In the past decade it became apparent that low normal levels of certain vitamins may cause diseases in at-risk populations, such as middle to elderly age groups and pregnant women, and that such abnormalities might be overcome by ensuring high normal plasma levels of the respective vitamins [40-42]. Metabolic defects of folate are associated with circulatory diseases [43,44] as well as neural and cognitive disorders [45]. Folate deficiency has recently been associated with pathogenesis in a variety of malignancies [46-50]. The most understood functions of folate and vitamin B12 are in the area of synthesis of purines and pyrimidines, as well as the maintenance of the methylation process that is essential for regulated cell division [51].

Several lines of evidence, both in vitro and in vivo, suggest that folate deficiency has pro-neoplastic effects. Deoxynucletide pool imbalance and uracil misincorporation into DNA in folate deficient cell lines has been described [52,53]. Enhanced development of colonic neoplasia was observed in a folate-deficient rat model [54,55]. Several human studies demonstrate that folate deficiency may potentiate neoplastic processes and that high dietary folate intake is protective [46-50,56]. It is well established that folate deficiency leads to nucleotide pool imbalance (uracil misincorporation), DNA strand breaks [57,58], hypomethylation of DNA [59-61], increased gene expression [62-64], altered chromatin conformation [63,64], as well as altered cellular proliferation [62,67]. All these phenomena have been associated with carcinogenesis and tumorigenesis.

It has been recommended that patients undergoing chronic methotrexate or other antifolate therapy increase folate intake [68]. In such cases, high dose of folic acid (5 mg/day) have reduced therapy-associated toxicity with apparent preservation of antitumor activity [69]. This supports the view that antifolates act through a direct cytotoxic mechanism [70].

There is a close interrelationship between folate and vitamin B12 in the synthesis, repair and methylation of DNA. In a human clinical trial, a three-month-long supplementation with 3.5 times the Australian Recommended Daily Allowance (RDA) for folic acid and vitamin B12 was found to reduce micronuclei frequency, a DNA damage marker, in healthy young adults by 25% [71]. This study emphasized that supplementation levels higher than the RDA may be required in large populations to minimize DNA damage. Our RDAs were based on information on acute effects, because optimum amounts for long-term health is unknown. However, these data suggest that RDA levels may need to be reevaluated to make sure that adequate levels of these nutrients are available for genomic stability.

Supplementation with folic acid and vitamin B12 has reduced the severity of smoking-induced bronchial metaplasia in humans [72,73], underscoring the importance of these vitamins. Folate and vitamin B12 deficiencies that lead to chromosome breaks affect a significant 10–14% of the U.S. population [74-77]. The two deficiencies may act synergistically. Vitamin B6, which also participates in DNA methylation, was also found to be deficient in about 10% of the U.S. population [76].

Besides the above micronutrients, niacin, iron, selenium and zinc deficiencies that also affect DNA integrity are common in the United States [76,78]. All these data suggest that micronutrient deficiencies, which can mimic radiation or chemical damage to DNA, are affecting a considerable proportion of the U.S. population, and the correction of these deficiencies will be a major public health concern in the coming decades.

Cancer and nutrients: Introduction
Cancer: Enviromental factors and plant phenolics
Cancer: Folate, vitamin B12 and other micronutrients
Cancer: Iodine
Cancer: Lipids and gastrointestinal factors
Cancer: Subtle energetic properties of nutrients and overcoming tumor adaptation
Cancer: Discussion
References