Vitamin E was established as an essential micronutrient for proper fetal development  and the amount of vitamin E required to maintain proper fetal development has been defined in International Units. In addition to its role in reproduction, vitamin E is known to be a lipid-soluble antioxidant that blocks peroxidation of polyunsaturated fatty acids in cellular membranes and is known to stabilize biological membranes [14–17]. Because vitamin E has multiple biological activities, it is best to report dosage in weight units. The recommended dietary allowance and tolerable upper intake limit for sE, the commercially available form, has been calculated to be about 22 and 1470 mg per day respectively for 70 kg adult humans .
In animal species, oral intake of up to 200 mg/kg body weight per day was reported not to result in noticeable side effects . Thus, we selected to use a dietary dose of sE at the level of 200 mg/kg body weight per day in tumor bearing mice in an attempt to maximize inhibition of lipid peroxidation in the cellular membranes of the tumor without an expectation of finding harmful side-effects. Specifically, this experiment was originally designed to test the hypothesis that DOX, a prooxidative cancer chemotherapeutic drug, inhibits tumor growth by increasing lipid peroxidation products in the tumor to cytostatic or cytotoxic levels and that suppression of lipid peroxidation by sE would suppress the antitumor effects of DOX [11, 12]. The results demonstrated that sE supplementation did markedly suppress DOX-induced lipid peroxidation, yet tumor growth was still suppressed in mice treated with DOX and sE. It was concluded that increased levels of lipid peroxidation products were not the sole cause of tumor growth inhibition by DOX. As reported here (Fig. 1), the dietary supplementation with this high dose of sE, by itself, retarded tumor growth to a significant extent.
It is not known how such a high intake of sE works to suppress tumor growth. What is known from the current study is that the sE supplement reduced lipid peroxidation (Fig. 1) and preferentially stabilized membrane polyunsaturated fatty acids with more double bonds (Fig. 3). It has been proposed that vitamin E may incorporate into cellular membranes by association of the tocopherol side chain with the polyenoic fatty acid residues in the membrane fatty acids [15, 19]. This interaction may stabilize cell membranes by making highly unsaturated fatty acids less liable to peroxidation as well as by making highly unsaturated fatty acids less available for phospholipid hydrolysis by phospholipase [15, 16]. The latter action may reduce mobilization of arachidonic acid (AA) from the membranes and in this way reduce the amount of AA available as a substrate to cyclooxygenase and/or lipoxygenase to produce eicosanoids with mitogenic and with inflammatory properties [17, 20]. Other possible antitumor actions include: induction of apoptosis, interference with hormone production, modulation of cellular signaling and gene transcription, and induction of differentiation [4, 21–24].
In comparison to the inhibitory effect of vitamin E on mammary tumor growth (this report), Cognault et al. report a stimulatory effect of vitamin E on mammary tumor growth. Specifically, Cognault et al. report that when the diet was high in omega-3 PUFAs, tumor growth was significantly increased by vitamin E supplementation. However, when the diet was relatively low in omega-3 PUFAs, the promotional effect of vitamin E was not observed . It is noteworthy that the diet used in the presently reported study was very low in omega-3 PUFAs and that this diet, combined with the high dietary level of sE, resulted in suppression of tumor growth. Thus, the different results may be attributable to the type and the amount of omega-3 polyunsaturated fatty acids (PUFAs) in the diet.
Evidence for cardiotoxicity, as observed in this study, was not expected as supplementation with vitamin E at extremely high doses gave no significant indications of harmful side-effects in animals or in humans [18, 25]. Perhaps vitamin E supplementation acts to inhibit lipid peroxidation but at the same time acts to down regulate other protective antioxidant systems as suggested by the antioxidant enzyme gene expression data in Table 4. If gene expression levels in Table 4 reflect antioxidant enzyme activity, then an increase in SOD and decrease in GPX without an increase in CAT would result in accumulation of inorganic and organic peroxides and hydroperoxides that can react with Fe2+ to yield highly reactive free radical products that can damage cellular proteins and DNA as well as lipids. Likewise, the sE supplementation used caused low expression of the stress-induced isoform of heme oxygenase, (HO-1). HO-1 catalyzes the breakdown of prooxidant heme to biliverdin with release of carbon monoxide and iron ion. It should be realized that these observations are suggestive of cardiotoxicity but are not definitive.
Early studies suggested that vitamin E lessened the cardiotoxic effects of DOX chemotherapy  whereas other studies indicate potentiation of DOX induced cardiotoxicity [27, 28]. Shinoyawa et al.  suggest that vitamin E, when combined with DOX, may increase levels of toxic products in the heart and in the tumor while Liu and Tan  suggest that vitamin E may have prooxidant properties at high dosage levels.
The micronuclei results in Table 5 suggest that while sE protects against lipid peroxidation, it did not protect the genome of erythroblasts against the prooxidant effects of DOX in this study. Thus, while the toxic effect of DOX was not significantly enhanced by vitamin E supplementation, neither was the toxic effect of DOX lessened by vitamin E supplementation.