Rapid Screen for Genotoxicants, Chemoprotectors, and Radioprotectors

快速筛查基因毒物、化学保护剂和放射保护剂

• 批准号: 7404983
• 负责人: STEPHEN D DERTINGER
• 金额: $ 57.76万
• 依托单位: LITRON LABORATORIES, LTD.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7404983
• 关键词: Address; Aneugens; Automation; Biological Assay; Biological Response Modifiers; Businesses; Cancer Patient; Cell Line; Cells; Characteristics; Chemical Industry; Chemicals; Chemistry; Chromosomes; Collaborations; Compatible; DNA Damage; Data; Development; Devices; Drug Industry; End Point; Evaluation; Flow Cytometry; Hepatocyte; Human; Human Cell Line; In Vitro; Industry; Investigation; Laboratories; Lead; Libraries; Liquid substance; Malignant Neoplasms; Measurement; Measures; Medical center; Medicine; Metabolic Activation; Methodology; Methods; Micronucleus Tests; Military Personnel; Miniaturization; Molecular Biology; Mutagenicity Tests; Numbers; Operative Surgical Procedures; Other Resources; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Poison; Protocols documentation; Purpose; Radiation Oncology; Radio; Range; Reagent; Reproducibility; Research Personnel; Research Project Grants; Resources; Robotics; Safety; Sales; Scientist; Score; Screening procedure; Sensitivity and Specificity; Series; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solutions; Staging; System; TP53 gene; Technology; Testing; Therapeutic; Time; Toxic effect; Universities; Upper arm; Validation; War; Work; assay development; base; clastogen; cytotoxicity; design; genotoxicity; instrumentation; micronucleus; miniaturize; next generation; portability; programs; protocol development; radiation effect; research study; tool

DESCRIPTION (provided by applicant): This research project addresses an important problem faced by the chemical and drug industries-their requirement to evaluate the DNA damaging potential of ever increasing numbers of new chemical entities in shorter periods of time. This situation presents opportunities for small businesses that are able to provide solutions to these challenges. Our proposal answers industry's need for higher throughput toxicity assessment through the development of an automated in vitro chromosomal damage assay. Chromosome damage will be quantified by flow cytometric micronucleus measurements. Importantly, the methodology that will be developed over the course of this project not only represents a high volume genotoxicant screening system, but also one that can be configured to identify agents which protect against chromosomal damage, i.e. biological response modifiers (BRMs). BRMs provide chemo- or radio-protection benefits that hold great promise in several important arenas, including treatment of cancer patients, protection of our troops during times of war, and for treatment of civilian victims of chemical or radiological terrorist attacks. The proposed Phase II experiments will initially focus on developing the methodologies that will allow us to incorporate automatic liquid handling devices into a miniaturized assay. By eliminating transfer steps and other labor-intensive tasks, the assay will meet the specifications of pharmaceutical and chemical companies that have high volume testing requirements. Once this is established, we, and our collaborators in the pharmaceutical industry, will evaluate a panel of genotoxicants and non-genotoxicants, thereby providing information regarding assay portability, sensitivity, and specificity. Additionally, two other lines of investigation will be undertaken: evaluation of the HepG2 liver cell line; and utilization of the micronucleus scoring assay for the purposes of radioprotectant identification/characterization. Ultimately, optimization and validation of this screening assay will help chemical and drug companies allocate their resources to their most promising candidates, eliminating hazardous entities early in development. Furthermore, by aiding in the identification of next generation BRMs, cancer patients and armed forces will benefit from the availability of chemo- and radio-protectant drugs. Along with recent advancements in the fields of molecular biology, chemistry and medicine comes an ever- increasing number of new and potentially helpful drugs and industrial chemicals. The ability of pharmaceutical and chemical companies to prioritize these agents in terms of safety and efficacy is often hampered by the use of outdated methods and/or technologies. This proposal addresses the stated need for an automated and miniaturized in vitro micronucleus assay designed to rapidly and efficiently detect the chromosome damaging potential of drugs and chemicals. In addition, this assay can be used to investigate agents designed to ameliorate the effects of radiation exposure, e.g. biological response modifiers.

描述（由申请人提供）：该研究项目解决了化学和药品工业所面临的重要问题，即评估较短时间内新化学实体数量不断增加的DNA损害潜力。这种情况为能够为这些挑战提供解决方案的小型企业提供了机会。我们的提案通过开发自动体外染色体损伤测定法回答行业对更高吞吐量毒性评估的需求。染色体损伤将通过流式细胞术微核测量值来量化。重要的是，将在该项目过程中开发的方法不仅代表了高体积的遗传毒性筛选系统，而且还代表了可以配置的方法，以识别可防止染色体损伤的药物，即生物反应修饰符（BRMS）。 BRM提供化学或无线电保护益处，在几个重要领域，包括癌症患者的治疗，战争时期的部队保护以及治疗化学或放射恐怖袭击的平民受害者。拟议的II期实验最初将集中于开发方法，使我们能够将自动液体处理设备纳入微型化测定法。通过消除转移步骤和其他劳动密集型任务，该测定法将符合具有高批量测试要求的药品和化学公司的规格。一旦建立了这一点，我们和我们在制药行业的合作者将评估一组遗传毒性和非生殖器毒素，从而提供有关测定可移植性，敏感性和特异性的信息。此外，还将进行另外两种调查线：评估HEPG2肝细胞系；用于放射保护剂鉴定/表征的目的，对微核评分测定法的利用。最终，对本筛查测定法的优化和验证将有助于化学和药品公司将其资源分配给他们最有前途的候选人，从而消除开发的危险实体。此外，通过帮助鉴定下一代BRMS，癌症患者和武装力将受益于化学和无线电保护药物的可用性。除了分子生物学领域的最新进展外，化学和医学还越来越多的新的和潜在的有用的药物和工业化学品。使用过时的方法和/或技术通常会阻碍制药和化学公司在安全性和疗效方面优先考虑这些代理的能力。该提案旨在解决对自动化和微型的体外微核测定法，旨在快速有效地检测药物和化学物质的染色体破坏潜力。此外，该测定法可用于调查旨在改善辐射暴露的影响的药物，例如生物反应修饰符。