High-Throughput Flow Cytometry Drug Combination Discovery with Novel Synergy Analysis Software, SynScreen

SLAS Discovery
Dominique R PerezAlexandre Chigaev

Abstract

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 table...Continue Reading

References

Jun 12, 2003·Proceedings of the National Academy of Sciences of the United States of America·Alexis A BorisyCurtis T Keith
Mar 3, 2007·Molecular Systems Biology·Joseph LehárCurtis T Keith
Jan 29, 2014·Proceedings of the National Academy of Sciences of the United States of America·Lesley A Mathews GrinerCraig J Thomas
Apr 24, 2014·Molecular Cancer Therapeutics·Muhammad KashifMats G Gustafsson
Mar 26, 2015·Journal of Biomolecular Screening·Bruce S Edwards, Larry A Sklar
Jul 15, 2015·Pharmacology Research & Perspectives·Julie Foucquier, Mickael Guedj
Jan 1, 2015·Computational and Structural Biotechnology Journal·Bhagwan YadavJing Tang
Apr 30, 2016·Oncotarget·Dominique R PerezAlexandre Chigaev
May 7, 2016·Bioinformatics·Giovanni Y Di VeroliDuncan I Jodrell

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Methods Mentioned

BETA
flow cytometry

Software Mentioned

Genendata Screener
CalcuSyn
IntelliCyt
DRUGXfa
HyperView
CompuSyn
SynScreen
Combenefit
MixLow
Excel

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