In Vitro Systems: Predict Drug-induced Pulmonary Injury

体外系统：预测药物引起的肺损伤

• 批准号: 6656363
• 负责人: CHARLES A TYSON
• 金额: $ 9.82万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6656363
• 关键词: antineoplastics; biomarker; bleomycin; carmustine; cytotoxicity; dosage; drug adverse effect; electrospray ionization mass spectrometry; gel electrophoresis; histopathology; iatrogenic disease; laboratory rat; lung injury; matrix assisted laser desorption ionization; mixed tissue /cell culture; nitrosourea; respiratory epithelium; serum; technology /technique development; tissue /cell culture

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.

描述（由申请人提供）：国家癌症研究所需要快速，便宜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进行开发，标准化和验证。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剂的潜在剂量限制肺损伤。 R21阶段的研究将集中在一个或多个主要的多中心系统的开发，评估和优化上，这些系统可以符合该目标，特别是精确切割的肺切片和肺内皮和上皮细胞的共培养。要开发的测定最终将能够区分抗癌药物诱导的肺部主要损伤，毒性效力的差异以及敏感性的种间差异。在这项工作中，将研究已知和新颖的指标，以评估代理在体外产生的损伤的程度和性质与体内反应的对应，并使用大鼠作为模型和临床化学以及晚期蛋白质组学和激光MS（JET-REMPI）技术。用于开发和验证该测定法的参考化合物将是具有特定，明确的，代表性毒性的抗癌药。 R33阶段将集中于开发分析的全部能力，作为NCI所需的体外毒性测试电池的重要组成部分，以筛选靶心器官毒性，并有助于预测用于临床试验的安全剂量水平和治疗方案。