Synergistic drug combinations tend to improve therapeutically relevant selectivity

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  • An Erratum to this article was published on 01 September 2009

Abstract

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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Figure 1: Measuring selectivity bias.
Figure 2: Simulation results identify drug combinations that inhibit E. coli growth in fermentation (minimal glucose) rather than aerobic (minimal acetate) conditions.
Figure 3: Selectivity bias for 13 sets of combination data focused on six disease areas.
Figure 4: Examples of therapeutically and mechanistically selective synergistic combinations, showing the control (left) and test (center) matrices, and the test isobologram (right).
Figure 5: Selective synergy between glucocorticoids and tricyclic antidepressants (TCA).

Change history

  • 08 July 2009

    In the version of this article initially published, in the legend of Figure 5b, line 2, “stress” is followed by a period. The period should be a comma, so that the sentence reads, “In response to stress, lymphoctyes…” The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors are grateful to many people at CombinatoRx who provided technical materials for this paper. We also thank T. Golub and F. Roth for comments on the manuscript. The simulations were performed using Boston University's computing facilities. Antiviral research was conducted in collaboration with CombinatoRx Singapore, funded by the Singapore Economic Development Board. Anthrax studies were funded through the National Institutes of Health/National Institute of Allergy and Infectious Diseases under grant U01 AI61345. Cardiovascular screens were done in collaboration with Angiotech. Huntington's disease experiments were done in collaboration with and funded by the CHDI Foundation. MM.1R and MM.1S were kindly provided by S. Rosen, Northwestern University.

Author information

J.L. drafted and edited most of this paper, in addition to developing and performing the selectivity analyses. A.A.B. conceived the underlying premise and made major contributions to the abstract, introduction and conclusion. G.R.Z. wrote the in vivo validation sections and oversaw many of the screening projects. M.S.L. and J.E.S. oversaw the remaining screening projects reported. A.S.K. performed the theoretical simulations. W.A. performed and analyzed the preclinical experiments; A.M.H. designed and conducted the cancer 180×180 2005 screen; L.M.J. designed and directed the viral infection, bacterial and anthrax experiments; E.R.P. planned and directed most of the in vitro inflammatory cytokine experiments; R.J.R. planned and conducted two of the cancer screens; G.F.S. designed and oversaw the cardiovascular experiments; and X.J. designed and directed the Huntington's disease screen.

Correspondence to Joseph Lehár or Alexis A Borisy.

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All of the authors are currently, or were previously, employed by CombinatoRx, Inc.

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