Biology of the Prostate Cancer Prevention Trial (PCPT)

前列腺癌是最常见的非皮肤癌，是美国男性癌症死亡的第二大原因，而且发病率正在上升。有效的预防需要更好地了解前列腺癌的病因，这是本P01‘S前列腺癌预防试验(PCPT)历史生物学研究的主要目标。在对18882名男性进行的非那雄胺随机对照试验中，PCPT发现总体前列腺癌风险降低了24.8%，高级别疾病的风险明显增加(《新英格兰医学杂志》，2003年7月)。前列腺癌是一种雄激素依赖性疾病，非那雄胺抑制5a-还原酶，从而阻止睾酮(通过5a-还原酶)转化为二氢睾酮，双氢睾酮是最活跃的前列腺癌雄激素。拟议的五项关于PCPT的高度互动的P01研究是：项目1，雄激素代谢；项目2，饮食和饮食相关因素；项目3，胰岛素样 生长因子轴和胰岛素抵抗；项目4，炎症的基因和表型研究；以及项目5，氧化损伤和DNA修复。这些项目将使用嵌套病例(n=1800)-对照(n=1800)设计来开发P01主题，即与前列腺癌总体或高级别疾病的风险相关的遗传、代谢和环境因素，以及这些因素对非那雄胺预防效果的影响。还将对这些风险因素关联的机制进行评估。P01主题的主要内容是研究(1)基因多态以确定分子前列腺癌风险因素并确定药物遗传学特征，以及(2)体细胞突变以发现与非那雄胺相关的高级别前列腺癌风险增加的机制。P01为每个项目提供了对PCPT生物标本和数据的宝贵储存库的访问。每个项目都通过互动的具体目标以及与其他4个项目和3个核心的有计划的协作紧密联系在一起。P01的独特优势包括其经活检证实的对照组，PCPT数据表明，在前列腺特异性抗原和直肠指检“正常”的男性中，癌症和高度疾病的发病率很高(《新英格兰医学杂志》，2004年5月)，以及标准的集中式组织学分类，这一点突显了这一组的价值。随着相互作用的充分阐明和大量高度相关的新的初步数据，重新提交的P01有望开发出全面的前列腺癌风险模型，对未来前列腺癌的研究和预防具有重要意义。

Prostate cancer is the most frequent non-skin cancer, the second leading cause of cancer death in U.S. men, and is increasing in incidence. Effective prevention requires a better understanding of the etiology of prostate cancer, a major goal of this P01's biological studies of the historical Prostate Cancer Prevention Trial (PCPT). A randomized, controlled trial of finasteride in 18,882 men, the PCPT found a 24.8% decrease in overall prostate cancer risk and an apparently increased risk of high-grade disease (New England Journal of Medicine [NEJM], July 2003). Prostate cancer is an androgen-dependent disease, and finasteride inhibits 5a-reductase, thus blocking the conversion of testosterone (by 5a-reductase) to dihydrotestosterone, the most active prostate androgen. The five proposed highly interactive P01 studies of the PCPT are: Project 1, Androgen Metabolism; Project 2, Diet and Diet-Related Factors; Project 3, Insulin-like Growth Factor Axis and Insulin Resistance; Project 4, Genotypic and Phenotypic Studies of Inflammation; and Project 5, Oxidative Damage and DNA Repair. These projects will use nested case (n=1800)-control (n=1800) designs to develop the P01 theme, which is the genetic, metabolic and environmental factors associated with the risk of prostate cancer overall or high-grade disease and the effects of these factors on finasteride preventive efficacy. The mechanisms underlying these risk-factor associations also will be assessed. Major elements of the P01 theme are the study (1) of genetic polymorphisms to identify molecular prostate cancer risk factors and determine pharmacogenetic profiles and (2) of somatic mutations to discover the mechanisms underlying increased high-grade prostate cancer risk associated with finasteride. The P01 provides each project access to the invaluable repository of PCPT biospecimens and data. Each project is closely linked by interactive specific aims and planned collaborations with the other 4 projects and 3 cores. Unique P01 strengths include its biopsy-confirmed control group, the value of which is underscored by PCPT data indicating a substantial prevalence of cancer and high-grade disease in men with "normal" prostate-specific antigen and digital rectal exam (NEJM, May 2004), and standard centralized histological classifications. With fully clarified interactions and a large amount of highly relevant new preliminary data, this resubmitted P01 promises to develop comprehensive prostate cancer risk models important to the future study and prevention of prostate cancer.