ATOS

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Functional Signalling Hydrophobic Domain Domain Domain

Responsible for Affects Mediates docking in redox/apoptotic PP2A/PKC membranes and activity pathway lipoproteins

FIGURE 6.1 Major domains in VE analogs. Shown are the structures of a-TOH and a-TOS with the specification and major function of the three main domains. Domains I and II are identical; Domain III differs. While Domains I and II are important for the extent of the activity, Domain III determines whether the agent does or does not induce apoptosis.

important to enhance our knowledge in this respect, so that clinical trials can commence that will, we hope, lead to generation and use of novel antineoplastic strategies.

6.2 VITAMIN E AS AN ANTICANCER AGENT — MORE THAN AN ANTIOXIDANT?

Great interest has been given to the potential use of VE as anticancer drugs. This is rather logical, since VE and other redox-active micronutrients are ingested regularly and their dose can be increased by food fortification. They may be beneficial since they do not exert deleterious effects.

The term VE refers to eight naturally occurring, structurally related agents, four tocopherols (a-, P-, y-, and S-TOH), and four tocotrienols (a-, P-, y-, and S-T3H). The biological activity of VE has been determined by the rat fetal resorption assay, in which a-TOH exhibits the highest activity among the forms of VE. a-TOH is also the form of VE present at the highest level in serum and dietary supplements. However, the predominant form of VE in a typical Western diet is y-TOH, which is present in food at levels two to four times higher than those of a-TOH.2 Plasma as well as tissue concentrations of y-TOH and a-TOH can be enhanced by supplementation.2

Many attempts have been made to find out whether dietary VE has an anticancer activity. Although the best understood function of VE is linked to its redox activity, studies show that VE compounds exhibit antitumor properties. However,

the epidemiological evidence supporting a link between a-TOH or other forms of VE and cancer is limited and intervention studies are scarce.

In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) trial, smokers who took a-TOH supplements had a 32% lower incidence of prostate cancer and 41% lower mortality from prostate cancer than the unsupplemented subjects.3 Higher serum a-TOH was associated with lower lung cancer risk, in particular among those with less cigarette smoke exposure.4 In contrast, gastric, pancreatic, or colorectal cancers were not affected in the ATBC study.5-7 In the Linxian trial, subjects who received a-TOH, selenium, and P-carotene, showed a 13% reduced incidence of cancer and 50% reduced mortality from stomach cancer.8 An ongoing Selenium and Vitamin E Cancer Prevention Trial (SELECT) is the second large-scale study of prevention of prostate cancer with final results anticipated not before the year 2013.9 The SELECT project offers an opportunity to conduct molecular epidemiologic investigations for assessment of the gene-environment interactions and their role in carcinogenesis. These results may provide much needed evidence about association of VE and cancer.

Observational studies in humans potentially suggesting association between a-TOH and cancer risk have provided inconsistent results. Prediagnostic serum a-TOH levels are inversely associated with lung cancer in some but not all studies, and case-control investigations have been generally supportive of reduced lung cancer risk among persons with higher blood a-TOH levels.10-12 No association has been found between serum a-TOH and cancer risk in some cohort and case-control studies of prostate, breast, or colon cancers.13-16 The epidemiological evidence of association of VE with cancer risk is presented in Table 6.1 and Table 6.2.

Attempts to prevent cancer by VE are based on the rationale that tumorigen-esis results from free radicals attacking DNA. a-TOH is the major chain-breaking antioxidant in the lipid phase. It is thought to inhibit carcinogenesis at the level of transformation of normal cells into malignant cells, primarily through its antioxidative activity, i.e., by scavenging ROS and reactive nitrogen species. In addition, a-TOH may also inhibit cancer formation through various alternative mechanisms, including inhibition of cell proliferation, cell cycle arrest, prevention of angiogenesis, and enhancement of the immune function. In the prostate cancer lines LNCaP and PC3, a-TOH caused a dramatic reduction of the population of cells in the S phase.17 VE deficiency has been shown to be associated with impairment of the immune system, including both T- and B-cell-mediated functions. Further, VE restored age-related immune dysfunction.1819 a-TOH has also been shown to regulate cell growth, probably through its influence on several interconnected pathways. For example, it is thought to increase the level of p27Kip1 while decreasing the level of the proliferating cell nuclear antigen,20 blocking prostaglandin and arachidonic acid metabolism, inhibiting protein kinase C activity, and affecting the expression of hormones and growth factors. Subjects who received a-TOH had significantly lower serum androstenedione and testosterone compared to the placebo group.21 This finding has been regarded as a possible explanation of the selective reduction in prostate cancer observed in the ATBC

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