In Vitro Systems to Predict Hepatobiliary Toxicity

描述（由申请人提供）： 国家癌症研究所需要发展，标准化， 可以快速和廉价地确定或预测 潜在癌症治疗剂的器官特异性毒性。 的 拟议项目的目的是开发一种体外肝细胞测定法 确定或预测潜在的剂量限制性肝细胞损伤， 抗癌剂对人体胆道的损伤。 这项研究将 专注于多单元系统的开发、验证和确认 其可以满足该目，特别是精确切割的肝脏切片， 肝细胞和胆管上皮细胞的共培养物。 待测定 （1）能够区分伤害的类型， 在肝脏中产生的抗癌剂，（2）辨别差异， 模拟敏感性，（3）区分种间差异， 敏感性，和（4）确定血清中诊断价值的指标， 识别人类肝损伤的特定类型。 这项研究将 评估已知临床诊断的实用性、灵敏度和 在检测和量化由以下因素产生的肝损伤类型方面的保真度 抗癌剂的测定，并将寻找新的指标，使用 R21期的蛋白质组学技术，这可能是上级鉴定 试验中的靶细胞损伤和机制，并且具有临床相关性， 有价值 用于开发和验证试验的参比化合物将 主要是抗癌药物，具有特异性，明确定义，代表性 对动物和/或人类的毒性。 R33阶段将专注于开发 本检测试剂盒的全部功能作为 NCI筛选靶器官所需的体外毒性试验组合 毒性，并帮助预测临床应用的安全剂量水平和方案。 审判

DESCRIPTION (provided by applicant): The National Cancer Institute has a need for development, standardization, and validation of assays that can quickly and cheaply determine or predict organ-specific toxicities of potential cancer therapeutic agents. The objective of the proposed project is to develop an in vitro liver cell assay to determine or predict potential dose-limiting hepatocellular injury and injury to the biliary tract by anticancer agents in humans. The research will focus on the development, verification, and validation of multicell systems that can meet that objective, in particular precision-cut liver slices and co-cultures of hepatocytes and biliary epithelial cells. The assay to be developed will be able to (1) discriminate the types of injury that can be produced in liver by anticancer agents, (2) discriminate differences in analogue sensitivity, (3) discriminate interspecies differences in sensitivity, and (4) identify indicators of diagnostic value in serum for identifying specific types of liver injury in humans. The research will evaluate known clinical diagnostics for their utility, sensitivity, and fidelity in detecting and quantifying the types of liver injury produced by anticancer agents in the assay and will search for novel indicators, using proteomic techniques in the R21 phase, that may be superior for identifying target cell injury and mechanisms in the assay and be clinically relevant and valuable. Reference compounds used to develop and validate the assay will be primarily anticancer agents with specific, well-defined, representative toxicities in animals and/or humans. The R33 phase will focus on developing the full capabilities of this assay as an important and critical part of the in vitro toxicity test battery needed by the NCI to screen for target organ toxicities and to aid in predicting safe dose levels and regimens for clinical trials.