A pragmatic definition of therapeutic synergy suitable for clinically relevant in vitro multicompound analyses

Molecular Cancer Therapeutics
Muhammad KashifMats G Gustafsson

Abstract

For decades, the standard procedure when screening for candidate anticancer drug combinations has been to search for synergy, defined as any positive deviation from trivial cases like when the drugs are regarded as diluted versions of each other (Loewe additivity), independent actions (Bliss independence), or no interaction terms in a response surface model (no interaction). Here, we show that this kind of conventional synergy analysis may be completely misleading when the goal is to detect if there is a promising in vitro therapeutic window. Motivated by this result, and the fact that a drug combination offering a promising therapeutic window seldom is interesting if one of its constituent drugs can provide the same window alone, the largely overlooked concept of therapeutic synergy (TS) is reintroduced. In vitro TS is said to occur when the largest therapeutic window obtained by the best drug combination cannot be achieved by any single drug within the concentration range studied. Using this definition of TS, we introduce a procedure that enables its use in modern massively parallel experiments supported by a statistical omnibus test for TS designed to avoid the multiple testing problem. Finally, we suggest how one may perfor...Continue Reading

References

Apr 1, 1988·The Journal of Antimicrobial Chemotherapy·M C Berenbaum
Jun 5, 1996·Journal of the National Cancer Institute·W R GrecoL Levasseur
Oct 23, 1997·Statistics in Medicine·E M LaskaD I Tang
Jun 12, 2003·Proceedings of the National Academy of Sciences of the United States of America·Alexis A BorisyCurtis T Keith
Jul 11, 2003·Statistics in Medicine·Margaret ShihWalter H Carter
Feb 3, 2005·Nature Reviews. Drug Discovery·Curtis T KeithBrent R Stockwell
Mar 31, 2006·Anesthesiology·Eleonora ZanderigoMichele Curatolo
Aug 3, 2006·Nature Reviews. Drug Discovery·Janet E Dancey, Helen X Chen
Aug 22, 2006·Nature Chemical Biology·Jonathan B FitzgeraldPeter K Sorger
Jan 3, 2007·Drug Discovery Today·Grant R ZimmermannCurtis T Keith
Mar 3, 2007·Molecular Systems Biology·Joseph LehárCurtis T Keith
Aug 21, 2008·Nature Protocols·Elin LindhagenRolf Larsson

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Citations

Jun 14, 2015·Expert Review of Anti-infective Therapy·Kaat De CremerKatrijn De Brucker
Sep 22, 2015·Frontiers in Pharmacology·Jing TangTero Aittokallio

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