Contextual compound screening for improved therapeutic discovery.
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.
Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen (Norway).
Lasse
L
Evensen
Kristin
K
Odlo
David R
DR
Micklem
Amanda
A
Littlewood-Evans
Jeanette
J
Wood
Christian
C
Kuzniewski
Karl-Heinz
KH
Altmann
Trond Vidar
TV
Hansen
James B
JB
Lorens
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D018920:Coculture Techniques / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D011651:Pulmonary Artery / Q000166:cytology; D013329:Structure-Activity Relationship; D015027:Zebrafish
D020533:Angiogenesis Inhibitors
angiogenesis; cancer; combretastatin; compound screening; vascular disruption