The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Synergistic drug combinations tend to improve therapeutically relevant selectivity
Open accessAbstract
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.
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Cited by
Gao, H., Korn, J. M., Ferretti, S., Monahan, J. E., Wang, Y., Singh, M., Zhang, C., Schnell, C., Yang, G., Zhang, Y., et al. (2015) · Nature Medicine · doi:10.1038/nm.3954 · Cited by 1,393
Analysis of drug combinations: current methodological landscape
Foucquier, J., & Guedj, M. (2015) · Pharmacology Research & Perspectives · doi:10.1002/prp2.149 · Cited by 1,115
Searching for Drug Synergy in Complex Dose–Response Landscapes Using an Interaction Potency Model
Yadav, B., Wennerberg, K., Aittokallio, T., & Tang, J. (2015) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2015.09.001 · Cited by 845
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Recent advances of cocktail chemotherapy by combination drug delivery systems
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Nanotechnology-based combinational drug delivery: an emerging approach for cancer therapy
Parhi, P., Mohanty, C., & Sahoo, S. K. (2012) · Drug Discovery Today · doi:10.1016/j.drudis.2012.05.010 · Cited by 573
Metadata
- Authors
- Lehár, J., Krueger, A. S., Avery, W., Heilbut, A. M., Johansen, L. M., Price, E. R., Rickles, R. J., Short III, G. F., Staunton, J. E., Jin, X., Lee, M. S., Zimmermann, G. R., & Borisy, A. A.
- Venue
- Nature Biotechnology
- Published
- 2009-07
- Volume
- 27
- Issue
- 7
- Pages
- 659-666
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2044025814
- Cited by
- 938
- References
- 48
- FWCI
- 27.04
- Type
- journal article
- Language
- en
- Open access
- green
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- Lehár, J., Krueger, A. S., Avery, W., Heilbut, A. M., Johansen, L. M., Price, E. R., Rickles, R. J., Short III, G. F., Staunton, J. E., Jin, X., Lee, M. S., Zimmermann, G. R., & Borisy, A. A. (2009). Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nature Biotechnology. https://doi.org/10.1038/nbt.1549
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