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Diet, Carcinogenesis & Cancer Prevention

There is considerable epidemiologic evidence that diet can influence cancer incidence and mortality. In particular diets rich in fruit and vegetables are protective and various phytochemicals found in these foods may contribute to their cancer chemopreventive properties. Studies in our laboratory have sought to link biological and chemical properties of various phytochemicals with their anti-cancer activity. Previous research in our laboratory has contributed significantly to the understanding of the mechanisms of action for a variety of dietary and pharmaceutical agents including the tocopherols, carotenoids, tamoxifen and ascorbate.

Fundamental studies in my laboratory have sought to elucidate the role of nitrogen oxides, of both endogenous and exogenous origin, in the development of a neoplasia. We have previously demonstrated the inhibition of carcinogenesis by inhibitors of nitric oxide synthase, such as methyl arginine and aminoguanidine (Carcinogenesis, 14:1555-1559; Carcinogenesis, 21:1989-1995). Using antisense DNA oligonucleotide sequences against mRNA for the inducible nitric oxide synthase (iNOS) enzyme, we have shown that inhibition of this enzyme by antisense oligonucleotides leads to enhanced neoplastic foci formation (Cancer Letters, 147:163-174). This is in direct contrast to chemical inhibitors of iNOS, which are observed to suppress carcinogenesis, probably through mechanisms independent of NO inhibition. Research in our laboratory mirrors that for NO in many other fields, suggesting that nitric oxide may both positively and negatively impact cancer initiation and progression. This is presumably related to the ability of NO to oxidize to agents that cause mutations (Mutation Research, 281:193-202), whereas NO may also function as an important signal transduction molecule as well as as an antioxidant.

Figure 1: Association of biological markers with a-tocopherol in human plasma.

Current efforts are focused on better defining the optimal role of lipid-phase antioxidants and nutrients in human health and nutrition. Studies are directed at identifying interactions between lipid-soluble nutrients as well as identifying structure-function relationships for molecules, such as the tocopherols, in the prevention of carcinogenesis (Tanaka & Cooney below). Our finding that g-tocopherol, the predominant tocopherol in the American diet, is more effective at preventing tumor cell formation in the C3H 10T1/2 transformation assay (PNAS 90:1771-1775) has stimulated a number of studies identifying unique chemical and biological properties of g-tocopherol. Our identification of 5-nitro g-tocopherol (Free Radical Biology and Medicine, 19:259-269), as a product of reaction between nitrogen dioxide and g-tocopherol, has led to its use as a biomarker of endogenous nitration reactions associated with NO synthesis in vivo. Studies indicate that this marker is elevated in cardiovascular disease and Alheimer’s Disease (Nitric Oxide, 6:221-227). The observed chemical and biological differences between tocopherol analogues have highlighted the importance of tocopherol structure for biological activity and have stimulated considerable interest in the role of tocopherols other than a-tocopherol in human health beyond the traditional bioactivity of Vitamin E.

We have previously shown a significant association in women between plasma tocopherol and autoantibodies against oxidized DNA (figure 1) as well as with plasma lipid oxidation (Free Radical Biology & Medicine, 31:460-468). More recent work has shown a strong association in men between tocopherols and plasma levels of coenzyme Q10, the only major lipid-phase antioxidant synthesized by humans and an important component in mitochrondrial ATP synthesis (Figure 1). The curious similarity of the observed association between alpha-tocopherol and these disparate biomarkers is being explored. One possibility is that all are indicators of a strong immune response in humans, which may be relevant to both the initiation of carcinogenesis due to chronic inflammation and to immune clearance and apoptosis of tumors. These studies point to both greater complexity as well as redundancy in the interactions and functions of lipid-phase micronutrients.