H, Selhub J, Rozen R. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations.  Circulation. 1996;  93 7-9
• 71 Girelli D, Friso S, Trabetti E, Olivieri O, Russo C, Pessotto R, Faccini G, Pignatti P F, Mazzucco A, Corrocher R. Methylenetetrahydrofolate reductase C677T mutation, plasma homocysteine, and folate in subjects from northern Italy with or without angiographically documented severe coronary atherosclerotic disease: evidence for an important genetic-environmental interaction.  Blood. 1998;  91 4158-4163
• 72 Kauwell G P, Wilsky C E, Cerda J J, Herrlinger-Garcia K, Hutson A D, Theriaque D W, Boddie A, Rampersaud G C, Bailey L B. Methylenetetrahydrofolate reductase mutation (677C→T) negatively influences plasma homocysteine response to marginal folate intake in elderly women.  Metabolism. 2002;  49 1440-1443
• 73 Bree A de, Verschuren W M, Bjorke-Monsen A L, Put N M van der, Heil S G, Trijbels F J, Blom H J. Effect of the methylenetetrahydrofolate reductase 677C→T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample.  Am J Clin Nutr. 2003;  77 687-693
• 74 Amouzou E K, Chabi N W, Adjalla C E, Rodriguez-Gueant R M, Feillet F, Villaume C, Sanni A, Gueant J L. High prevalence of hyperhomocysteinemia related to folate deficiency and the 677C→T mutation of the gene encoding methylenetetrahydrofolate reductase in coastal West Africa.  Am J Clin Nutr. 2004;  79 619-624
• 75 Kim K N, Kim Y J, Chang N. Effects of the interaction between the C677T 5,10-methylenetetrahydrofolate reductase polymorphism and serum B vitamins on homocysteine levels in pregnant women.  Eur J Clin Nutr. 2004;  58 10-16
• 76 Hustad S, Ueland P M, Vollset S E, Zhang Y, Bjorke-Monsen A L, Schneede J. Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism.  Clin Chem. 2000;  46 1065-1071
• 77 Jacques P F, Kalmbach R, Bagley P J, Russo G T, Rogers G, Wilson P W, Rosenberg I H, Selhub J. The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene.  J Nutr. 2002;  132 283-288
• 78 McNulty H, McKinley M C, Wilson B, McPartlin J, Strain J J, Weir D G, Scott J M. Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements.  Am J Clin Nutr. 2002;  76 436-441
• 79 Moat S J, Ashfield-Watt P A, Powers H J, Newcombe R G, McDowell I F. Effect of riboflavin status on the homocysteine-lowering effect of folate in relation to the MTHFR (C677T) genotype.  Clin Chem. 2003;  49 295-302
• 80 Stern L L, Mason J B, Selhub J, Choi S W. Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene.  Cancer Epidemiol Biomarkers Prev. 2000;  9 849-853
• 81 Friso S, Choi S W, Girelli D, Mason J B, Dolnikowski G G, Bagley P J, Olivieri O, Jacques P F, Rosenberg I H, Corrocher R, Selhub J. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status.  Proc Natl Acad Sci U S A. 2002;  99 5606-5611
• 82 Ma J, Stampfer M J, Giovannucci E, Artigas C, Hunter D J, Fuchs C, Willett W C, Selhub J, Hennekens C H, Rozen R. Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer.  Cancer Res. 1997;  57 1098-1102
• 83 Chen J, Giovannucci E, Kelsey K, Rimm E B, Stampfer M J, Colditz G A, Spiegelman D, Willett W C, Hunter D J. A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer.  Cancer Res. 1996;  56 4862-4864
• 84 Levine A J, Siegmund K D, Ervin C M, Diep A, Lee E R, Frankl H D, Haile R W. The methylenetetrahydrofolate reductase 677C→T polymorphism and distal colorectal adenoma risk.  Cancer Epidemiol Biomarkers Prev. 2000;  9 657-663
• 85 Marugame T, Tsuji E, Inoue H, Shinomiya S, Kiyohara C, Onuma K, Hamada H, Koga H, Handa K, Hayabuchi H, Kono S. Methylenetetrahydrofolate reductase polymorphism and risk of colorectal adenomas.  Cancer Lett. 2000;  151 181-186
• 86 Ulvik A, Evensen E T, Lien E A, Hoff G, Vollset S E, Majak B M, Ueland P M. Smoking, folate and methylenetetrahydrofolate reductase status as interactive determinants of adenomatous and hyperplastic polyps of colorectum.  Am J Med Genet. 2001;  101 246-254
• 87 Delgado-Enciso I, Martinez-Garza S G, Rojas-Martinez A, Ortiz-Lopez R, Bosques-Padilla F, Calderon-Garciduenas A L, Zarate-Gomez M, Barrera-Saldana H A. 677T mutation of the MTHFR gene in adenomas and colorectal cancer in a population sample from the Northeastern Mexico. Preliminary results.  Rev Gastroenterol Mex. 2001;  66 32-37
• 88 Giovannucci E, Chen J, Smith-Warner S A, Rimm E B, Fuchs C S, Palomeque C, Willett W C, Hunter D J. Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas.  Cancer Epidemiol Biomarkers Prev. 2003;  12 970-979
• 89 Marugame T, Tsuji E, Kiyohara C, Eguchi H, Oda T, Shinchi K, Kono S. Relation of plasma folate and methylenetetrahydrofolate reductase C677T polymorphism to colorectal adenomas.  Int J Epidemiol. 2003;  32 64-66
• 90 Park K S, Mok J W, Kim J C. The 677C > T mutation in 5,10-methylenetetrahydrofolate reductase and colorectal cancer risk.  Genet Test. 1999;  3 233-236
• 91 Sharp L, Little J, Brockton N. et al . Genetic polymorphisms in folate metabolism, dietary folate intake and colorectal cancer: a population-based case-control study.  J Epidemiol Community Health. 2001;  55 A27
• 92 Marchand L Le, Donlon T, Hankin J H, Kolonel L N, Wilkens L R, Seifried A. B-vitamin intake, metabolic genes, and colorectal cancer risk (United States).  Cancer Causes Control. 2002;  13 239-248
• 93 Sachse C, Smith G, Wilkie M J, Barrett J H, Waxman R, Sullivan F, Forman D, Bishop D T, Wolf C R. Colorectal Cancer Study Group . A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer.  Carcinogenesis. 2002;  23 1839-1849
• 94 Shannon B, Gnanasampanthan S, Beilby J, Iacopetta B. A polymorphism in the methylenetetrahydrofolate reductase gene predisposes to colorectal cancers with microsatellite instability.  Gut. 2002;  50 520-524
• 95 Sharp L, Little J, Brockton N, Cotton S C, Haites N E, Cassidy J. Dietary Intake of Folate and Related Micronutrients, Genetic Polymorphisms in MTHFR and Colorectal Cancer: A Population-Based Case-Control Study in Scotland.  J Nutr. 2002;  132 (11 Suppl) 3542S
• 96 Slattery M L, Potter J D, Samowitz W, Schaffer D, Leppert M. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer.  Cancer Epidemiol Biomarkers Prev. 1999;  8 513-518
• 97 Keku T, Millikan R, Worley K, Winkel S, Eaton A, Biscocho L, Martin C, Sandler R. 5,10-Methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites.  Cancer Epidemiol Biomarkers Prev. 2002;  11 1611-1621
• 98 Eaden J A, Abrams K R, Mayberry J F. The risk of colorectal cancer in ulcerative colitis: a meta-analysis.  Gut. 2001;  48 526-535
• 99 Munkholm P. Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease.  Aliment Pharmacol Ther. 2003;  18 (Suppl 2) 1-5
• 100 Fernandez-Banares F, Abad-Lacruz A, Xiol X, Gine J J, Dolz C, Cabre E, Esteve M, Gonzalez-Huix F, Gassull M A. Vitamin status in patients with inflammatory bowel disease.  Am J Gastroenterol. 1989;  84 744-748
• 101 Koutroubakis I E, Dilaveraki E, Vlachonikolis I G, Vardas E, Vrentzos G, Ganotakis E, Mouzas I A, Gravanis A, Emmanouel D, Kouroumalis E A. Hyperhomocysteinemia in Greek patients with inflammatory bowel disease.  Dig Dis Sci. 2000;  45 2347-2351
• 102 Lashner B A. Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis.  J Cancer Res Clin Oncol. 1993;  119 549-554
• 103 Lashner B A, Heidenreich P A, Su G L, Kane S V, Hanauer S B. Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study.  Gastroenterology. 1989;  97 255-259
• 104 Lashner B A, Provencher K S, Seidner D L, Knesebeck A, Brzezinski A. The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis.  Gastroenterology. 1997;  112 29-32
• 105 Biasco G, Zannoni U, Paganelli G M, Santucci R, Gionchetti P, Rivolta G, Miniero R, Pironi L, Calabrese C, Febo G Di, Miglioli M. Folic acid supplementation and cell kinetics of rectal mucosa in patients with ulcerative colitis.  Cancer Epidemiol Biomarkers Prev. 1997;  6 469-471
• 106 Khosraviani K, Weir H P, Hamilton P, Moorehead J, Williamson K. Effect of folate supplementation on mucosal cell proliferation in high risk patients for colon cancer.  Gut. 2002;  51 195-199
• 107 Cravo M, Fidalgo P, Pereira A D, Gouveia-Oliveira A, Chaves P, Selhub J, Mason J B, Mira F C, Leitao C N. DNA methylation as an intermediate biomarker in colorectal cancer: modulation by folic acid supplementation.  Eur J Cancer Prev. 1994;  3 473-479
• 108 Cravo M L, Pinto A G, Chaves P, Cruz J A, Lage P, Nobre Leitao C, Costa Mira F. Effect of folate supplementation on DNA methylation of rectal mucosa in patients with colonic adenomas: correlation with nutrient intake.  Clin Nutr. 1998;  17 45-49
• 109 Kim Y I, Baik H W, Fawaz K, Knox T, Lee Y M, Norton R, Libby E, Mason J B. Effects of folate supplementation on two provisional molecular markers of colon cancer: a prospective, randomized trial.  Am J Gastroenterol. 2001;  96 184-195
• 110 Slesinski M J, Subar A F, Kahle L L. Dietary intake of fat, fiber and other nutrients is related to the use of vitamin and mineral supplements in the United States: The 1992 National Health Interview Survey.  J Nutr. 1996;  126 3001-3008
• 111 Kaartinen P, Ovaskainen M-L, Pietinen P. The use of dietary supplements among Finish adults.  Scand J Nutr. 1997;  41 13-17
• 112 Harrison R A, Holt D, Pattison D J, Elton P J. Are those in need taking dietary supplements? A survey of 21 923 adults.  Br J Nutr. 2004;  91 617-623
• 113 White E, Shannon J S, Patterson R E. Relationship between vitamin and calcium supplement use and colon cancer.  Cancer Epidemiol Biomarkers Prev. 1997;  6 769-774
• 114 Vecchia C La, Negri E, Pelucchi C, Franceschi S. Dietary folate and colorectal cancer.  Int J Cancer. 2002;  102 545-547
• 115 Beitz R, Mensink G B, Fischer B, Thamm M. Vitamins - dietary intake and intake from dietary supplements in Germany.  Eur J Clin Nutr. 2002;  56 539-545
• 116 Wolters M, Hermann S, Hahn A. B vitamins, homocysteine, and methylmalonic acid in elderly German women.  Am J Clin Nutr. 2003;  78 765-772
• 117 Gonzalez-Gross M, Prinz-Langenohl R, Pietrzik K. Folate status in Germany 1997 - 2000.  Int J Vitam Nutr Res. 2002;  72 351-359
• 118 Wald D S, Law M, Morris J K. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.  BMJ. 2002;  325 1202
• 119 Stanger O, Herrmann W, Pietrzik K, Fowler B, Geisel J, Dierkes J, Weger M. DACH-LIGA Homocystein e. V. . DACH-LIGA homocystein (german, austrian and swiss homocysteine society): consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations.  Clin Chem Lab Med. 2003;  41 1392-1403
• 120 Kuntz S, Wenzel U, Daniel H. Comparative analysis of the effects of flavonoids on proliferation, cytotoxicity, and apoptosis in human colon cancer cell lines.  Eur J Nutr. 1999;  38 133-142
• 121 Wenzel U, Kuntz S, Brendel M D, Daniel H. Dietary flavone is a potent apoptosis inducer in human colon carcinoma cells.  Cancer Res. 2000;  60 3823-3831
• 122 Ferguson L R, Harris P J. Protection against cancer by wheat bran: role of dietary fibre and phytochemicals.  Eur J Cancer Prev. 1999;  8 17-25
• 123 Croog V J, Ullman T A, Itzkowitz S H. Chemoprevention of colorectal cancer in ulcerative colitis.  Int J Colorectal Dis. 2003;  18 392-400
• 124 Whittle S L, Hughes R A. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review.  Rheumatology (Oxford). 2004;  43 267-271
• 125 Bailey L B, Moyers S, Gregory III J F. Folate. In: Bowman BA, Russell RM (eds) Pressent Knowledge in Nutrition. Washington DC; ILSI Press 2001: 214-229
• 126 Su L J, Arab L. Nutritional status of folate and colon cancer risk: evidence from NHANES I epidemiologic follow-up study.  Ann Epidemiol. 2001;  11 65-72
• 127 Meyer F, White E. Alcohol and nutrients in relation to colon cancer in middle-aged adults.  Am J Epidemiol. 1993;  138 225-236