Prevention of Urinary Bladder Carcinogenesis in Mice

描述(由申请人提供) 这项建议的总体目的是评估化学预防药物和替代标记物，用于未来预防前吸烟者癌症的临床试验。流行病学研究表明，吸烟与膀胱癌之间存在很强的相关性。我们将使用的化学诱导膀胱癌模型将允许生物标志物的变化与药物(S)抑制膀胱癌发生的能力之间的关联。第一个具体目标是评估三类化学预防药物(脂氧合酶抑制剂、维甲酸和表皮生长因子受体(EGFR)抑制剂)单独或联合应用预防膀胱癌的效果。药剂分别为MK-886、Targretin和Iressa。我们尤其对Targretin(一种RXR选择性维甲酸)的评估感到兴奋，因为之前的研究表明维甲酸(例如，4-羟基苯基维甲酰胺)在预防膀胱癌方面是有效的。第二个特定目的是检测经致癌物OH-BBN和/或化学预防药物处理的小鼠膀胱病变和尿液中Survivin的表达。具体地说，我们将在膀胱的早期病变中寻找Survivin；确定在接受致癌物质治疗的小鼠的尿液中检测到Survivin的速度；以及确定化学预防药物是否会调节Survivin的表达。第三个具体目标将确定化学预防药物对Affymetrix Gone芯片分析评估的基因表达谱的影响，以建立与膀胱癌发生有关的新生物标记物。在动物模型中检测癌症和癌前病变中改变的RNA水平将有助于开发用于癌症化学预防研究的相关替代生物标记物(这是本RFA声明的目标之一)。

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).