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来预防前列腺癌的发展。关于这一点，人类研究中没有明确的数据。很少有实验研究报告证实了这一假设，而那些确实使用了不涉及氧化应激机制的模型系统。此外，还没有关于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)在涉及氧化应激机制的前列腺癌发生的动物模型中解决这一假设；(b)利用该模型生成数据，以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；(d)探讨-生育酚的功效及抗氧化活性。该项目将使用一种独特的动物模型，适合测试抗氧化剂的化学预防活性，这将有助于批判性地评估SELECT试验的基本原理；(d)确定这些抗氧化剂单独和组合的保护活性的大小，以提供功效信息，支持预防临床试验的设计。该项目的具体目的是：(1)确定硒、维生素E （α -生育酚）和番茄红素对经雌二醇和睾酮治疗的NBL大鼠前列腺癌的预防作用。该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剂量给予，与先前在不涉及氧化应激的前列腺癌模型研究中使用的剂量相当。(2)确定这些抗氧化剂是否能降低与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。这些参数将在雌二醇和睾酮治疗诱发癌症和癌前病变的NBL大鼠前列腺区域进行测量，观察到的效果将与Specific Aim 1疗效研究的结果相关。前列腺抗氧化水平也将被测量。(3)确定-生育酚的功效和抗氧化活性。有流行病学迹象表明-生育酚比-生育酚对前列腺癌的保护作用更强，我们将与Aims 1和Aims 2中α -生育酚的研究结果进行比较。(4)确定三种抗氧化剂联合治疗对雌二醇和睾酮治疗的NBL大鼠前列腺癌的预防效果，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Aims 2中单药研究的结果进行比较。

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.