Evaluation of Selected Transgenic Mouse Models as Altern

几年来，我们一直在努力开发和评估基于转基因小鼠品系的替代短期模型，以确定潜在的环境致癌物。这项工作的假设基础是，当这些动物暴露于化学物质中时，引入或改变已知参与致瘤性关键途径的选定基因可能导致肿瘤过程的截断。本实验室重点研究的主要模型是p53缺陷系和v-Ha-ras齐塔蛋白促进系（Tg.AC）。我们发表的研究成果有助于促进国际上对这些和其他短期模型进行评估的努力，这些模型是由国际生命科学研究所组织的，涉及50多个代表私营制药和化学公司的组织，以及政府研究和监管机构。该项目的最终成果验证了所选转基因模型的价值，并导致了这些模型的实施，特别是在美国食品和药物管理局的指导下，在美国制药工业中。此外，我们提出了一种策略，通过该策略，转基因模型可以在化学物质亚慢性毒理学表征期间的传统致癌性研究中实施，这将导致可用的信息数据，从而可以排除进行长期两年生物测定的必要性，或者能够修改长期研究的进行。这将降低成本，减少表征化学品的时间，减少表征化学品致癌特性的毒理学所需的动物数量。

We are bringing to culmination several years effort to develop and evaluate alternative short-term models for identifying potential environmental carcinogens based upon the use of genetically modified mouse lines. The hypothesis underlying this work was that introduction or alteration of selected genes known to be involved in critical pathways of tumorigenicity could result in a truncation of the neoplastic process when such animals were exposed to chemicals. The principle models focus upon in this laboratory were the p53 deficient line and a v-Ha-ras zetaglobin promoted line (Tg.AC). The results of work published from our studies have helped to catalyze an international effort to evaluate these and other short-term models that was organized by the International Life Sciences Institute and involved over 50 organizations representing private sector pharmaceutical and chemical companies, and government research and regulatory agencies. The culmination of this project has verified the value of selected transgenic models and has resulted in the implementation of the use of the models, particularly within the US pharmaceutical industry under the guidance of the Food and Drug Administration. In addition, we have proposed a strategy through which transgenic models could be implemented in conventional carcinogenicity studies during the subchronic toxicological characterization of chemicals that would result in informative data being available that could preclude the necessity to conduct a long-term two year bioassay or to be able to modify the conduct of long-term studies. This would result in reducing costs, decreasing the time in which the chemical is characterized and in reducing the number of animals necessary to characterize the toxicologic in carcinogenic properties of chemicals.