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.

Schlüsselwörter

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

Key words

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

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