Continuous measurement of cell growth as an optimal tool in drug toxicity testing

连续测量细胞生长作为药物毒性测试的最佳工具

• 批准号: 8832745
• 负责人: DANIEL L COOK
• 金额: $ 22.35万
• 依托单位: ENTOX SCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832745
• 关键词: Adverse drug effect; Adverse effects; Algorithms; Automation; Award; Benchmarking; Biological Assay; Cell Count; Cell Death; Cell Maintenance; Cells; Chronic; Clinical; Clinical Trials; Data; Data Set; Detection; Development; Drug Industry; Drug toxicity; Ethics; Exposure to; Feasibility Studies; Foundations; Funding; Genetic Transcription; Goals; Grant; Growth; Heart; Hepatocyte; In Vitro; Industry; Islet Cell; Islets of Langerhans; Lead; Licensing; Liver; Marketing; Measurement; Measures; Metabolic; Metabolism; Methodology; Methods; Molecular; Motivation; Noise; Organ; Oxygen; Oxygen Consumption; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Poisoning; Preclinical Drug Evaluation; Process; Protocols documentation; Reading; Research; Resolution; Rest; Safety; Science; Services; Side; Signal Transduction; Slice; Staging; System; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxicity Tests; Toxicology; Translations; Universities; Validation; Washington; base; candidate selection; cell growth; cell type; clinical investigation; commercialization; drug candidate; drug development; drug testing; in vitro testing; in vivo; killings; meetings; novel; public health relevance; response; sensor; tool

 DESCRIPTION (provided by applicant): During the process of screening for drugs with therapeutic potential, often times several candidates emerge as prime candidates with similar efficacy and the choice for a lead compound is difficult to make. However, people's lives and billions of dollars may rest on the choice of which compound to bring to clinical investigation and trials. Since any levels of toxicity caused the by drug would contra-indicate its choice as a lead compound, detection of very low-level toxicity could form the basis for ranking such groups of compounds in an objective fashion. Accordingly, the overall goal of the proposal is to build an algorithm relating a novel ultra-sensitive in vitro measure of toxicity to clinical toxicity, whichwill be used to rank candidate drugs being considered as lead compound of clinical trials. We reasoned that even a very slow rate of cell death induced by a chronically administered drug might -- over the years -- kill off a significant proportion of an organ or cell type. However, a change in cell number of only a few percent is below the detection limit of current in vitro tests. We hypothesize that some side effects of drugs occurring in vivo could be revealed in in vitro tests if they were sensitive enough. We have established unique methods to measure cell number and metabolic viability as reflected by continuous measurement of oxygen consumption with the required sensitivity. The key to establishing the utility of our approach will be to demonstrate strong correlation with in vivo safety and toxicology using a relevant panel of benchmark compounds about which prior in vivo data is well known, and that contains a spectrum from highly "safe" drugs to those with known toxicity. We will optimize methods to measure small changes in oxygen consumption (a measure of cell number) in various selected cell types, and verify the methods by testing with compounds that have varying degrees of toxicity. This will lay the foundation for the eventual construction of an objective algorithm that can be used to rank the potential of lead compounds on the basis of toxicity caused by chronic administration.

 描述（由适用提供）：在筛查具有治疗潜力的药物的过程中，通常会出现几个候选人，作为具有相似效率的主要候选者，并且很难选择铅化合物。但是，人们的生活和数十亿美元可能取决于选择哪种化合物进行临床调查和 试验。由于通过药物引起的任何水平的毒性都将与其选择作为铅化合物相反，因此检测非常低水平的毒性可能构成以客观方式对此类化合物进行排名的基础。彼此之间，该提案的总体目标是建立一种算法，该算法将新型的超敏感性测量毒性与临床毒性相关，将其用于对候选药物进行对被视为临床试验的铅化合物。我们认为，即使是由长期给药的药物引起的细胞死亡率也很慢，多年来 - 可能会杀死一定比例的器官或细胞类型。但是，只有几％的细胞数量的变化低于当前体外测试的检测极限。 我们假设，如果足够敏感的话，可以在体外测试中揭示出在体内发生的某些副作用。我们已经建立了独特的方法来测量细胞数量和代谢生存能力，如连续测量氧气消耗所必需的灵敏度所反映的。建立我们方法的实用性的关键是使用相关基准化合物与体内安全和毒理学相关性很强，围绕该基准化合物众所周知，该化合物众所周知，其中包含从高度“安全”药物到具有已知毒性的人的频谱。我们将优化测量各种选定细胞类型中氧气消耗的小变化（一种细胞数量），并通过测试具有不同程度毒性的化合物来验证方法的方法。这将为最终构建客观算法奠定基础 可用于根据长期给药引起的毒性来对铅化合物的潜力进行排名。