EFFICACY STUDIES OF CHEMOPREVENTIVE AGENTS

化学预防剂的功效研究

• 批准号: 6159881
• 负责人: BAHARA A REDDY
• 金额: --
• 依托单位: INSTITUTE FOR CANCER PREVENTION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2001-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6159881
• 关键词: Epstein Barr virus; antineoplastics; carcinogenesis inhibitor; chemoprevention; cyclins; disease /disorder model; drug screening /evaluation; esophagus neoplasm; gene targeting; genetically modified animals; histology; immunocytochemistry; laboratory mouse; p53 gene /protein; polymerase chain reaction

Previous work to elucidate the underlying molecular mechanisms of esophageal carcinogenesis, focused on the generation and characterization of genetically engineered animal models (Oncogene 14:1185, 1997), including characterization of the Epstein-Barr virus (EBV) ED-L2 promoter and demonstration that it is uniquely active in oral-esophageal squamous epithelial cells. This is mediated through the interaction of oral-esophageal specific nuclear transcriptional factors. These keratins are keratins 4 and 13. In fact, targeted disruption of the keratin 4 gene in murine embryonic stem cells leads to severe impairment of differentiation in esophageal epithelial cells. The EBV ED-L2 promoter is being used to target the cyclin D1 oncogene, a critical gene product in the progression of cell cycle through G1 phase, and one that is frequently amplified and overexpressed in head/neck and esophageal cancers in transgenic mice. Previous work has revealed that these mice develop histological evidence of mild dysplasia by 6-8 months and severe dysplasia by 16 months with accompanying increased cell proliferation, preferential activation of cdk6 (one target of cyclin D1/cdk6 is the retinoblastoma protein), p53 overexpression and EGFR overexpression (Cancer Res. 57:5542, 1997). P53 mutations are a common genetic alteration in head/neck and esophageal cancers. The ability to cross cyclin D1 with p53 null mice represents a unique opportunity to analyze the combinatorial effects of two critical genetic alterations in their contribution to multistage oral-esophageal carcinogenesis. The objective of this study is to utilize cyclin D1 x p53 null mice for the analysis of oral and esophageal tissues by histology, immunohistochemistry and PCR. The effects of chemopreventive agents on the development of oral and esophageal cancers in these transgenic animals is being studied.

先前阐明食管癌发生的潜在分子机制的工作集中于基因工程动物模型的产生和表征（Oncogene 14：1185，1997），包括Epstein-Barr病毒（EBV）ED-L2启动子的表征和证明其在口腔-食管鳞状上皮细胞中具有独特活性。 这是通过口食管特异性核转录因子的相互作用介导的。这些角蛋白是角蛋白4和13。事实上，鼠胚胎干细胞中角蛋白4基因的靶向破坏导致食管上皮细胞分化严重受损。EBV ED-L2启动子被用于靶向细胞周期蛋白D1癌基因，细胞周期通过G1期的进展中的关键基因产物，并且在转基因小鼠的头颈癌和食管癌中经常扩增和过表达。 先前的工作已经揭示，这些小鼠在6-8个月时发展出轻度发育异常的组织学证据，在16个月时发展出严重发育异常的组织学证据，伴随着增加的细胞增殖、cdk 6的优先活化（细胞周期蛋白D1/cdk 6的一个靶点是视网膜母细胞瘤蛋白）、p53过表达和EGFR过表达（Cancer Res.57：5542，1997）。P53突变是头颈癌和食管癌中常见的遗传变异。交叉细胞周期蛋白D1与p53基因缺失小鼠的能力代表了一个独特的机会，以分析两个关键的遗传改变在其多阶段口腔食管癌发生的贡献的组合效应。本研究的目的是利用细胞周期蛋白D1 x p53基因敲除小鼠的口腔和食管组织的组织学，免疫组化和PCR分析。目前正在研究化学预防剂对这些转基因动物口腔癌和食道癌发展的影响。