PREVENTION OF PROSTATIC CARCINOGENESIS BY ANTIOXIDANTS

描述(由申请人提供)：该项目提出的假设是，维生素E最普遍的饮食形式--γ-生育酚通过其抗氧化活性防止前列腺癌的发生。目前还没有人类和动物研究的相关数据。有一些实验研究报告测试了其他抗氧化剂可以预防前列腺癌的假设，但那些测试了的实验研究使用的模型系统不涉及氧化应激机制，也没有发现保护作用。此外，还没有研究这些抗氧化剂之间可能存在的关键协同作用的研究报告。因此，该项目的目的是：(A)在前列腺癌发生的独特动物模型中解决这一假设，该模型确实涉及氧化应激机制；(B)利用该模型产生证明抗氧化剂活性是伽马生育酚预防前列腺癌的主要机制的原则证明数据；以及(C)确定这种抗氧化剂单独和与其他抗氧化剂联合使用的保护活性的大小，以提供支持预防临床试验设计的有效性信息。该项目的具体目标是：(1)确定RRR-γ-生育酚的最大耐受量，以便为AIMS 2和3的研究选择剂量。(2)确定γ-生育酚预防雌二醇和睾酮处理的NBL大鼠前列腺癌的效果。这一模型重要地涉及氧化应激机制。抗氧化剂将在饮食中以两种无毒剂量给予，其效果将与α-生育酚、硒和番茄红素进行比较。(3)确定γ-生育酚处理是否能降低与DNA碱基氧化、脂质过氧化和抗氧化酶失活或改变有关的氧化应激参数。这些参数将在荷尔蒙治疗诱发癌症的大鼠前列腺区域进行测量，观察到的效果将与AIM 2的疗效研究结果相关。(4)在NBL大鼠模型中，确定伽马-生育酚延迟治疗或与其他三种抗氧化剂联合治疗预防前列腺癌的有效性，并确定这些治疗是否降低氧化应激参数。观察到的效果将与AIMS 2和AIMS 3的单剂研究结果以及针对α-生育酚、硒和番茄红素的保护和抗氧化作用的父母基金的结果进行比较。

DESCRIPTION (provided by applicant): 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.