Predictive Genes Sets For Chemically-Induced Liver Cancer

描述(由申请人提供)： 根据目前的监管政策，被认为在人类人口中同时具有重大暴露和健康风险的化学品被选为接受毒性和致癌效力测试。评价一种特定化学物质的致癌活性和慢性毒性的传统方法是两年一次的生物测定。由于涉及的资源相对较多，每次生物检测的成本在200万至400万美元之间，需要几年的时间才能完成。根据国家毒理学计划(NTP)，目前测试的化学物质数量在长期研究中为505种，短期测试中为66种，并且只有一项亚慢性研究。通过将完成的生物检测的数量与今天商业上的70,000至85,000种化学品进行比较，不可能将目前的检测系统应用于所有令人担忧的化学品。为了保护人类健康和节约经济资源，必须制定替代办法。为了有效和准确地评估一种未知化学物质的致癌潜力，我们建议：(1)在使用组织工程啮齿动物肝脏模型的标准啮齿动物2年生物测定中识别一组预测化学诱导肝癌发生的基因；以及(2)将来自啮齿动物研究的诊断基因表达谱应用于等效的组织工程人类肝脏模型，以评估化学诱导致癌终点的跨物种尺度。为了实现这一点，工程三维肝脏共培养物的体内暴露和暴露将与一组化合物一起进行，这些化合物包括非肝癌致癌物质和以下类别的致癌物质：遗传毒性、非遗传毒性、性别依赖和物种依赖。在为期两年的动物生物检测中，将对来自暴露的动物和肝脏培养物的信使核糖核酸进行微阵列分析，并将结果用于识别统计上预测肝癌发生的基因集。这项研究产生的一种商业产品将能够优先考虑未经测试的化学物质的致癌潜力，并为政府机构以及与化学制造、食品添加剂和制药相关的私营行业节省大量的时间、金钱和动物。

DESCRIPTION (provided by applicant): Under current regulatory policies, chemicals that are believed to comprise both a significant exposure and health risk in the human population are selected to undergo testing for toxicity and carcinogenic potency. The traditional method for evaluating carcinogenic activity and chronic toxicity of a specific chemical has been the two-year bioassay. Due to relatively large amounts of resources involved, each bioassay costs between 2 million and 4 million dollars and takes several years to complete. According to the National Toxicology Program (NTP), the number of chemicals currently tested stands at 505 in long-term studies and 66 in short-term tests, and only a single sub-chronic study. By comparing the number of completed bioassays with the 70,000 to 85,000 chemicals in commerce today it is impossible to apply the current testing system to all chemicals of concern. Alternative approaches must be developed in the interest of protecting human health and in saving economic resources. To develop an efficient and accurate assessment of the carcinogenic potential of an unknown chemical we propose to: (1) identify a set of genes that is predictive of chemically induced hepatocarcinogenesis in a standard rodent 2-year bioassay using a tissue-engineered rodent liver model; and (2) apply the diagnostic gene expression profile derived from the rodent studies to the equivalent tissue-engineered human liver model to evaluate cross-species scaling of the chemically-induced carcinogenic endpoint. To accomplish this, in vivo exposures and exposures of engineered three-dimensional liver co-cultures will be performed with a training set of compounds that include non-hepatocarcinogens and hepatocarcinogens of the following classes: genotoxic, non-genotoxic, sex-dependent and species-dependent. Microarray analysis will be performed on mRNA derived from the exposed animal and liver cultures and the results used to identify gene sets that are statistically predictive of hepatocarcinogenicity in the two-year animal bioassay. A commercial product derived from this research will enable prioritization of hepatocarcinogenic potential of untested chemicals and allow a significant savings of time, money and animals for both governmental agencies as well as private industry related to chemical manufacturing, food additives and pharmaceuticals.