1 Department of Pathology, Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.
2 Center for Molecular Discovery, Health Sciences Center, University of New Mexico Albuquerque, NM, USA.
SLAS Discov. 2018 Aug;23(7):751-760. doi: 10.1177/2472555218775913. Epub 2018 May 29.
Classical therapeutic regimens are subject to toxicity, low efficacy, and/or the development of drug resistance. Thus, the discovery of synergistic drug combinations would permit treatment with lower, tolerable dosages of each agent and restored sensitivity. We describe the development and use of the SynScreen software application, which allows for visual and mathematical determinations of compound concentrations that produce super-additive effects. This software uses nonlinear regression fits of dose responses to determine synergism by the Bliss independence and Loewe additivity analysis models. We demonstrate the utility of SynScreen with data analysis from in vitro high-throughput flow cytometry (HTFC) combination screens with repurposed drugs and multiplexed synergy analysis of multiple biologic parameters in parallel. The applicability of SynScreen was confirmed by testing open-source data sets used in published drug combination literature. A key benefit of SynScreen for high-throughput drug combination screening is that observed measurements are graphically depicted in comparison with a three-dimensional surface that represents the theoretical responses at which Bliss additivity would occur. These images and summary tables for the calculated drug interactions are automatically exported. This allows for substantial data sets to be visually assessed, expediting the quick identification of efficacious drug combinations and thereby facilitating the design of confirmatory studies and clinical trials.
经典的治疗方案受到毒性、低疗效和/或耐药性发展的限制。因此，发现协同药物组合可以允许以每个药物的更低、可耐受的剂量进行治疗，并恢复敏感性。我们描述了 SynScreen 软件应用程序的开发和使用，该应用程序允许直观和数学地确定产生超加性效应的化合物浓度。该软件使用剂量反应的非线性回归拟合来通过 Bliss 独立性和 Loewe 添加性分析模型确定协同作用。我们通过对重新利用药物的体外高通量流式细胞术 (HTFC) 组合筛选以及对多个生物学参数的多路复用协同分析进行数据分析，展示了 SynScreen 的实用性。SynScreen 的适用性通过测试已发表药物组合文献中使用的开源数据集得到了验证。SynScreen 对高通量药物组合筛选的一个关键优势是，观察到的测量值与代表 Bliss 添加性发生时的理论响应的三维表面进行图形比较。这些图像和计算药物相互作用的摘要表会自动导出。这允许对大量数据集进行直观评估，加快有效药物组合的快速识别，从而促进验证性研究和临床试验的设计。
