Current observations in the literature suggest that vitamin E may be a suitable candidate for the adjuvant treatment of cancer. Even though historically most research focused on a-tocopherol, more recent evidence suggests that the other isomers of vitamin E (b-, cand d-tocopherols and a-, b-, c-and d-tocotrienols) differ in their proapoptotic potencies. The main focus of this communication is the current understanding of the molecular mechanisms regulated by vitamin E isomers and their analogs during the induction of apoptosis. This review highlights that the mitochondria are the major target for the induction of apoptosis by vitamin E isomers and analogs and that the various signaling pathways regulated by these agents are likely to contribute towards maximizing the intrinsic pathway of apoptosis triggered initially by the mitochondria. Overall, the presentation of recent studies from the literature in this communication allows the drawing of the following important conclusions: (i) no direct link exists between the antioxidant activity of each isomer/derivative and proapoptotic potency, (ii) tocotrienols are more effective proapoptotic agents than tocopherols, (iii) synthetic modifications of the naturally occurring compounds may improve their apoptotic potency and (iv) vitamin E isomers and derivatives regulate caspase-independent pathways of apoptosis. The latter combined with the evidence presented in this review regarding the additive or synergistic anticarcinogenic effects obtained when vitamin E analogs are used in combination with other cancer chemotherapeutic agents, supports further research to design the most promising vitamin E derivatives and clinically test them in adjuvant chemotherapeutic treatments. ' 2008 Wiley-Liss, Inc.Key words: vitamin E; tocopherol; tocotrienol; apoptosis; atocopherol succinate; cancer chemoprevention; chemotherapy Despite great advances in molecular medicine, effective treatment and prevention of cancer has not yet been achieved. Deaths from neoplastic disease in both men and women have exceeded deaths from heart disease. Breast and prostate cancers are the cancers with highest incidence in females and males, respectively, and these cancers are third and second, respectively, to lung cancer in causing death.

Plasma and lipoprotein a-tocopherol concentrations of four patients with familial isolated vitamin E deficiency and six control subjects were observed for 4 d after an oral dose (-15 mg) of RRR-a-tocopheryl acetate labeled with six deuterium atoms (d6-tocopherol). Chylomicron d6-tocopherol concentrations were similar in the two groups. d6-Tocopherol concentrations of plasma, very low (VLDL), low (LDL), and high (HDL) density lipoproteins were similar in the two groups only during the first 12 h; then these were significantly lower, and the rate of disappearance faster, in the patients. The times (t.u) of the maximum chylomicron d6-tocopherol concentrations were similar for the two groups, but t1.,,, values in the controls increased in the order: chylomicrons < VLDL . LDL -HDL, while the corresponding values in the patients were similar to the chylomicron t,. Thus, plasma d4-tocopherol in controls increased during chylomicron and VLDL catabolism, whereas in patients it increased only during chylomicron catabolism, thereby resulting in a premature and faster decline in the plasma tocopherol concentration due to a lack of d6-tocopherol secretion from the liver. We suggest that these patients are lacking or have a defective liver "tocopherol binding protein" that incorporates a-tocopherol into nascent VLDL. (J. Clin. Invest. 1990. 85:397-407.) deuterated a-tocopherol * tocopherol binding protein Introduction Humans do not readily become vitamin E deficient. It has been generally accepted that the quantities of vitamin E in the diet are adequate and that the vitamin E stores in the body are sufficient to prevent any symptoms of vitamin E deficiency from occurring even in the face of a prolonged absence of dietary vitamin E. However, vitamin E deficiency does occur in humans as a consequence ofa variety oflipid malabsorption syndromes, most notably as a result of cholestatic liver disease in children, and in the genetic disorders, abetalipoproteinemia and homozygous hypobetalipoproteinemia (as reviewed in 1).

Colorectal cancer is the second most common cause of cancer deaths in the United States for both sexes. Considerable evidence suggests that the risk of this cancer is increased by the mutagenic actions of free radicals, which are produced during oxidation reactions. Dietary factors, the intestinal flora (bacteria), and endogenously produced metabolites contribute to the production of free radicals in the colon. Dietary antioxidants, such as vitamin E, should reduce the levels of these harmful oxidation products. In the absence of vitamin E, polyunsaturated fats can be oxidized in the colon to produce mutagens, such as lipid hydroperoxides and malondialdehyde. Furthermore, fecal bacteria can generate a high flux of reactive oxygen species (e.g., the superoxide radical [O2*-]) at the surface of the intestinal lumen, and inflammatory cells in close proximity to the colon can produce reactive nitrogen species (e.g., nitrogen dioxide [NO2]). Increasing evidence suggests that the different chemical (e.g., alpha- and gamma-tocopherol) and stereochemical (e.g., RRR- and all-racemic-alpha-tocopherol) forms of vitamin E have distinct biologic potencies, pharmacokinetics, and different abilities to prevent neoplastic transformation. This review considers and evaluates recent studies relating vitamin E and oxidative stress to colon cancer, emphasizing the distinct roles of alpha- and gamma-tocopherols. In addition, recent findings on the antioxidant/pro-oxidant status of the digesta (ingested food) are discussed with respect to the use of antioxidants in chemo-prevention trials for colon cancer.

Antioxidant status in humans reflects the dynamic balance between the antioxidant system and prooxidants and has been suggested as a useful tool in estimating the risk of oxidative damage. This paper reviews determinants of antioxidant status such as diet including antioxidant nutrient and nonnutrient intake, absorption and bioavailability, dietary components such as polyunsaturated fatty acids and transition metals, food storage and processing, chemical form, chirality and formulation of supplemental compounds and alcohol intake; environmental factors such as pollutants, ultraviolet radiation and smoking; injury and disease, medications and other medical treatments such as radiation; strenuous exercise; and physiological stage or conditions such as those in premature babies and the elderly. It is proposed that, in addition to current focus on tissues, the antioxidant status of digesta should be considered because of its effect on specific tissues and potential health implications.