Tomatoes, Lycopene, and Prostate Carcinogenesis in Mice

描述(申请人提供)：来自伊利诺伊大学和俄亥俄州立大学的合作团队的总体研究重点一直是确定西红柿及其生物活性成分，特别是番茄红素对前列腺癌发生的影响。前列腺癌是美国男性最常见的癌症，降低风险或推迟发病的饮食方法将对公众健康产生深远影响。流行病学和动物研究表明，食用番茄产品可降低患前列腺癌的风险。我们建议在转基因小鼠中进行研究，以确定番茄类胡萝卜素、番茄红素、植烯和植物荧烯或它们的代谢产物是否降低前列腺癌的发生和进展风险。为了回答这项建议中提出的问题，我们将利用两个新的小鼠品系，它们缺乏两种已知的哺乳动物类胡萝卜素裂解酶中的一种，即类胡萝卜素15，15‘单加氧酶(CMO-I)和类胡萝卜素9’，10‘单加氧酶(CMO-II)。三个主要的具体目标是：1)描述CMO-I和CMO-II在A)野生型、CMO-I基因敲除(KO)和CMO-II KO小鼠中对短期(3天)和长期(30天)不同水平的番茄粉或番茄红素喂养的响应，以及B)在致癌过程中在不稳定的小鼠中的组织特异性表达；2)精确确定CMO-I和CMO-II表达的变化如何决定A)番茄类胡萝卜素的组织生物分布，以及B)番茄红素和其他类胡萝卜素代谢物的产生，3)研究番茄类胡萝卜素代谢的改变对前列腺癌的影响，包括：A)建立双转基因小鼠；B)比较饲料中番茄粉和番茄红素对TRAMP、TRAMP X CMO-I KO和TRAMP X CMO-II KO小鼠前列腺癌的抑制作用。由于我们在类胡萝卜素和癌症模型方面的广泛专业知识，接触到CMO-I KO和II KO小鼠，以及我们使用番茄细胞悬浮培养生物合成放射性标记番茄类胡萝卜素的能力，我们是唯一有资格开展拟议研究的公司。我们继续的假设是，参与类胡萝卜素代谢的基因多态，如CMO-I和CMO-II，是番茄产品对人类前列腺癌的益处的关键决定因素。这些研究将使我们能够确定番茄类胡萝卜素或其代谢产物是否能够预防或抵消前列腺癌的发展。

DESCRIPTION (provided by applicant): The overall research focus of the collaborative team from the University of Illinois and The Ohio State University has been to determine the impact of tomatoes and their bioactive components, especially lycopene, on prostate carcinogenesis. Prostate cancer is the most common cancer in American men and dietary approaches that reduce risk, or delay onset, would have profound impact on public health. Epidemiological and animal studies suggest that consumption of tomato products reduces the risk of prostate cancer. We propose to carry out studies in transgenic mice to determine if the tomato carotenoids, lycopene, phytoene, and phytofluene, or their metabolic products reduce the risk of development and progression of prostate cancer. In order to answer the questions raised in this proposal, we will utilize two new mouse strains that lack one of the two known mammalian carotenoid cleavage enzymes, carotenoid 15, 15' monooxygenase (CMO-I) and carotenoid 9', 10' monooxygenase (CMO-II). The three major specific aims are: 1) delineate the tissue-specific expression of CMO-I and CMO-II in A) wild-type, CMO-I knockout (KO), and CMO-II KO mice in response to short (3 days) and long term (30 days) feeding of different levels of tomato powder or lycopene, and in B) TRAMP mice during the development of carcinogenesis, 2) precisely determine how changes in CMO-I and CMO-II expression dictate A) tissue biodistribution of tomato carotenoids, and B) production of lycopenoids and other tomato carotenoid metabolites, and 3) to investigate the effect of altered tomato carotenoid metabolism on prostate cancer by A) creating double transgenic mice and B) differentiating the ability of dietary tomato powder and lycopene to inhibit prostate cancinogenesis in TRAMP, TRAMP X CMO-I KO, and TRAMP X CMO-II KO mice. We are uniquely qualified to carry out the proposed studies due to our broad expertise with carotenoids and cancer models, access to CMO-I KO and II KO mice, and our ability to biosynthesize radiolabeled tomato carotenoids using tomato cell suspension culture. Our continuing hypothesis is that genetic polymorphisms involved in metabolism of carotenoids, such as CMO-I and II, are critical determinants of the benefits of tomato products against prostate carcinogenesis in humans. These studies will allow us to determine if tomato carotenoids, or their metabolic products, are able to prevent or counteract the development of prostate cancer.