Chemoprevention of Chemically-Induced Bladder Cancers

描述(由申请人提供)： 大量的流行病学研究已经建立了与 吸烟和膀胱癌。这个项目的总体目标是 建议评估化学预防药物和替代标记物 未来预防前吸烟者癌症的临床试验。化学上的 将使用的诱导性膀胱癌模型将允许 代理终点的变化与代理人能力的相关性(S) 抑制膀胱癌的发生。第一个具体目标将评估三个 化学预防药物类别(脂氧合酶抑制剂，法尼基 转移酶抑制剂(FTI)和COX-2抑制剂)单独或在 联合用于预防膀胱癌的疗效。代理是 秦皮乙素、R115777和塞来昔布。第二个具体目标是 膀胱癌患者尿液及膀胱病变组织中Survivin的表达 用致癌物OH-BBN和/或化学预防药物治疗的大鼠。这个 在这些研究中使用Survivin作为分子标记/预测因子的理论基础 是双重的。首先，Survivin在癌症中的表达比正常组织高 组织由相关的RAS贡献，其次，Survivin提供 高度敏感和特异的膀胱癌发生发展标志物 癌症。这与化学预防实验特别相关 法尼基转移酶抑制剂R115777，并建议监测 在这项研究中对Survivin表达的调节可能提供一种分子 RAS依赖转型的指标。第三个具体目标是 初步确定R115777对基因表达谱的影响如下 通过Affymetrix基因芯片分析评估，以建立新的生物标志物 参与膀胱癌发生并可通过化学预防进行调节 探员们。假设法尼基转移酶抑制剂将阻止 化学诱导膀胱癌的基因表达调控 与细胞凋亡和细胞周期调控途径相关的基因。取决于 根据FTI治疗的大鼠的结果，可以在 塞来昔布和秦皮乙素治疗动物。

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.