体外血液毒性模型:骨髓干细胞/祖细胞向造血谱系分化及谱系特异性血液毒性评价

Prathap Kumar Mahalingaiah, Tammy Palenski, Terry R. Van Vleet
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引用次数: 7

摘要

血液毒性是药物安全性的一个重要问题,它可能是由于对循环中的成熟血细胞类型以及针对骨髓中未成熟造血干细胞/祖细胞的直接细胞毒性引起的。了解和研究新测试项目/药物的血液毒性潜力的体外模型在早期临床前药物开发中至关重要。传统的方法,菌落形成单位(CFU)测定,是常用的,并已被验证为血液毒性筛选的方法。CFU测定法在侦查工作中的应用存在诸多局限性。在本文中,我们描述了一个详细的方案液体培养,微板为基础的体外血液毒性试验,以评估谱系特异性(髓系,红系和巨核细胞)在不同分化阶段的血液毒性。与传统的CFU分析相比,该分析具有多种优势,包括适合高通量筛选,并且足够灵活,可以包含额外的机制研究终点。因此,它是科学家在药物发现和开发方面非常有用的工具。©2018 by John Wiley &儿子,Inc。
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An In Vitro Model of Hematotoxicity: Differentiation of Bone Marrow–Derived Stem/Progenitor Cells into Hematopoietic Lineages and Evaluation of Lineage-Specific Hematotoxicity

Hematotoxicity is a significant issue for drug safety and can result from direct cytotoxicity toward circulating mature blood cell types as well as targeting of immature blood-forming stem cells/progenitor cells in the bone marrow. In vitro models for understanding and investigating the hematotoxicity potential of new test items/drugs are critical in early preclinical drug development. The traditional method, colony forming unit (CFU) assay, is commonly used and has been validated as a method for hematotoxicity screening. The CFU assay has multiple limitations for its application in investigative work. In this paper, we describe a detailed protocol for a liquid-culture, microplate-based in vitro hematotoxicity assay to evaluate lineage-specific (myeloid, erythroid, and megakaryocytic) hematotoxicity at different stages of differentiation. This assay has multiple advantages over the traditional CFU assay, including being suitable for high-throughput screening and flexible enough to allow inclusion of additional endpoints for mechanistic studies. Therefore, it is an extremely useful tool for scientists in pharmaceutical discovery and development. © 2018 by John Wiley & Sons, Inc.

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