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Chemoprevention of Tobacco Related Cancer in Animals

动物中烟草相关癌症的化学预防

基本信息

批准号：
6707998
负责人：
MICHAEL A. PEREIRA
金额：
$ 55.93万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2007-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6707998
关键词：
adenoma biomarker bladder neoplasm cancer prevention chemical carcinogenesis chemical related neoplasm /cancer chemoprevention laboratory mouse laboratory rat lung neoplasms nitrosamines smoking tobacco tobacco abuse

项目摘要

DESCRIPTION (provided by applicant): Our overall goal is to develop biomarkers for chemoprevention studies of cigarette smoke-related cancers that can be translated to clinical studies in former smokers. To obtain this aim, we propose: Specific Aim 1: Develop biomarkers for chemoprevention of lung cancer in former smokers using a mouse model for lung cancer and related biological and molecular alterations; and Specific Aim 2: Develop biomarkers for chemoprevention of bladder cancer in ex-smokers using a rat model for urinary bladder cancer and associated biological and molecular alterations. Our hypothesis is that chemopreventive agents will decrease cancer incidence by modulating and reversing biological and molecular alterations in phenotypically normal tissue, precancerous tissues and tumors. Further, we hypothesize that the modulation of the biological and molecular alterations can be developed as biomarkers for chemoprevention in animal and clinical studies including studies in former smokers. To accomplish Aim 1, lung tumors will be induced in strain A mice by exposure to cigarette smoke, benzo(a)pyrene and 4-(Methyl nitrosamino)-1-(3- pyridyl)-1-butanone (NNK) and to accomplish Aim 2, bladder tumors will be induced in F344 rats by N-butyl-N-hydroxybutyl)nitrosamine (OH-BBN). After exposure to the carcinogens including cigarette smoke has ceased the animals will be administered the chemo-preventive agents: budesonide and the farnesyl transferase inhibitor, R115777 in the lung studies and budesonide, ketoprofen and sulindac in the bladder study. Biological and molecular alterations of cell proliferation, apoptosis, methylation of genes (both hypomethylation of protooncogenes and hypermethylation of tumor suppressor genes) and alteration in mRNA and protein expression will be determined in phenotypically normal tissues, precancerous lesions and tumors at different times during the progression to cancer. The ability of the chemopreventive agents to modulate and reverse these biological and molecular alterations in tissue and lesions will be determined in parallel with the ability of the agents to prevent cancer. Thus, biological and molecular alterations that are modulated in parallel with the prevention of cancer by the chemopreventive agents will be indicated as biomarkers for chemoprevention studies including those in former smokers where the agents will similarly be administered after exposure to cigarette smoke had ceased.

描述(由申请人提供)：我们的总体目标是开发用于化学预防研究的生物标记物与吸烟相关的癌症可转化为临床研究曾经的吸烟者。为了实现这一目标，我们提出：具体目标1：发展利用小鼠进行肺癌化学预防的生物标志物的研究肺癌模型及相关的生物学和分子改变；以及具体目标2：开发用于膀胱癌化学预防的生物标志物使用膀胱癌大鼠模型的前吸烟者及其相关生物和分子变化。我们的假设是化学预防药物将通过调节和逆转生物效应来降低癌症发病率在表型正常的癌前组织中的分子变化组织和肿瘤。此外，我们还假设，对生物和分子变化可以发展为生物标志物动物和临床研究中的化学预防，包括以前的研究吸烟者。为了实现目标1，将通过以下方法诱导A品系小鼠的肺癌暴露于香烟烟雾、苯并(A)芘和4-(甲基亚硝胺)-1-(3- 为了达到目标2，膀胱肿瘤将被用N-丁基-N-羟丁基)亚硝胺(OH-BBN)诱导F344大鼠。之后暴露在包括香烟烟雾在内的致癌物质中，这些动物已经停止了将给予化学预防药物：布地奈德和法尼赛肺研究中的转移酶抑制剂R115777和布地奈德、酮洛芬和舒林酸在膀胱研究中。细胞的生物学和分子变化细胞增殖、细胞凋亡、基因甲基化(两者均为低甲基化原癌基因和抑癌基因的高甲基化)和改变在表型正常的情况下，将确定其在mRNA和蛋白质中的表达组织、癌前病变和肿瘤在不同的时间进展为癌症。化学预防药物的调节能力并逆转这些组织和损伤的生物和分子变化将与代理人的预防能力同时确定癌症。因此，生物和分子的改变被调节在在通过化学预防药物预防癌症的同时，作为化学预防研究的生物标记物，包括以前的吸烟者，在暴露于香烟的烟雾已经停止了。