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Published on: March 3, 2015
Contextual compound screening for improved therapeutic discovery
Lasse Evensen1, Kristin Odlo, David R Micklem
1Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen (Norway).
Abstract:
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.
Insights
This study developed an in vitro model to test drug effectiveness by mimicking the tumor microenvironment. The model identified new compounds that disrupt tumor blood vessel formation in vivo.
Area of Science:
- * Cellular Biology
- * Pharmacology
- * Biomedical Engineering
Background:
- * Cellular behavior and drug sensitivity are influenced by systemic and microenvironmental factors.
- * In vitro models that replicate cellular behavior in context are crucial for therapeutic development.
- * Angiogenesis, the formation of new blood vessels, is a complex process involving endothelial cells, growth factors, and the vascular extracellular matrix.
Purpose of the Study:
- * To develop and utilize an in vitro organotypic contextual screening approach to model angiogenesis.
- * To analyze the structure-activity relationships of combretastatin A-4 analogues.
- * To identify novel compounds with potent in vivo vascular-disrupting activity.
Main Methods:
- * Co-culture of primary human vascular cells to self-assemble into capillary-like structures, mimicking angiogenic context.
- * Temporal live-cell imaging-based analysis to delineate unique angiogenic microenvironments.
- * Quantification of contextual activity of compound inhibitors using the developed in vitro model.
Main Results:
- * The in vitro organotypic contextual screening approach successfully modeled angiogenic dynamics.
- * Structure-activity relationship analysis was performed on a combretastatin A-4 analogue series.
- * Novel compounds with potent vascular-disrupting activity were identified.
Conclusions:
- * In vitro models that mimic the angiogenic microenvironment are valuable for therapeutic development.
- * The developed screening approach enables the identification of potent vascular-disrupting compounds.
- * This research contributes to the discovery of novel anti-angiogenic agents for cancer therapy.
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