Chemoprevention of Tobacco Related Cancer in Animals

描述（由申请人提供）： 我们的总体目标是开发生物标志物用于化学预防研究， 吸烟相关的癌症，可以转化为临床研究， 前吸烟者为实现这一目标，我们建议： 具体目标1：发展 使用小鼠在前吸烟者中化学预防肺癌的生物标志物 肺癌模型及相关生物学和分子学改变;以及 具体目标2：开发膀胱癌化学预防的生物标志物， 使用膀胱癌大鼠模型和相关的 生物和分子的改变。我们的假设是化学预防 药物将通过调节和逆转生物学效应来降低癌症发病率。 和表型正常组织、癌前病变组织、 组织和肿瘤。此外，我们假设，调制的 生物学和分子学改变可以作为生物标志物， 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，将通过以下方法在品系A小鼠中诱导肺肿瘤： 暴露于香烟烟雾、苯并（a）芘和4-（甲基亚硝胺）-1-（3- 吡啶基）-1-丁酮（NNK），并且为了实现目标2，膀胱肿瘤将被 N-丁基-N-羟丁基）亚硝胺（OH-BBN）诱导的F344大鼠。后 暴露在致癌物中，包括香烟烟雾， 将给予化学预防剂：布地奈德和法呢基 转移酶抑制剂，R115777在肺研究和布地奈德，酮洛芬 和舒林酸在膀胱研究中。生物学和分子学改变 细胞增殖、细胞凋亡、基因甲基化（低甲基化和低甲基化）、 原癌基因和肿瘤抑制基因的超甲基化）和改变 在mRNA和蛋白质表达将在表型正常的 组织，癌前病变和肿瘤在不同的时间， 进展为癌症。化学预防剂调节 并逆转组织和病变中的这些生物和分子改变 将与药物预防的能力平行确定 癌因此，生物和分子的变化，是调制在 与通过化学预防剂预防癌症平行的是， 作为化学预防研究的生物标志物，包括以前的 吸烟者，在暴露于 香烟烟雾已经停止。

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.