Chemoprevention of Early Pulmonary Lesions in Mice

小鼠早期肺部病变的化学预防

• 批准号: 6604209
• 负责人: ALVIN M MALKINSON
• 金额: $ 52万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-28 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6604209
• 关键词: adenoma; antiinflammatory agents; biomarker; butylated hydroxytoluene; cancer prevention; chemoprevention; functional /structural genomics; glucocorticoids; immunocytochemistry; laboratory mouse; lung neoplasms; methylcholanthrene; microarray technology; neoplastic process; proteomics

DESCRIPTION (provided by applicant): At UCHSC, we have assembled mature Genomics and Proteomics and mouse carcinogenesis groups to study preclinical chemoprevention of lung cancer in former-smokers. Our rationale is that anti-inflammatory drugs inhibit chemically-induced lung tumorigenesis, early lung lesions are reversible, and no verified biomarkers exist for human lung neoplasia. Mouse hyperplastic foci and microadenomas model the small nodules present in the lungs of former smokers, and a better understanding of the progression to cancer will lend insight into human lung cancer chemoprevention. A two-stage carcinogenesis regimen, in which 3-methylcholanthrene (MCA) is injected ip followed by four weekly ip doses of butylated hydroxytolulene (BHT), induces these lung lesions in male BALB mice. Budesonide, a synthetic glucocorticoid, and three other anti-inflammatory drugs, each with a unique mechanism of action, will be administered (orally) singly and in combination after foci and microadenomas have developed. The three other drugs are LM4111 (a COX-2 specific inhibitor), PBIT (an iNOS-specific inhibitor), and Iloprost (a stable prostacyclin agonist). The number of foci, and the number and sizes of microadenomas and pleural surface adenomas will be quantified at established time points up to 20 weeks after the MCA injection. Several proteins whose expression increases in early mouse lung lesions will be examined by immunohistochemistry to see if they can predict successful chemoprevention. These include pro-inflammatory enzymes (COX-1, COX-2, and iNOS) and hnRNP proteins (AUF1 , HuR, and A1). We have combined two global strategies, genomics and proteomics, as discovery tools for novel surrogate markers. RNA and protein expression patterns will be examined by microarray, LC/MS/MS, and 2D-PAGE/MS analyses, respectively. Expression in normal lungs will be compared with dissectable adenomas, and then our analyses will move proximally to examine samples more practically obtainable from humans (bronchoalveolar lavage cells and fluid, and serum). Our goals are: (1) to successfully inhibit lung tumor progression when anti- inflammatory drugs are applied after early lesions have forms; and (2) to identify novel early-stage predictive biomarkers.

描述(由申请人提供)： 在UCHSC，我们组装了成熟基因组学和蛋白质组学以及小鼠 致癌小组将研究肺癌的临床前化学预防 前吸烟者。我们的理论基础是抗炎药物抑制 化学诱导的肺肿瘤发生，早期肺损害是可逆的，并且 目前还没有已证实的人类肺部肿瘤的生物标志物。小鼠增生性疾病 病灶和微腺瘤模拟前者肺部出现的小结节 吸烟者，以及对癌症进展的更好理解将有助于 洞察人类肺癌的化学预防。两阶段致癌 方案，注射3-甲基胆蒽(MCA)，然后注射四次 每周ip剂量的丁基羟基甲苯(BHT)，可引起这些肺部病变 在雄性BALB小鼠身上。布地奈德，一种合成糖皮质激素，以及其他三种 抗炎药物，每种都有独特的作用机制，将是 病灶和微腺瘤后单独或联合(口服)给药 已经发展起来了。另外三种药物是LM4111(一种COX-2特异性抑制剂)， PBIT(iNOS特异性抑制物)和iloprost(一种稳定的前列环素 激动剂)。病灶的数量、微腺瘤的数量和大小以及 胸膜表面腺瘤将在确定的时间点进行量化，直到 MCA注射后20周。表达增加的几种蛋白质 早期小鼠的肺部病变将通过免疫组织化学进行检查，看看 他们可以预测成功的化学预防。其中包括促炎因子 酶(COX-1、COX-2和iNOS)和hnRNP蛋白(AUF1、HUR和A1)。我们 已经将基因组学和蛋白质组学这两个全球战略结合在一起，作为发现 用于新型代理标记的工具。RNA和蛋白质的表达模式将 分别用芯片、LC/MS/MS和2D-PAGE/MS分析进行检测。 正常肺中的表达将与可解剖的腺瘤进行比较，以及 然后我们的分析将转移到更接近实际的样本检查 可从人体获取(支气管肺泡灌洗液细胞和液体，以及血清)。 我们的目标是：(1)成功地抑制肺癌的进展 在早期病变形成后应用炎性药物；和(2) 识别新的早期预测生物标记物。