We have located links that may give you full text access.
Combination Therapy and the Evolution of Resistance: The Theoretical Merits of Synergism and Antagonism in Cancer.
Cancer Research 2018 May 2
The search for effective combination therapies for cancer has focused heavily on synergistic combinations because they exhibit enhanced therapeutic efficacy at lower doses. Although synergism is intuitively attractive, therapeutic success often depends on whether drug resistance develops. The impact of synergistic combinations (vs. antagonistic or additive combinations) on the process of drug-resistance evolution has not been investigated. In this study, we use a simplified computational model of cancer cell numbers in a population of drug-sensitive, singly-resistant, and fully-resistant cells to simulate the dynamics of resistance evolution in the presence of two-drug combinations. When we compared combination therapies administered at the same combination of effective doses, simulations showed synergistic combinations most effective at delaying onset of resistance. Paradoxically, when the therapies were compared using dose combinations with equal initial efficacy, antagonistic combinations were most successful at suppressing expansion of resistant subclones. These findings suggest that, although synergistic combinations could suppress resistance through early decimation of cell numbers (making them "proefficacy" strategies), they are inherently fragile toward the development of single resistance. In contrast, antagonistic combinations suppressed the clonal expansion of singly-resistant cells, making them "antiresistance" strategies. The distinction between synergism and antagonism was intrinsically connected to the distinction between offensive and defensive strategies, where offensive strategies inflicted early casualties and defensive strategies established protection against anticipated future threats. Our findings question the exclusive focus on synergistic combinations and motivate further consideration of nonsynergistic combinations for cancer therapy. Significance: Computational simulations show that if different combination therapies have similar initial efficacy in cancers, then nonsynergistic drug combinations are more likely than synergistic drug combinations to provide a long-term defense against the evolution of therapeutic resistance. Cancer Res; 78(9); 2419-31. ©2018 AACR .
Full text links
Related Resources
Trending Papers
Heart failure with preserved ejection fraction: diagnosis, risk assessment, and treatment.Clinical Research in Cardiology : Official Journal of the German Cardiac Society 2024 April 12
Proximal versus distal diuretics in congestive heart failure.Nephrology, Dialysis, Transplantation 2024 Februrary 30
Efficacy and safety of pharmacotherapy in chronic insomnia: A review of clinical guidelines and case reports.Mental Health Clinician 2023 October
World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management.American Journal of Hematology 2024 March 30
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.
By using this service, you agree to our terms of use and privacy policy.
Your Privacy Choices
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app