Chemoprevention of Chemically-Induced Bladder Cancers

描述（由申请人提供）： 许多流行病学研究已经建立了一个强有力的联系， 吸烟和膀胱癌本项目的总体目标 建议是评估化学预防剂和替代标志物， 未来的临床试验，以预防癌症的前吸烟者。化学 将使用的诱导膀胱癌模型将允许 替代终点变化与药物能力的相关性 抑制膀胱癌的发生。第一个具体目标将评估三个 化学预防剂的种类（脂氧合酶抑制剂、法呢基 转移酶抑制剂（FTI）和考克斯-2抑制剂）单独或与 本发明还提供了用于预防膀胱癌的功效的组合。述药剂 escuaoke、R115777和塞来昔布。第二个具体目标将 检测Survivin在膀胱病变组织和正常人尿液中的表达， 用致癌物OH-BBN和/或化学预防剂处理的大鼠。的 在这些研究中使用生存素作为分子标志物/预测因子的基本原理 是双重的。首先，与正常人相比， 组织是由相关的Ras贡献的，其次，生存素提供了 膀胱炎发病和进展高度敏感和特异性标志物 癌这与化学预防实验特别相关， 法呢基转移酶抑制剂R115777，并建议监测 在这项研究中，生存素表达的调节可能提供了一种分子机制， Ras相关转换的指示器。第三个具体目标是 初步确定R115777对基因表达谱的影响， 通过Affyssin基因芯片分析进行评估，以建立新的生物标志物， 参与膀胱癌的发生并可通过化学预防调节 剂.假设法呢基转移酶抑制剂将阻止 化学诱导的膀胱癌，通过调节 与细胞凋亡和细胞周期调控途径相关的基因。取决 关于FTI处理大鼠的结果，可以在 塞来昔布和escuaoke治疗的动物。

DESCRIPTION (provided by applicant): Numerous epidemiological studies have established a strong association between cigarette smoking and urinary bladder cancer. The overall goals of this proposal are to evaluate chemopreventive agents and surrogate markers for future clinical trials to prevent cancers in former smokers. The chemically induced urinary bladder cancer model that will be used will allow the correlation of changes in surrogate endpoints with the ability of the agent(s) to inhibit bladder carcinogenesis. The first specific aim will evaluate three classes of chemopreventive agents (lipoxygenase inhibitor, farnesyl transferase inhibitor (FTI), and COX-2 inhibitor) either alone or in combination for efficacy in the prevention of bladder cancers. The agents are esculetin, R115777, and celecoxib, respectively. The second specific aim will measure the expression of survivin in urinary bladder lesions and in urine of rats treated with the carcinogen OH-BBN and/or chemopreventive agents. The rationale for using survivin as a molecular marker/predictor in these studies is twofold. First, increased expression of survivin in cancer versus normal tissues is contributed by associated Ras and secondly, survivin provides a highly sensitive and specific marker of onset and progression of bladder cancer. This is particularly relevant for the chemopreventive experiments with the farnesyl transferase inhibitor R115777 and suggests that monitoring the modulation of survivin expression during this study may provide a molecular indicator of Ras-dependent transformation. The third specific aim will initially determine the effect of R115777 on gene expression profiles as assessed by Affymetrix gene chip analysis to establish new biomarkers that are involved in urinary bladder carcinogenesis and modulatable by chemopreventive agents. The hypothesis is that farnesyl transferase inhibitors will prevent chemically-induced urinary bladder cancers by modulating the expression of genes associated with apoptosis and cell cycle regulation pathways. Depending on the results in the FTI treated rats, additional profiles can be assessed in the celecoxib and esculetin treated animals.