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一种微量营养素的作用， 效益它似乎提供保护，防止广泛的上皮癌，包括肺癌，前列腺癌，胃癌， 和结肠。然而，在吸烟者中进行的β-胡萝卜素干预试验（使用 高剂量的β-胡萝卜素和肺癌风险增加）与观察性流行病学研究显示， 饮食中富含含有类胡萝卜素的水果和蔬菜（但浓度比干预组低得多）， 研究）与降低肺癌风险有关，番茄红素对肺的影响的结果相互矛盾， 动物研究中的致癌作用促使我们将注意力集中在番茄红素补充剂的剂量上， 番茄红素的生物活性及番茄红素代谢与卷烟烟气的相互作用。 本研究的目的是了解可能的化学预防效果的机制基础 番茄红素（及其代谢物）对肺癌发展的作用以及番茄红素在良好环境下的代谢途径。 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） 暴露于烟雾中的致癌物处理的雪貂的癌前病变和恶性肺部病变; 2）番茄红素（或番茄红素 代谢物）通过上调胰岛素样生长因子结合蛋白-3（IGFBP-3）作为一种抑制肺癌发生的药物， IGF-I分子靶向和阻断IGF-I信号转导途径作为化学预防的机制 番茄红素的氧化代谢和胡萝卜素9 ′，10 ′-单加氧酶的表达 （类胡萝卜素的裂解酶）可以通过补充番茄红素和吸烟来改变。 我们的具体目标是：1）确定番茄红素（和脱辅基-10 '-番茄红素酸）在两种生理学中的有效性， (low和中值）和药理学（高）剂量对番茄红素（和脱辅基-10 ′-番茄红素酸）的血浆和组织水平的影响 酸）、烟雾诱导的氧化应激、DNA损伤以及肺肿瘤前病变和肿瘤的发展 在致癌物处理，香烟烟雾暴露的雪貂形成; 2）检查是否诱导IGFBP-3 番茄红素或其代谢产物抑制IGF-1和细胞增殖的信号转导途径， 在雪貂和细胞培养模型中的细胞凋亡;和3）通过检测番茄红素的代谢途径来研究番茄红素的代谢途径。 胡萝卜素9 ′，10 ′-单加氧酶的表达和活性以及脱辅基-10 ′-类番茄红素的形成均受到抑制， 番茄红素在体内和体外。我们的研究工作将提供重要的见解有关的机制， 番茄红素及其代谢产物的生物活性。这些信息对于未来的人类研究至关重要， 番茄红素用于预防肺癌和其他组织部位的癌症。此外，建立肺 雪貂致癌模型为肺癌和类胡萝卜素研究领域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.