PREVENTION OF PROSTATIC CARCINOGENESIS BY ANTIOXIDANTS

描述(由申请人提供)：本项目提出的假设是，硒、维生素E和番茄红素通过其抗氧化活性防止前列腺癌的发生。关于这一点，目前还没有来自人体研究的明确数据。验证这一假设的实验研究报告很少，而那些验证这一假设的实验研究使用的是不涉及氧化应激机制的模型系统。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，本项目的目的是：(A)在前列腺癌发生的动物模型中解决这一假说，该模型确实涉及氧化应激机制；(B)利用该模型产生数据，支持抗氧化活性是硒、维生素E和番茄红素预防前列腺癌的主要机制这一概念；(D)探索γ-生育酚的疗效和抗氧化活性。该项目将使用一种独特的动物模型，该模型适用于测试抗氧化剂的化学预防活性，它将有助于对选定试验的理论基础进行批判性评估；以及(D)确定这些抗氧化剂单独和组合的保护活性的大小，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)确定硒、维生素E(α-生育酚)和番茄红素对雌激素和睾酮治疗的NBL大鼠前列腺癌的预防效果。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无毒的剂量给予，与之前在不涉及氧化应激的前列腺癌模型研究中使用的抗氧化剂相当。(2)确定这些抗氧化剂的处理是否降低了与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。这些参数将在雌激素和睾酮治疗诱发癌症和癌前病变的NBL大鼠的前列腺区域进行测量，观察到的效果将与特定目标1的疗效研究的结果有关。还将测量前列腺抗氧化水平。(3)为了确定γ-生育酚的疗效和抗氧化活性，有流行病学迹象表明，伽马-生育酚对前列腺癌的保护作用强于α-生育酚，并且将与AIMS 1和2的α-生育酚研究进行比较。(4)确定三种抗氧化剂联合治疗对雌激素和睾酮治疗的NBL大鼠前列腺癌的疗效，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 1和2的单剂研究结果进行比较。

DESCRIPTION (provided by applicant): The hypothesis addressed by this project is that selenium, vitamin E, and lycopene protect against prostate cancer development through their antioxidant activities. There are no definitive data about this from human studies. There are very few reports of experimental studies that tested this hypothesis, and those that did used models systems that do not involve oxidative stress mechanisms. 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 an animal model of prostate carcinogenesis that does involve oxidative stress mechanisms; (b) To generate with this model data in support of the notion that antioxidant activity is a major mechanism by which selenium, vitamin E, and lycopene protect against prostate cancer; (d) To explore the efficacy and antioxidant activity of gamma-tocopherol. The project will use a unique animal model that is suitable to test chemopreventive activity of antioxidants and it will make a contribution to critically assessing the rationale for the SELECT trial; and (d) To determine the magnitude of the protective activity of these antioxidants individually and in combination to provide efficacy information in support of the design of prevention clinical trials. The Specific Aims of the project are: (1) To determine the efficacy of selenium, vitamin E (alpha-tocopherol), and lycopene 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 non-toxic doses comparable to those used in previous studies with prostate cancer models that do not involve oxidative stress. (2) To determine whether treatments with these antioxidants 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 prostate of NBL rats where treatment with estradiol & testosterone induces cancer and preneoplastic lesions, and the effects observed will be related to the outcome of the efficacy studies of Specific Aim 1. Prostatic antioxidant levels will also be measured. (3) To determine the efficacy and antioxidant activity of gamma-tocopherol There are epidemiological indications that gamma-tocopherol has stronger protective effects against prostate cancer than alpha-tocopherol and the effects of gamma-tocopherol will be compared with those of the alpha-tocopherol studies of Aims 1 and 2. (4) To determine the efficacy of combination treatment with the three antioxidants to prevent prostate cancer in NBL rats treated with estradiol & testosterone and to determine whether these treatments reduce oxidative stress parameters. The observed effects will be compared with the outcome of the single agent studies of Aims 1 and 2.