Selenium Prevention of Tobacco Smoke-Induced Lung Cancer

硒预防烟草烟雾诱发的肺癌

• 批准号: 6752141
• 负责人: Teresa Whei-Mei Fan
• 金额: $ 23.32万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752141
• 关键词: 13 cis retinoate; NAD(P)H oxidoreductase; apoptosis; biomarker; cancer prevention; chemoprevention; cysteine endopeptidases; cytochrome c; dietary supplements; glucocorticoids; immunocytochemistry; in situ hybridization; laboratory mouse; liquid chromatography mass spectrometry; lung neoplasms; nuclear magnetic resonance spectroscopy; nutrition aspect of cancer; nutrition related tag; selenium; selenomethionine; selenoprotein; smoking; terminal nick end labeling; tobacco abuse; western blottings; yeasts

DESCRIPTION (provided by applicant) The long-term objectives of the proposed work are to understand the biochemical mechanism(s) of supranutritional Se in chemoprevention and to utilize this information for mechanistic clinical studies. A chemopreventive role of selenium (Se) in cancers has been implicated in several clinical and numerous animal studies but whether Se is effective against tobacco smoke (TS)-induced lung cancers is unknown. Nor is it clear in general on the form(s) of Se that are chemopreventive. Lung cancer is a leading cause of cancer death and TS-induced lung cancer may be on the rise worldwide due to growing smoking habit. Thus, the specific aims of this proposal are: 1) To examine whether dietary Se supplement in the form of selenized yeast (Se-yeast) or its major component selenomethionine (Se-Met) is chemopreventive for mice that have "quit" smoking; 2) To characterize biomarkers of Se action such as apoptotic markers and selenoproteins that have been established in other chemoprevention studies so that Se chemoprevention can be understood better at the molecular level; 3) To investigate whether a synergism exists between Se and other chemopreventive agents such as the glucocorticoid hormone budesonide and retinoid isotretinoin in TS induction of lung cancers. To fulfill these aims, the A/J mice model which is the only animal model for TS-induced lung cancer will be employed. Mice will be pre-exposed to tobacco smoke to induce lung tumors during the recovery phase. The effect of dietary Se-yeast or Se-Met supplement during the recovery phase on tumor incidence and/or multiplicity will be measured to see if Se supplement is effective in reducing tumor formation and if additional Se form(s) in Se-yeast may be active. Major Se metabolites present in Se-yeast in addition to Se-Met will be characterized by a combination of NMR and HPLC coupled to mass spectrometry. The Se action will be characterized both immunocytochemically and in lung extracts by a series of apoptotic markers including cytochrome c release, activation of caspases, production of caspase cleavage products, and DNA fragmentation will be measured, along with the activation of selenoprotein, thioredoxin reductase. These biomarkers are known to be elicited in other Se chemoprevention studies. A similar approach will be used to investigate any interactive effect of Se-yeast supplement and budesonide or isotretinoin administered via inhalation; the latter two agents are also known to cause apoptosis. Biomarker characterization should reveal whether synergism is mediated via apoptosis.

描述（由申请人提供） 拟议工作的长期目标是了解超营养硒在化学预防中的生化机制，并将这些信息用于机制临床研究。多项临床和大量动物研究表明硒 (Se) 在癌症中具有化学预防作用，但硒是否对烟草烟雾 (TS) 诱发的肺癌有效尚不清楚。一般来说，硒的化学预防形式也不清楚。肺癌是癌症死亡的主要原因，由于吸烟习惯的增加，TS 诱发的肺癌可能在全球范围内呈上升趋势。因此，该提案的具体目标是： 1) 研究以硒化酵母（Se-yeast）或其主要成分硒代蛋氨酸（Se-Met）形式补充膳食硒是否对“戒烟”小鼠具有化学预防作用； 2) 表征其他化学预防研究中已建立的硒作用生物标志物，例如细胞凋亡标志物和硒蛋白，以便在分子水平上更好地理解硒化学预防； 3) 研究硒与其他化学预防药物（如糖皮质激素布地奈德和维A酸异维A酸）在肺癌TS诱导中是否存在协同作用。为了实现这些目标，将采用 A/J 小鼠模型，这是唯一的 TS 诱导肺癌的动物模型。在恢复阶段，小鼠将被预先暴露于烟草烟雾中以诱发肺部肿瘤。将测量恢复阶段膳食硒酵母或硒蛋氨酸补充剂对肿瘤发生率和/或多重性的影响，以确定硒补充剂是否能有效减少肿瘤形成，以及硒酵母中额外的硒形式是否可以积极一点。除 Se-Met 之外，Se-酵母中存在的主要 Se 代谢物将通过 NMR 和 HPLC 与质谱联用进行表征。 Se 作用将通过免疫细胞化学和肺提取物中的一系列细胞凋亡标记物进行表征，包括细胞色素 c 释放、半胱天冬酶激活、半胱天冬酶裂解产物的产生、DNA 片段化以及硒蛋白、硫氧还蛋白还原酶的激活进行测量。已知这些生物标志物是在其他硒化学预防研究中引发的。类似的方法将用于研究硒酵母补充剂和布地奈德或异维A酸吸入给药的相互作用；后两种药物也可引起细胞凋亡。生物标志物表征应揭示协同作用是否是通过细胞凋亡介导的。