The Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, North Carolina Research Campus, Kannapolis, NC, 28081, USA.
Division of Hematology/Oncology, Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Sci Rep. 2021 Mar 11;11(1):5715. doi: 10.1038/s41598-021-85141-5.
Personalized medicine holds tremendous promise for improving safety and efficacy of drug therapies by optimizing treatment regimens. Rapidly developed patient-derived xenografts (pdx) could be a helpful tool for analyzing the effect of drugs against an individual's tumor by growing the tumor in an immunodeficient animal. Severe combined immunodeficiency (SCID) mice enable efficient in vivo expansion of vital tumor cells and generation of personalized xenografts. However, they are not amenable to large-scale rapid screening, which is critical in identifying new compounds from large compound libraries. The development of a zebrafish model suitable for pdx could facilitate large-scale screening of drugs targeted against specific malignancies. Here, we describe a novel strategy for establishing a zebrafish model for drug testing in leukemia xenografts. We used chronic myelogenous leukemia and acute myeloid leukemia for xenotransplantation into SCID zebrafish to evaluate drug screening protocols. We showed the in vivo efficacy of the ABL inhibitor imatinib, MEK inhibitor U0126, cytarabine, azacitidine and arsenic trioxide. We performed corresponding in vitro studies, demonstrating that combination of MEK- and FLT3-inhibitors exhibit an enhanced effect in vitro. We further evaluated the feasibility of zebrafish for transplantation of primary human hematopoietic cells that can survive at 15 day-post-fertilization. Our results provide critical insights to guide development of high-throughput platforms for evaluating leukemia.
个性化医学通过优化治疗方案，为提高药物治疗的安全性和疗效提供了巨大的前景。快速发展的患者来源异种移植物（pdx）可以通过在免疫缺陷动物中生长肿瘤，成为分析药物对个体肿瘤影响的有用工具。严重联合免疫缺陷（SCID）小鼠能够有效地在体内扩增重要的肿瘤细胞，并生成个性化的异种移植物。然而，它们不适合大规模快速筛选，这对于从大型化合物库中识别新化合物至关重要。适合 pdx 的斑马鱼模型的开发可以促进针对特定恶性肿瘤的药物的大规模筛选。在这里，我们描述了一种用于白血病异种移植物药物测试的斑马鱼模型建立的新策略。我们使用慢性髓性白血病和急性髓性白血病进行异种移植到 SCID 斑马鱼中，以评估药物筛选方案。我们展示了 ABL 抑制剂伊马替尼、MEK 抑制剂 U0126、阿糖胞苷、阿扎胞苷和三氧化二砷的体内疗效。我们进行了相应的体外研究，证明 MEK 和 FLT3 抑制剂的联合使用在体外具有增强的效果。我们进一步评估了斑马鱼移植可在受精后 15 天存活的人原发性造血细胞的可行性。我们的结果为开发评估白血病的高通量平台提供了重要的见解。
