Prevention of Prostate Carcinogenesis in Transgenic Mice

描述（由申请人提供） 前列腺癌是美国男性中最常见的癌症。然而，亚洲国家中具有临床意义的前列腺肿瘤的发生率显著低于美国和其他西方国家。从前列腺癌发病率低的国家移居到发病率高的国家的男性患前列腺癌的风险增加，这表明饮食因素可能是东西方差异的基础。在水果、蔬菜和豆制品、全谷物的消费以及膳食脂肪的类型和数量方面的饮食模式差异也有牵连。基于流行病学相关性或其在细胞系中的活性，已经鉴定了许多潜在的前列腺癌化学预防剂。最近的数据表明，环氧合酶-2（考克斯-2）和磷脂酰肌醇-3-激酶（PI 3 K）/蛋白激酶B（Akt）途径在前列腺癌中均上调。在本申请中，我们将评估许多已被证明能够阻断癌细胞增殖的膳食成分和脂肪，因为它们能够阻断考克斯-2或P13 K/Akt通路作为其主要作用机制。由于胰岛素样生长因子-1（IGF-1）被认为在人前列腺癌发展中起作用，因此将在自发性前列腺癌的IGF-1转基因小鼠模型（BK 5.IGF-1小鼠）中评价这些药物抑制前列腺癌发生的能力。我们将检验这样的假设，即对考克斯-2表达或活性和/或对PI 3 K/Akt活性具有强抑制作用的膳食组分将对前列腺癌具有显著的化学预防活性，并且这种作用将通过改变所消耗的膳食脂肪酸的类型来加强。具体目的是（1）评价一系列先前证明抑制癌细胞增殖的药剂抑制考克斯-2表达或活性或PI 3 K/Akt活性的能力（激酶活性/磷酸化状态）;（2）评估特定类型的膳食脂肪改变BK 5中前列腺素（PG）水平以及考克斯-2表达水平和Akt活性的能力。1例体内前列腺;和（3）检查（i）抑制考克斯-2途径和/或PI 3 K/Akt途径的最有效的膳食组分（Aim 1）在体内抑制自发性前列腺癌发生的能力和（ii）特定膳食脂肪酸（Aim 2）在BK 5.IGF-1模型中增强或抑制自发性前列腺癌发展的能力。

DESCRIPTION (provided by applicant) Prostate cancer is the most commonly diagnosed cancer in men in the USA. However, the rates of clinically significant prostate tumors are considerably lower in Asian countries than in the USA and other Western countries. An increase in risk of developing prostate cancer is observed in males emigrating from countries with low prostate cancer rates to countries where the rate is high, suggesting that dietary factors may underlie the East-West differences. Differences in dietary patterns with regard to consumption of fruits, vegetables and soy-based products, whole grains, and type and quantity of dietary fat have been implicated. A number of potential chemopreventive agents for prostate cancer have been identified based on epidemiological correlations or their activity in cell lines. Recent data suggest that both the cyclooxygenase-2 (COX-2) and the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathways are upregulated in prostate cancers. In this application, we will evaluate a number of dietary components and fats that have been shown to block cancer cell proliferation for their ability to block either the COX-2 or the P13 K/Akt pathways as their primary mechanism of action. Because insulin-like growth factor- 1(IGF-1) is believed to play a role in human prostate cancer development, these agents will be evaluated for their ability to inhibit prostate carcinogenesis in an IGF-1 transgenic mouse model (BK5.IGF-1 mice) of spontaneous prostate cancer. We will test the hypothesis that dietary components having either strong inhibitory effects on COX-2 expression or activity and/or on PI3K/Akt activity will have significant chemopreventive activity for prostate cancer and that this effect will be potentiated by altering the type of dietary fatty acids consumed. The Specific Aims are to (1) evaluate the ability of a series of agents previously demonstrated to inhibit cancer cell proliferation for their ability to inhibit either COX-2 expression or activity, or PI3K/Akt activity (kinase activity/phosphorylation state); (2) evaluate the ability of specific types of dietary fats to alter prostaglandin (PG) levels as well as COX-2 expression levels and Akt activity in BK5.IGF-1 prostates in vivo; and (3) examine (i) the most effective dietary components that inhibit either the COX-2 pathway and/or the PI3K/Akt pathway (Aim 1) for their ability to inhibit spontaneous prostate carcinogenesis in vivo and (ii) the ability of specific dietary fatty acids (Aim 2) to enhance or inhibit the development of spontaneous prostate cancer in the BK5.IGF-1 model.