Tomatoes, Lycopene, and Prostate Carcinogenesis in Mice

描述（由申请人提供）：伊利诺伊大学和俄亥俄州州立大学的合作团队的总体研究重点是确定番茄及其生物活性成分（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中最常见的癌症，降低风险或延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，食用番茄制品可以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、八氢番茄红素和六氢番茄红素或其代谢产物是否降低前列腺癌发生和发展的风险。为了回答这个提议中提出的问题，我们将利用两种新的小鼠品系，它们缺乏两种已知的哺乳动物类胡萝卜素裂解酶之一，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）。三大具体目标是：1）描述在A）野生型、CMO-1敲除（KO）和CMO-II KO小鼠中响应于短期（3天）和长期（30天）喂食不同水平的番茄粉或番茄红素的CMO-1和CMO-II的组织特异性表达，以及在B）TRAMP小鼠中在癌发生过程中的CMO-1和CMO-II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，和B）类番茄红素和其它番茄类胡萝卜素代谢物的产生，3）通过A）建立双转基因小鼠和B）区分饮食番茄粉和番茄红素抑制TRAMP、TRAMP X CM 0 - 1 KO和TRAMP X CM 0-II KO小鼠中前列腺增生的能力。由于我们在类胡萝卜素和癌症模型方面的广泛专业知识，能够获得CMO-I KO和II KO小鼠，以及我们使用番茄细胞悬浮培养物生物合成放射性标记的番茄类胡萝卜素的能力，我们唯一有资格进行拟议的研究。我们继续假设，参与类胡萝卜素代谢的遗传多态性，如CMO-Ⅰ和Ⅱ，是番茄制品对人类前列腺癌发生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.