Synergistic drug combinations improve therapeutic selectivity
By Joseph Lehar, Andrew S Krueger, W. Avery, Adrian M Heilbut, L. Johansen, E. R. Price, R. Rickles, Glenn F Short, J. E. Staunton, Xiaowei Jin and 3 more. Nature Biotechnology, 2009
611 citations recorded by the source corpus.
Drug combinations are a promising strategy to overcome the compensatory mechanisms and unwanted off-target effects that limit the utility of many potential drugs. However, enthusiasm for this approach is tempered by concerns that the therapeutic synergy of a combination will be accompanied by synergistic side effects. Using large scale simulations of bacterial metabolism and 94,110 multi-dose experiments relevant to diverse diseases, we provide evidence that synergistic drug combinations are generally more specific to particular cellular contexts than are single agent activities. We highlight six combinations whose selective synergy depends on multitarget drug activity. For one anti-inflammatory example, we show how such selectivity is achieved through differential expression of the drugs' targets in cell types associated with therapeutic, but not toxic, effects and validate its therapeutic relevance in a rat model of asthma. The context specificity of synergistic combinations creates many opportunities for therapeutically relevant selectivity and enables improved control of complex biological systems.
Subfields: Computational Theory and Mathematics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/92a8e62ea4da470c15eedfac396250a7d3e4aff9
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In Computational Theory and Mathematics
In Molecular Biology
Citations in the corpus
- ETCM: an encyclopaedia of traditional Chinese medicine (2018, background): “Multi-drug combination therapeutics has been considered as a rational and efficient therapeutic approach to control complex diseases by regulating various targets and exerting multiple pharmacological effects simultaneously (22).”
- Synergy Maps: exploring compound combinations using network-based visualization (2015, background): “The phenomenon of super-additivity of the therapeutic effect of a combination, known as synergy, has the potential for improved pharmaceutical treatment options in terms of increased efficacy [5] and therapeutically relevant selectivity [6], whilst reducing the risk of toxicity [7] and side-effects ”