Chemoprevention of Esophageal Squamous Cell Carcinoma

食管鳞状细胞癌的化学预防

基本信息

批准号：
6806756
负责人：
Gary Stoner
金额：
$ 0.44万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2005-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Cancers of the human esophagus are the eighth most common malignancy. Worldwide, greater than 90% of esophageal cancers are squamous cell carcinomas (SCCs); a multifactorial disease with a significant behavioral component. A large majority of esophageal SCC patients present with advanced, metastatic disease. Five year survival rate in such cases is less than 10%. Epidemiological studies have identified tobacco use and alcohol consumption as the two main risk factors for esophageal SCC in developed countries. Recent evidence suggests that the risk for esophageal SCC remains high for almost a decade in smokers even after they quit tobacco use. There is a necessity for developing effective strategies that inhibit progression of precancerous lesions to clinical disease in this high risk population of former tobacco smokers. Primary chemoprevention is a viable approach in achieving this important health objective. N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in the Fischer 344 rat is a valuable animal model to identify putative chemopreventive agents against this disease. The multistep process of tumor development in this model closely mimics the progression of human esophageal SCC in former tobacco smokers. Therefore, this animal model is an ideal surrogate to identify agents that can inhibit progression of precancerous lesions to malignant tumors. In this proposal we outline our strategy to identify compounds that inhibit tumor development when given subsequent to carcinogen exposure. These agents will potentially inhibit progression of precancerous lesions to frank tumors and may be valuable for use as chemopreventive agents in former tobacco smokers. During the course of these studies, we will also identify morphological and molecular markers that may help assess the efficacy of these compounds. Studies in Specific Aim 1 will evaluate the effects of a known chemopreventive, freeze-dried strawberries on several known morphological and molecular markers to validate their use in human clinical studies. In Specific Aim 2, we will determine the efficacy of three additional chemopreventive agents against tumor progression. Further studies will be undertaken to develop a combination of agents that may have synergistic activity. In Specific Aim 3 we will identify novel biomarkers for future use in human clinical studies. Overall, the results from this proposal will provide important data to enhance our understanding of the molecular mechanisms of malignant progression of esophageal precancerous lesions and will identify candidate chemoprevention agents to reduce esophageal cancer risk in former tobacco smokers.

描述（由申请人提供）：人类食管的癌症是第八大最常见的恶性肿瘤。在全球范围内，超过90％的食道癌是鳞状细胞癌（SCCS）;具有重要行为成分的多因素疾病。一个绝大多数食管SCC患者都有晚期转移性疾病。在这种情况下，五年生存率小于10％。流行病学研究已经确定烟草的使用和饮酒是发达国家食管SCC的两个主要危险因素。最近的有证据表明，几乎吸烟者十年后，即使他们戒烟了。有必要制定有效的策略，以抑制癌前的进展以前烟草的高风险人群中临床疾病的病变吸烟者。主要化学预防是实现这一目标的可行方法重要的健康目标。 N-亚硝基甲基苯胺诱导的食管 Fischer 344大鼠中的肿瘤发生是一种有价值的动物模型推定的化学预防剂针对该疾病。多步骤的过程该模型中的肿瘤发展密切模仿人类的发展前烟草吸烟者的食管SCC。因此，该动物模型是理想的替代物以识别可以抑制进展进展的药物癌性病变对恶性肿瘤。在这个建议中，我们概述了我们的识别给出抑制肿瘤发育的化合物的策略致癌物暴露之后。这些试剂可能会抑制癌前病变向弗兰克肿瘤的发展，可能很有价值用作以前吸烟者的化学预防剂。在这些研究，我们还将确定形态和分子标记可能有助于评估这些化合物的功效。特定目标的研究1 将评估已知的化学预防，冷冻干燥的效果在几个已知的形态和分子标记上的草莓以验证它们在人类临床研究中的使用。在特定目标2中，我们将确定另外三种化学预防剂对肿瘤进展的功效。将进行进一步的研究，以发展可能具有协同活性。在特定目标3中，我们将确定新颖的生物标志物供未来在人类临床研究中使用。总体而言，这是此的结果建议将提供重要的数据，以增强我们对食管前癌的恶性进展的分子机制病变并将识别候选化学预防剂以减少前烟草吸烟者的食管癌风险。