Combinational Approaches to the Chemoprevention of Esophageal Cancer

描述（由申请人提供）： 食管癌是世界范围内第六大常见恶性肿瘤，超过90%的病例为食管鳞状细胞癌（SCC）。食管鳞状细胞癌的危险因素包括吸烟、饮酒、营养缺乏和摄入被各种霉菌毒素污染的食物。食管鳞状细胞癌比其他类型的胃肠道恶性肿瘤生长更快，患有这种疾病的患者预后非常差。虽然手术、化疗和放疗单独或联合使用，但这种疾病的总体5年生存率仍然很低，范围从5%到15%。为降低食管癌的发病率，通过饮食和/或化学干预进行癌症化学预防将是一种合理和实用的方法。许多化合物已被测试;然而，迄今为止的试验并没有导致食管癌发病率的降低。有一个迫切需要确定的保护剂，可以防止这种疾病的个人与食管癌的风险增加。我们研究的长期目标是开发机制驱动的安全有效的预防策略，以降低高危人群中食管癌的发病率。N-亚硝基甲基苄胺（NMBA）诱导的大鼠食管癌临床前模型已被广泛用于研究食管癌的发生机制和评价潜在的化学预防药物的疗效。食管鳞状细胞癌的多阶段演变，从正常到增生，异型增生和乳头状瘤，是理想的化学预防策略的应用。在这个建议中，我们概述了我们的战略，以开发组合的方法来化学预防食管癌。我们的中心假设是，环氧化酶-2（考克斯-2）抑制剂、塞来昔布、诱导型一氧化氮合酶（iNOS）抑制剂、S，S '-1，4-亚苯基-双（1，2-乙二基）双异噻唑烷（PBIT）和冻干黑树莓（BRB）的组合将增加对NMBA-大鼠临床前模型中肿瘤发展的疗效，同时将毒性降至最低。具体目标是：1.目的：1.建立联合应用考克斯-2和iNOS抑制剂预防食管癌的策略。建立通过纯化合物和天然食品的组合来提高食管癌预防效果的策略，并确定其作用的细胞和分子机制; 3.探讨丝裂原活化蛋白激酶（MAPK）和核因子：B（NF：B）通路在N-甲基-N-甲基-N-苯丙氨酸（NMBA）诱导的大鼠食管肿瘤发生中的作用。总体而言，该假设驱动的临床前研究的成功结果将为开发与可能在食管癌化学预防的人体临床试验中具有协同活性的药物的组合提供重要信息和依据。公共卫生相关性：该项目的总体目标是评估联合方法对食管癌发展的有效性，研究这些药物的机制基础，并使用与人类食管鳞状细胞癌高度相似的大鼠临床前模型鉴定食管肿瘤发生的细胞和分子生物标志物。

DESCRIPTION (provided by applicant): Esophageal cancer is the 6th most common malignant neoplasm worldwide with more than 90% of all cases being esophageal squamous cell carcinoma (SCC). Risk factors for esophageal SCC include tobacco use, alcohol consumption, nutritional deficiency, and intake of food contaminated with various mycotoxins. Esophageal SCC grows more quickly than other kinds of gastrointestinal malignancies and patients with this disease have a very poor prognosis. Although surgery, chemotherapy, and radiotherapy alone or combined are used, the overall 5-year survival rate for this disease is still very low, ranging from 5% to 15%. To decrease the incidence of esophageal cancer, cancer chemoprevention through dietary and/or chemical intervention would be a logical and practical approach. Numerous compounds have been tested; however, the trails to date have not resulted in a decrease of esophageal cancer incidence. There is an urgent need to identify protective agents, which can prevent this disease in the individuals associated with increasing esophageal cancer risk. The long-term goal of our studies is to develop mechanism-driven safe and effective prevention strategies for reducing the incidence of esophageal cancer in high-risk populations. N-nitrosomethylbenzylamine (NMBA)- induced rat preclinical model of esophageal cancer has been used extensively to investigate the mechanisms of esophageal carcinogenesis and to evaluate the efficacy of potential chemopreventive agents. The multistage evolution of esophageal SCC, from normal to hyperplasia, dysplasia and papilloma, is ideal for the application of chemoprevention strategies. In this proposal, we outline our strategy to develop combinational approaches to the chemoprevention of esophageal cancer. Our central hypothesis is that combination of cyclooxygenase-2 (COX-2) inhibitor, celecoxib, inducible nitric oxide synthase (iNOS) inhibitor, S,S'-1,4- phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), and freeze-dried black raspberries (BRB) will increase efficacy against tumor development while minimizing toxicity in NMBA-rat preclinical model. The specific aims are: 1. To establish strategies to improve efficacy of esophageal cancer prevention by a combination of COX-2 and iNOS inhibitors; 2. To establish strategies to improve efficacy of esophageal cancer prevention by a combination of pure compound(s) and natural food product and to determine the cellular and molecular mechanisms of their actions; 3. To investigate the roles of mitogen-activated protein kinase (MAPK) and nuclear factor :B (NF:B) pathways in NMBA-induced tumorigenesis in the rat esophagus. Overall, a successful outcome of this hypothesis-driven preclinical study will provide important information and rationale to develop a combination with agents that may have synergistic activity in human clinical trials of chemoprevention of esophageal cancer. PUBLIC HEALTH RELEVANCE: The overall objective of this project is to evaluate the efficacy of combinational approaches against esophageal cancer development, to investigate the mechanistic basis of these agents, and to identify cellular and molecular biomarkers of esophageal tumorigenesis using a rat preclinical model, which is highly analogous to human esophageal squamous cell carcinoma.