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、标准化和 验证能够快速且廉价地确定或预测的化验 潜在癌症治疗药物的器官特异性毒性。这个 该项目的目标是建立一种体外肝细胞检测方法。 以确定或预测潜在的剂量限制性肝细胞损伤和 抗癌药物对人体胆道的损伤。这项研究将 专注于多单元系统的开发、验证和确认 可以达到这一目标，特别是精确切割的肝脏切片和 肝细胞与胆管上皮细胞共培养。即将进行的化验 发展将能够(1)辨别伤害的类型， 由抗癌药物在肝脏中产生，(2)在 类比敏感度，(3)区分种间差异 敏感性，以及(4)确定血清中诊断价值的指标 确定人类特定类型的肝损伤。这项研究将 评估已知的临床诊断方法的实用性、敏感性和 肝损伤类型的检测和量化的保真度 抗癌剂在化验中并将寻找新的指示剂，使用 R21期的蛋白质组学技术，这可能是鉴定的优势 靶细胞损伤及其机制的检测和临床意义 很有价值。用于开发和验证化验的参考化合物将是 主要的抗癌药物具有特定的、明确的、具有代表性的 对动物和/或人类的毒性。R33阶段将专注于开发 作为重要和关键的部分，这项检测的全部能力 NCI筛选靶器官所需的体外毒性测试组件 毒性，并帮助预测临床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.