Evaluation of Selected Transgenic Mouse Models as Altern

我们将几年来的努力推向高潮，开发和评估基于转基因小鼠品系的潜在环境致癌物质识别的替代短期模型。这项工作背后的假设是，当这些动物暴露在化学物质中时，已知参与致癌关键途径的选定基因的引入或改变可能会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 zetaglobin促进系(Tg.AC)。我们研究发表的工作结果有助于催化一项国际努力，以评估这些模型和其他短期模型，该模型由国际生命科学研究所组织，涉及代表私营部门制药和化学公司的50多个组织，以及政府研究和监管机构。该项目的最终结果是验证了选定的转基因模型的价值，并导致这些模型的使用，特别是在美国食品和药物管理局的指导下，在美国制药行业内。此外，我们提出了一种策略，通过该策略，可以在化学物质的亚慢性毒理学表征期间，在传统的致癌性研究中实施转基因模型，从而获得信息数据，从而排除进行长期两年生物测试的必要性，或者能够修改长期研究的进行。这将导致降低成本，缩短对化学物质进行表征的时间，并减少对化学物质的致癌特性进行毒理学表征所需的动物数量。

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.