Biomarker Matrix for Genotoxicity Mode of Action

描述(由申请人提供)：众所周知，目前的遗传毒理学检测方法表现出相对较高的灵敏度，这意味着它们可以有效地识别遗传毒性致癌物。然而，目前的方法存在一个严重的缺陷--即，体外哺乳动物细胞基因毒性测试的特异性很低，因为它们产生了与体内无关的高比例阳性结果(所谓的“误导性”或“无关”阳性)。这种不相关的体外阳性结果的高发生率导致了广泛和昂贵的额外测试，通常是使用完整的动物模型，否则就会放弃潜在的有价值的产品。我们将通过开发商业试剂盒来解决当前体外哺乳动物细胞遗传毒性分析的主要问题，该试剂盒能够实现显示出高灵敏度和高特异度的自动化测试策略。该系统将根据遗传毒性活动的主要模式对阳性结果进行分类，重要的是，将可靠地识别可能在体内不起作用的无关作用模式(S)。的次要目标 建议的工作是开发表征碎屑岩的方法。也就是说，我们将开发工具来阐明断裂活动是DNA反应的结果，还是由间接机制介导的。

DESCRIPTION (provided by applicant): It is well recognized that current batteries of genetic toxicology assays exhibit relatively high sensitivity, meaning they effectively identify genotoxic carcinogens. However, a critical deficiency with current approaches exists-namely, the specificity of the in vitro mammalian cell genotoxicity tests is low, as they yield a high incidenc of positive results that do not have in vivo relevance (so-called "misleading" or "irrelevant" positives). This high incidence of irrelevant in vitro positive results leads to extensive and costy additional testing, often with whole animal models, or else abandonment of potentially valuable products. We will address this major problem with current in vitro mammalian cell genetic toxicity assays by developing commercial kits that enable an automated testing strategy that exhibits both high sensitivity and specificity. This system will categorize positive results according to the predominant mode of genotoxic activity, and importantly, will reliably identify irrelevant mode(s) of action that are likely to be nonoperational in vivo. A secondary objective of the proposed work is the development of methods for characterizing clastogens. That is, we will develop tools that elucidate whether clastogenic activity is the result of DNA-reactivity, or whether it is mediated by an indirect mechanism.