Lycopene Chemoprevention of Lung Cancer in Ferret

越来越多的流行病学证据支持番茄红素作为具有重要健康意义的微量营养素的作用 福利。它似乎可以预防多种上皮性癌症，包括肺癌、前列腺癌、胃癌。 和冒号。然而，在吸烟者中进行的p-胡萝卜素干预试验的相互矛盾的结果(使用 高剂量的p-胡萝卜素和增加肺癌风险)与观察性流行病学研究表明 高含类胡萝卜素的水果和蔬菜的饮食(但浓度远低于干预组 研究)与肺癌风险的降低有关，而番茄红素对肺部影响的结果相互矛盾 动物致癌研究促使我们将注意力集中在补充番茄红素的剂量上， 番茄红素的生物活性及其代谢与卷烟烟气的相互作用。 这项研究的目的是了解化学预防效果可能的机制基础。 番茄红素(及其代谢产物)抗肺癌作用及番茄红素代谢途径 控制实验条件，使用与人类高度相似的雪貂模型。我们假设 1)番茄红素(或其代谢物)与预防(或促进) 烟雾暴露、致癌物处理的雪貂的癌前病变和恶性病变；2)番茄红素(或番茄红素 代谢产物)通过上调胰岛素样生长因子结合蛋白-3(IGFBP-3)作为一种 作为化学预防机制的分子靶点和阻断IGF-I的信号转导途径 番茄红素的功效；3)番茄红素的氧化代谢和胡萝卜素9‘，10’-单加氧酶的表达 (类胡萝卜素的一种裂解酶)可以通过补充番茄红素和烟雾暴露而改变。 我们的具体目标是1)确定番茄红素(和脱脂番茄烯酸)在两种生理状态下的有效性 (低和中)和药理(高)剂量对血浆和组织中番茄红素(和apo-Lo‘-番茄烯酸)水平的影响 酸)、烟雾诱导的氧化应激、DNA损伤以及肺癌前病变和肿瘤的发展 2)检测IGFBP-3的诱导作用 番茄红素或其代谢物抑制IGF-1信号转导通路和细胞增殖并促进 雪貂和细胞培养模型中的细胞凋亡；以及3)通过检测 红曲霉菌中胡萝卜素9‘，LO’-单加氧酶的表达、活性及apo-Lo‘-番茄红素的形成 番茄红素在体内和体外。我们的研究工作将为我们提供关于导致 番茄红素及其代谢物的生物活性。这一信息对于未来的人类研究是至关重要的，包括 用于预防肺癌和其他组织部位癌症的番茄红素。此外，还设立了一个肺 雪貂致癌模型为肺癌和类胡萝卜素的研究提供了有价值的工具。

Increasing epidemiological evidence supports the role of lycopene as a micronutrient with important health benefits. It appears to provide protection against a broad range of epithelial cancers, including lung, prostate, stomach and colon. However, both the conflicting results of the p-carotene intervention trials in cigarette smokers (which used high doses of p-carotene and increased lung cancer risk) vs. the observational epidemiological studies showing that diets high in fruits and vegetables containing carotenoids (but at much lower concentrations than in the intervention studies) are associated with a decreased risk for lung cancer, and the conflicting results of lycopene effects on lung carcinogenesis in animal studies motivate us to focus our attention on the dosage of lycopene supplementation, biological activities of lycopene and interaction of lycopene metabolism with cigarette smoke. The objective of this investigation is to understand the mechanistic basis for the possible chemopreventive efficacy of lycopene (and its metabolites) against lung cancer development and the metabolic pathway of lycopene under well- controlled experimental conditions, using the ferret model, which is highly analogous to humans. We hypothesize that 1) there is a dose-dependent association between lycopene (or its metabolites) and the prevention (or promotion) of premalignant and malignant lung lesions in smoke-exposed, carcinogen-treated ferrets; 2) lycopene (or lycopene metabolites) inhibit lung carcinogenesis by up-regulating insulin-likegrowth factor binding protein-3 (IGFBP-3) as a molecular target and interrupting the signal transduction pathway of IGF-I as a mechanism for the chemopreventive efficacy of lycopene; and 3) both oxidative metabolism of lycopene and expression of carotene 9',10'-monooxygenase (a cleavage enzyme for carotenoids) can be altered by lycopene supplementation and smoke-exposure. Our specific aims are 1) determine the effectiveness of lycopene (and apo-lO'-lycopenoic acid) in both physiologic (low and median) and pharmacological (high) doses on plasma and tissue levels of lycopene (and apo-lO'-lycopenoic acid), smoke-induced oxidative stress, DNA damage, and development of lung preneoplastic lesions and tumor formation in the carcinogen treated, cigarette smoke-exposed ferrets; 2) examine whether the induction of IGFBP-3 with lycopene or its metabolites inhibits the signal transduction pathway of IGF-1 and cell proliferation and promotes apoptosis in both ferret and cell culture models; and 3) investigate the metabolic pathway of lycopene by examining both the expression and activity of carotene 9', lO'-monooxygenase and the formation of apo-lO'-lycopenoids from lycopene in vivo and in vitro. Our research effort will provide important insights regarding the mechanisms leading to the bioactivity of lycopene and its metabolites. This information is critically needed for future human studiesinvolving lycopene for prevention of lung cancer and cancers at other tissue sites. In addition, the establishment of a lung carcinogenesis model in ferrets provides a valuable tool for both lung cancer and carotenoid research fields.