Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen (Norway).
Chembiochem. 2013 Dec 16;14(18):2512-8. doi: 10.1002/cbic.201300409. Epub 2013 Nov 12.
Cellular behaviors are governed by combinations of systemic and microenvironmental factors; together, these regulate cell signaling responses to growth factors. This contextual microenvironmental influence also determines drug sensitivity. Hence using in vitro systems that model contextual cellular behavior is highly beneficial for effective therapeutic development. Angiogenesis (formation of blood vessels) is driven by a series of dynamic endothelial cell signaling responses to growth factors under the influence of the vascular extracellular matrix and adjacent pericytes. In vitro primary human vascular cell co-cultures self-assemble into capillary-like structures through reciprocal heterotypic interactions that mimic angiogenic context dynamics. By using temporal live-cell imaging-based analysis, unique angiogenic microenvironments can be delineated to quantify the contextual activity of compound inhibitors. We used this in vitro organotypic contextual screening approach to conduct structure-activity relationship analysis on a combretastatin A-4 analogue series to identify novel compounds with potent vascular disrupting activity in vivo.
细胞行为受系统性和微环境因素的组合控制；这些因素共同调节细胞对生长因子的信号反应。这种上下文微环境的影响也决定了药物的敏感性。因此，使用能够模拟上下文细胞行为的体外系统对于有效的治疗开发非常有益。血管生成（血管的形成）是由一系列动态的内皮细胞信号反应驱动的，这些反应受到血管细胞外基质和相邻周细胞的影响。在体外，原代人血管细胞共培养物通过模拟血管生成上下文动态的相互异性相互作用自组装成毛细血管样结构。通过使用基于时间的活细胞成像分析，可以描绘出独特的血管生成微环境，以定量化合物抑制剂的上下文活性。我们使用这种体外器官型上下文筛选方法，对 combretastatin A-4 类似物系列进行构效关系分析，以鉴定具有体内强大血管破坏活性的新型化合物。
