Biomarker Matrix for Genotoxicity Mode of Action

描述（由申请人提供）：众所周知，目前的遗传毒理学试验组具有相对较高的灵敏度，这意味着它们可有效识别遗传毒性致癌物。然而，目前的方法存在一个关键的缺陷，即体外哺乳动物细胞遗传毒性试验的特异性较低，因为它们产生的阳性结果的发生率很高，而这些结果与体内无关（所谓的“误导性”或“不相关”阳性）。这种不相关的体外阳性结果的高发生率导致广泛和昂贵的额外测试，通常使用整个动物模型，或者放弃潜在有价值的产品。我们将通过开发商业化试剂盒来解决目前体外哺乳动物细胞遗传毒性检测的这一主要问题，该试剂盒能够实现具有高灵敏度和特异性的自动化检测策略。该系统将根据遗传毒性活性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不相关作用模式。的次要目的 拟议的工作是制定鉴定断裂物的方法。也就是说，我们将开发工具，阐明是否致染色体断裂活性是DNA反应性的结果，或者它是否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.