Abstract
The idea of synergistic interactions between drugs and chemicals has been an important issue in the biomedical world for over a century. As complex diseases, especially cancer, are being treated with various drug cocktails, understanding the interactions among these drugs is increasingly vital to ensuring successful treatment regimens. However, the idea of synergy is not limited to only the biomedical realm and these ideas have developed across many different disciplines, as well. In this review, we first discuss the various terminology surrounding the idea of synergy, providing a comprehensive list of terms defined across numerous disciplines. We then review the most common methodology for detection and quantification of synergy, including the two most prominent reference models for describing additive interactions: Loewe Additivity and Bliss Independence. We also discuss advantages and limitations to each method, with a focus on the Chou-Talalay Combination Index method. Finally, we describe how methods development and terminology have developed among disciplines outside of biomedicine and pharmacology, to synthesize the literature for readers.
Highlights
The idea that 1 + 1 = 2 is not novel and virtually agreed upon and understood throughout various academic disciplines and even different cultures around the world
The general equation for this model is given in Equation (1), where E is the predicted response of the agent on the system, E0 is the baseline response for a drug concentration of 0, Emax is the maximum response, C is the concentration used for the predicted response E, and EC50 is the concentration for which 50 percent of the maximal response is obtained, and h is the hill coefficient of sigmoidicity, referred to as the slope parameter, which affects the shape of the curve (Goutelle et al, 2008)
Greco shows that the form of one of the equations, for a specific set of parameters, used to calculate the combination index for the mutually nonexclusive case is slightly incorrect. He mentions that when the median effects plot for the mutually exclusive with interaction case is nonlinear, incorrect conclusions can occur which was shown by Greco as the combination index for part of his data set incorrectly resulting in antagonism instead of synergy due to “incorrect linear extrapolation of the nonlinear median effects curve for the drug combination” (Greco et al, 1995)
Summary
Loewe Additivity requires that the dose response curves be accurately estimated individually for each drug in the combination (Foucquier and Guedj, 2015). This is often not a trivial task. According to Geary, this situation occurs frequently (Geary, 2013) and can be illustrated more in-depth by him as well as Tallarida (Tallarida, 2006, 2007; Geary, 2013) Despite these limitations, Loewe Additivity has still been one of the major reference models used and the foundation for many synergy methods. Many consider the “sham mixture” scenario to be fairly intuitive, so failure to adhere to this could pose a problem when advocating for use of this method
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