Prevention of Urinary Bladder Carcinogenesis in Mice

描述（由申请人提供） 该提案的总体目的是评估化学预防剂和替代标记物，用于未来的临床试验，以预防前吸烟者的癌症。流行病学研究表明，吸烟与膀胱癌之间存在密切联系。我们将使用的化学诱导的膀胱癌模型将允许生物标志物的变化与药剂抑制膀胱癌发生的能力的相关性。第一个具体目标是评估三类化学预防剂（脂氧合酶抑制剂、类维生素A和表皮生长因子受体（EGFr）抑制剂）单独或联合使用预防膀胱癌的疗效。这些药物分别是MK-886、targretin和Iressa。我们对targretin（一种RXR选择性类维生素A）的评估感到特别兴奋，因为以前的研究表明，类维生素A（例如，4-羟基苯基视黄酰胺）在预防膀胱癌中具有活性。第二个具体目的是测量膀胱病变和用致癌物OH-BBN和/或化学预防剂处理的小鼠的尿液中生存素的表达。具体来说，我们将寻找生存素在膀胱的早期病变，确定如何快速生存素可以检测到在尿液中的致癌剂治疗的小鼠，并确定是否化学预防剂将调节生存素的表达。第三个具体目标将确定化学预防剂对基因表达谱的影响，如通过Affygone芯片分析评估的，以建立参与膀胱癌发生的新生物标志物。在动物模型中检查癌症和癌前病变中RNA水平的改变将有助于开发癌症化学预防研究的相关替代生物标志物（本RFA的既定目标之一）。

DESCRIPTION (provided by applicant) The overall purpose of this proposal is to evaluate chemopreventive agents and surrogate markers for future clinical trials to prevent cancers in former smokers. Epidemiological studies have demonstrated a strong association between cigarette smoking and urinary bladder cancer. The chemically induced urinary bladder cancer model that we will use will allow the correlation of changes in biomarkers with the ability of the agent(s) to inhibit bladder carcinogenesis. The first specific aim will evaluate three classes of chemopreventive agents (lipoxygenase inhibitor, retinoid, and epidermal growth factor receptor (EGFr) inhibitor) either alone or in combination for efficacy in the prevention of bladder cancers. The agents are MK-886, targretin, and Iressa, respectively. We are particularly excited about the evaluation of targretin (an RXR selective retinoid) since previous studies have shown that retinoids (e.g., 4- hydroxyphenylretinamide) are active in the prevention of urinary bladder cancer. The second specific aim wilt measure the expression of survivin in urinary bladder lesions and in urine of mice treated with the carcinogen OH-BBN and/or chemopreventive agents. Specifically, we will look for survivin in early lesions of the urinary bladder; determine how quickly survivin can be detected in the urine of carcinogen-treated mice; and determine if chemopreventive agents will modulate the expression of survivin. The third specific aim will determine the effect of chemopreventive agents on gene expression profiles as assessed by Affymetrix gone chip analysis to establish new biomarkers involved in urinary bladder carcinogenesis. Examination of altered RNA levels in cancers and preneoplastic lesions in an animal model will facilitate the development of relevant surrogate biomarkers for cancer chemoprevention studies (one of the stated goals of this RFA).