PREVENTION OF PROSTATIC CARCINOGENESIS BY ANTIOXIDANTS

描述（由申请人提供）：本项目提出的假设是，γ-生育酚是维生素E最普遍的膳食形式，通过其抗氧化活性预防前列腺癌的发展。没有关于人类和动物研究的数据。有一些实验研究报告测试了其他抗氧化剂预防前列腺癌的假设，但是那些使用不涉及氧化应激机制的模型系统的实验研究没有发现保护作用。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报告。因此，本项目的目的是：（a）在涉及氧化应激机制的前列腺癌发生的独特动物模型中解决这一假设;（B）用这一模型生成原理证明数据，证明抗氧化活性是γ-生育酚预防前列腺癌的主要机制;及（c）确定该抗氧化剂单独及与其他抗氧化剂组合的保护活性的大小，以提供支持预防临床试验设计的功效信息。该项目的具体目的是：（1）确定RRR-gamma-生育酚的最大耐受剂量，以选择目的2和3研究的剂量。(2)确定γ-生育酚预防雌二醇和睾酮处理的NBL大鼠前列腺癌的功效。该模型重要地涉及氧化应激机制。抗氧化剂将以两种无毒剂量在饮食中给予，其效果将与α-生育酚、硒和番茄红素的效果进行比较。(3)确定γ-生育酚处理是否降低与DNA碱基氧化、脂质过氧化和抗氧化酶失活或改变相关的氧化应激参数。将在激素治疗诱导癌症的大鼠前列腺区域测量这些参数，观察到的效应将与目的2的疗效研究结果相关。(4)在NBL大鼠模型中确定γ-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疗效，并确定这些治疗是否降低氧化应激参数。将观察到的效应与目标2和3的单药研究结果以及解决α-生育酚、硒和番茄红素的保护和抗氧化作用的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.