In Vitro Systems: Predict Drug-induced Pulmonary Injury

描述（由申请人提供）：国家癌症研究所需要开发、标准化和验证能够快速、廉价地确定或预测潜在癌症治疗剂的器官特异性毒性的测定法。拟议项目的目的是开发一种体外肺细胞测定法，以确定或预测人类抗癌药物的潜在剂量限制性肺损伤。在R21阶段的研究将集中在一个或多个主要的多细胞系统，可以满足这一目标的开发，评估和优化，特别是精确切割肺切片和肺内皮细胞和上皮细胞的共培养。待开发的检测方法最终将能够区分由抗癌剂引起的肺损伤的主要类型、毒性效力的差异以及种间敏感性的差异。在这项工作中，已知的和新的指标将进行调查，以评估的程度和性质的损伤所产生的代理商在体外对应于在体内的反应，使用大鼠作为模型和临床化学和先进的蛋白质组学和激光-MS（喷射-REMPI）技术。用于开发和验证试验的参比化合物将是在动物和人体中具有特异性、明确定义的代表性毒性的抗癌药物。R33阶段将专注于开发该试验的全部功能，作为NCI筛选靶器官毒性所需的体外毒性试验组合的重要和关键部分，并帮助预测临床试验的安全剂量水平和方案。

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 lung cell assay to determine or predict potential dose-limiting pulmonary injury by anticancer agents in humans. Research in the R21 phase will focus on the development, evaluation, and optimization of one or more primary multicell systems that can meet that objective, in particular precision-cut lung slices and co-cultures of lung endothelial and epithelial cells. The assay to be developed will ultimately be able to discriminate between the major types of injury induced in lung by anticancer agents, differences in toxic potency, and interspecies differences in sensitivity. In this work, known and novel indicators will be investigated for assessing the degree and nature of the injury produced by the agents in vitro for correspondence with in vivo response, using the rat as a model and clinical chemistry and advanced proteomic and laser-MS (Jet-REMPI) techniques. Reference compounds used to develop and validate the assay will be anticancer agents with specific, well- defined, representative toxicities in animals and humans. The R33 phase will focus on developing the full capabilities of the 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.