In Vitro Systems to Predict Hepatobiliary Toxicity

描述（由申请人提供）： 国家癌症研究所需要开发、标准化和 验证可以快速且廉价地确定或预测的测定 潜在癌症治疗剂的器官特异性毒性。 的 拟议项目的目标是开发体外肝细胞检测方法 确定或预测潜在的剂量限制性肝细胞损伤和 人类抗癌药物对胆道的损伤。 该研究将 专注于多电池系统的开发、验证和确认 可以实现这一目标，特别是精密切割的肝脏切片和 肝细胞和胆管上皮细胞的共培养。 化验应为 开发的技术将能够（1）区分可能发生的伤害类型 抗癌剂在肝脏中产生，（2）区分 模拟敏感性，（3）区分种间差异 敏感性，以及（4）确定血清中具有诊断价值的指标 识别人类肝损伤的特定类型。 该研究将 评估已知临床诊断的实用性、敏感性和 保真度地检测和量化肝损伤类型 检测中的抗癌药物，并将寻找新的指标，使用 R21 阶段的蛋白质组学技术，可能更适合鉴定 测定中的靶细胞损伤和机制并具有临床相关性和 有价值的。 用于开发和验证该测定的参考化合物将是 主要抗癌药物具有特异性、明确性、代表性 对动物和/或人类的毒性。 R33阶段将重点开发 该测定的全部功能作为该测定的重要和关键部分 NCI 需要体外毒性测试电池来筛选靶器官 毒性并帮助预测临床安全剂量水平和治疗方案 试验。

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.