PREVENTION OF PROSTATIC CARCINOGENESIS BY ANTIOXIDANTS

通过抗氧化剂预防前列腺癌

• 批准号: 7339959
• 负责人: MAARTEN C BOSLAND
• 金额: $ 3.32万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339959
• 关键词: 4 hydroxynonenal; 8-hydroxy-2' -deoxyguanosine; Abbreviations; Address; Animal Model; Antioxidants; Applications Grants; Area; Biological Availability; Biological Models; COMT gene; Cancer Model; Carcinoma; Catechol O-Methyltransferase; Chemoprevention; Chemopreventive Agent; DNA; Data; Development; Diet; Dose; End Point; Enzymes; Epidemiologic Studies; Estradiol; Funding; Gonadal Steroid Hormones; Guidelines; Human; Intervention Studies; Lesion; Lipid Peroxidation; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Methylnitrosourea; Methyltransferase; Modeling; Nitrosourea Compounds; Outcome; Oxidative Stress; Paper; Prevention; Prostate; Prostatic; Prostatic Intraepithelial Neoplasias; Protocols documentation; Publishing; Purpose; Rattus; Reporting; Score; Selenium; Selenium/vitamin E; Selenomethionine; Testing; Testosterone; Thinking; Tissues; Uncertainty; United States National Institutes of Health; Update; Vitamin E; alpha Tocopherol; base; carcinogenesis; data modeling; design; dietary antioxidant; gamma-Tocopherol; human study; in vivo; lycopene; oxidation; oxidative DNA damage; prevent; prevention clinical trial; prostate cancer prevention; protective effect; research study; synergism

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 epxist 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 anti'oxidant 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.

该项目提出的假设是硒，维生素E和番茄红素预防前列腺 通过其抗氧化活性发展癌症。人类没有关于此的确定数据 研究。实验研究的报道很少来检验该假设，而那些确实 使用的模型系统不涉及氧化应激机制。此外，没有关于 研究了可能在这些抗氧化剂之间引起粘毒的重要协同作用的研究。 因此，该项目的目的是：（a）在前列腺动物模型中解决这一假设 确实涉及氧化应激机制的致癌作用； （b）在此模型数据中生成 支持抗氧化活性是硒，维生素E和 番茄红素预防前列腺癌； （d）探索γ-的功效和抗氧化活性 生育酚。该项目将使用适合测试化学预防活性的独特动物模型 抗氧化剂，它将为精选试验的批判性评估理由做出贡献； （d） 确定这些抗氧化剂的保护活性的大小，并结合 提供功效信息以支持预防临床试验的设计。特定目标 项目是：（1）确定硒，维生素E（α-生育酚）和番茄红素的功效以防止 用雌二醇和睾丸激素治疗的NBL大鼠的前列腺癌。该模型重要的是涉及氧化 压力机制。抗氧化剂将在饮食中以无毒剂量与所使用的剂量相当 在先前对不涉及氧化应激的前列腺癌模型的研究中。 （2）确定 用这些抗氧化剂处理是否会减少与DNA氧化有关的氧化应激参数 碱，脂质过氧化和抗氧化酶的灭活或改变。这些参数将是 在NBL大鼠的前列腺区域进行测量，雌二醇和睾丸激素诱导治疗 癌症和肿瘤性病变，观察到的效果将与功效的结果有关 特定目的的研究也将测量前列腺抗氧化剂水平。 （3）确定功效 γ-生育酚的抗氧化活性存在流行病学表明γ-生育酚 对前列腺癌具有比α-生育酚具有更强的保护作用，并且γ- 将生育酚与目标1和2的α-生育酚研究进行比较。（4）确定 使用三种抗氧化剂组合治疗的功效可以预防接受治疗的NBL大鼠前列腺癌 使用雌二醇和睾丸激素，并确定这些治疗是否减少了氧化应激参数。 观察到的效果将与目标1和2的单一试剂研究的结果进行比较。