The hypothesis addressed by this project is that gamma-tocopherol, the most ubiquitous dietary form of vitamin E, protects against prostate cancer development through its antioxidant activities. There are no data about this from human and animal studies. There are a few reports of experimental studies that tested the hypothesis that other antioxidants protect against prostate cancer, but those that did used models systems that do not involve oxidative stress mechanisms and did not find protective effects. Furthermore, there are no reports of studies that have investigated the probably critical synergisms that may exist between these antioxidants. Therefore, the purpose of this project is: (a) To address this hypothesis in a unique animal model of prostate carcinogenesis that does involve oxidative stress mechanisms; (b) To generate with this model proof-of-principle data demonstrating that antioxidant activity is a major mechanism by which gamma-tocopherol protects against prostate cancer; and (c) To determine the magnitude of the protective activity of this antioxidant individually and in combination with other antioxidants to provide efficacy information in support of the design of prevention clinical trials.
The Specific Aims of the project are: (1) To determine the maximally tolerated dose of RRR-gamma-tocopherol in order to select doses for the studies of Aims 2 and 3. (2) To determine the efficacy of gamma-tocopherol to prevent prostate cancer in NBL rats treated with estradiol & testosterone. This model importantly involves oxidative stress mechanisms. The antioxidants will be given in the diet at two non-toxic doses and the effects will be compared with those of alpha-tocopherol, selenium, and lycopene. (3) To determine whether treatments with gamma-tocopherol reduce oxidative stress parameters related to oxidation of DNA bases, lipid peroxidation, and inactivation or alteration of antioxidant enzymes. These parameters will be measured in the areas of the rat prostate where hormone treatment induces cancer, and the effects observed will be related to the outcome of the efficacy studies of Aim 2. (4) To determine the efficacy of delayed treatment with gamma-tocopherol or of combined treatment with the three other antioxidants to prevent prostate cancer in the NBL rat model, and to determine whether these treatments reduce oxidative stress parameters. The observed effects will be compared with the outcome of the single agent study of Aims 2 and 3 and with those of the parent grant that addresses protective and antioxidant effects of alpha-tocopherol, selenium, and lycopene. ? ?
