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What is synergy? The Saariselkä agreement revisited.

Tang J, Wennerberg K, Aittokallio T - Front Pharmacol (2015)

Bottom Line: During the last century, there has been an intensive debate on the suitability of these synergy models, both of which are theoretically justified and also in practice supported by different schools of scientists.The agreement was formulated at a conference held in Saariselkä, Finland in 1992, stating that one should use the terms Bliss synergy or Loewe synergy to avoid ambiguity in the underlying models.We review the theoretical relationships between these models and argue that one should combine the advantages of both models to provide a more consistent definition of synergy and antagonism.

View Article: PubMed Central - PubMed

Affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki Helsinki, Finland.

ABSTRACT
Many biological or chemical agents when combined interact with each other and produce a synergistic response that cannot be predicted based on the single agent responses alone. However, depending on the postulated hypothesis of non-interaction, one may end up in different interpretations of synergy. Two popular reference models for hypothesis include the Bliss independence model and the Loewe additivity model, each of which is formulated from different perspectives. During the last century, there has been an intensive debate on the suitability of these synergy models, both of which are theoretically justified and also in practice supported by different schools of scientists. More than 20 years ago, there was a community effort to make a consensus on the terminology one should use when claiming synergy. The agreement was formulated at a conference held in Saariselkä, Finland in 1992, stating that one should use the terms Bliss synergy or Loewe synergy to avoid ambiguity in the underlying models. We review the theoretical relationships between these models and argue that one should combine the advantages of both models to provide a more consistent definition of synergy and antagonism.

No MeSH data available.


Related in: MedlinePlus

The proposed terminology for classifying drug interactions. Using the interaction barometer allows a direct comparison between different drug combinations in terms of their degrees of interaction as well as their combination responses. If the observed drug combination effect yc is lower than the maximum single drug effect max(y1, y2) but higher than the minimum effect min(y1, y2), then the combination is called weak antagonism; if yc < min(y1, y2) it is called strong antagonism. To classify synergy, we consider the Bliss and Loewe models, with the expected effects denoted as yBLISS and yLOEWE, respectively. If max(y1, y2) < yc < min(yBLISS, yLOEWE), then we call the combination as non-interaction; if yHSA < yc < min(yBLISS, yLOEWE) it is called weak synergy, and for yc > max(yBLISS, yLOEWE) strong synergy.
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Figure 1: The proposed terminology for classifying drug interactions. Using the interaction barometer allows a direct comparison between different drug combinations in terms of their degrees of interaction as well as their combination responses. If the observed drug combination effect yc is lower than the maximum single drug effect max(y1, y2) but higher than the minimum effect min(y1, y2), then the combination is called weak antagonism; if yc < min(y1, y2) it is called strong antagonism. To classify synergy, we consider the Bliss and Loewe models, with the expected effects denoted as yBLISS and yLOEWE, respectively. If max(y1, y2) < yc < min(yBLISS, yLOEWE), then we call the combination as non-interaction; if yHSA < yc < min(yBLISS, yLOEWE) it is called weak synergy, and for yc > max(yBLISS, yLOEWE) strong synergy.

Mentions: To ease the model selection burden, we propose here the use of new terminology that incorporates both of the two reference models, together with the single drug responses, to distinguish non-interaction, synergy and antagonism. With simple algebra, one can show that max(y1, y2) ≤ yBLISS. For the Loewe additivity model with a monotonically increasing dose-response relation, one can also show that max(y1, y2) ≤ yLOEWE. We note that, max(y1, y2) is also the expected response from a popular reference model, called highest single agent (HSA) model (Berenbaum, 1989). If the combination response yc is lower than max(y1, y2), then one would intuitively infer antagonism. Therefore, we may use max(y1, y2), to distinguish antagonism from non-interaction. Similarly, one can use the response of the less effective single drug, that is min(y1, y2), to further distinguish between weak and strong antagonisms. For distinguishing synergy from non-interaction the answer is less obvious, as it depends on the comparison between yBLISS and yLOEWE. There has been considerable interest in the mathematical relationships between the Bliss independence and the Loewe additivity models to understand how much difference in the characterization of drug interaction one can expect when choosing one model over another (see e.g., Goldoni and Johansson, 2007). In particular, two authors of the Saariselkä agreement have reported results from such comparisons (Drescher and Boedeker, 1995; Dressler et al., 1999). They showed that yLOEWE > yBLISS is generally observed for very steep dose-response curves, while yLOEWE < yBLISS when the curves become more flat. Since, yBLISS and yLOEWE differ in a complex way depending on the parameterization of the dose-response functions, we propose two cut-offs, min(yBLISS, yLOEWE) and max(yBLISS, yLOEWE), for characterizing synergistic combinations. We reason that the consistency between the Bliss independence and the Loewe additivity models should be indicative of the degree of synergy: If both the Bliss model and the Loewe model classify a drug combination as synergistic, that is, yc > max(yBLISS, yLOEWE), then we call it a strong synergy; If the combination is classified as synergistic according to one model only, that is, min(yBLISS, yLOEWE) < yc < max(yBLISS, yLOEWE), then it is called weak synergy. Finally, non-interacting drugs have max(y1, y2) < yc < min(yBLISS, yLOEWE), reflecting our view that non-interaction should also be defined similarly as a range, rather than a single point as in the individual reference models. Given such a classification, one may continue to develop statistical testing methods for evaluation of its significance for replicate data. To facilitate better understanding of these definitions, we designed an interaction barometer that enables a systematic comparison of these proposed interaction terms along an axis of drug combination response yc (Figure 1).


What is synergy? The Saariselkä agreement revisited.

Tang J, Wennerberg K, Aittokallio T - Front Pharmacol (2015)

The proposed terminology for classifying drug interactions. Using the interaction barometer allows a direct comparison between different drug combinations in terms of their degrees of interaction as well as their combination responses. If the observed drug combination effect yc is lower than the maximum single drug effect max(y1, y2) but higher than the minimum effect min(y1, y2), then the combination is called weak antagonism; if yc < min(y1, y2) it is called strong antagonism. To classify synergy, we consider the Bliss and Loewe models, with the expected effects denoted as yBLISS and yLOEWE, respectively. If max(y1, y2) < yc < min(yBLISS, yLOEWE), then we call the combination as non-interaction; if yHSA < yc < min(yBLISS, yLOEWE) it is called weak synergy, and for yc > max(yBLISS, yLOEWE) strong synergy.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555011&req=5

Figure 1: The proposed terminology for classifying drug interactions. Using the interaction barometer allows a direct comparison between different drug combinations in terms of their degrees of interaction as well as their combination responses. If the observed drug combination effect yc is lower than the maximum single drug effect max(y1, y2) but higher than the minimum effect min(y1, y2), then the combination is called weak antagonism; if yc < min(y1, y2) it is called strong antagonism. To classify synergy, we consider the Bliss and Loewe models, with the expected effects denoted as yBLISS and yLOEWE, respectively. If max(y1, y2) < yc < min(yBLISS, yLOEWE), then we call the combination as non-interaction; if yHSA < yc < min(yBLISS, yLOEWE) it is called weak synergy, and for yc > max(yBLISS, yLOEWE) strong synergy.
Mentions: To ease the model selection burden, we propose here the use of new terminology that incorporates both of the two reference models, together with the single drug responses, to distinguish non-interaction, synergy and antagonism. With simple algebra, one can show that max(y1, y2) ≤ yBLISS. For the Loewe additivity model with a monotonically increasing dose-response relation, one can also show that max(y1, y2) ≤ yLOEWE. We note that, max(y1, y2) is also the expected response from a popular reference model, called highest single agent (HSA) model (Berenbaum, 1989). If the combination response yc is lower than max(y1, y2), then one would intuitively infer antagonism. Therefore, we may use max(y1, y2), to distinguish antagonism from non-interaction. Similarly, one can use the response of the less effective single drug, that is min(y1, y2), to further distinguish between weak and strong antagonisms. For distinguishing synergy from non-interaction the answer is less obvious, as it depends on the comparison between yBLISS and yLOEWE. There has been considerable interest in the mathematical relationships between the Bliss independence and the Loewe additivity models to understand how much difference in the characterization of drug interaction one can expect when choosing one model over another (see e.g., Goldoni and Johansson, 2007). In particular, two authors of the Saariselkä agreement have reported results from such comparisons (Drescher and Boedeker, 1995; Dressler et al., 1999). They showed that yLOEWE > yBLISS is generally observed for very steep dose-response curves, while yLOEWE < yBLISS when the curves become more flat. Since, yBLISS and yLOEWE differ in a complex way depending on the parameterization of the dose-response functions, we propose two cut-offs, min(yBLISS, yLOEWE) and max(yBLISS, yLOEWE), for characterizing synergistic combinations. We reason that the consistency between the Bliss independence and the Loewe additivity models should be indicative of the degree of synergy: If both the Bliss model and the Loewe model classify a drug combination as synergistic, that is, yc > max(yBLISS, yLOEWE), then we call it a strong synergy; If the combination is classified as synergistic according to one model only, that is, min(yBLISS, yLOEWE) < yc < max(yBLISS, yLOEWE), then it is called weak synergy. Finally, non-interacting drugs have max(y1, y2) < yc < min(yBLISS, yLOEWE), reflecting our view that non-interaction should also be defined similarly as a range, rather than a single point as in the individual reference models. Given such a classification, one may continue to develop statistical testing methods for evaluation of its significance for replicate data. To facilitate better understanding of these definitions, we designed an interaction barometer that enables a systematic comparison of these proposed interaction terms along an axis of drug combination response yc (Figure 1).

Bottom Line: During the last century, there has been an intensive debate on the suitability of these synergy models, both of which are theoretically justified and also in practice supported by different schools of scientists.The agreement was formulated at a conference held in Saariselkä, Finland in 1992, stating that one should use the terms Bliss synergy or Loewe synergy to avoid ambiguity in the underlying models.We review the theoretical relationships between these models and argue that one should combine the advantages of both models to provide a more consistent definition of synergy and antagonism.

View Article: PubMed Central - PubMed

Affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki Helsinki, Finland.

ABSTRACT
Many biological or chemical agents when combined interact with each other and produce a synergistic response that cannot be predicted based on the single agent responses alone. However, depending on the postulated hypothesis of non-interaction, one may end up in different interpretations of synergy. Two popular reference models for hypothesis include the Bliss independence model and the Loewe additivity model, each of which is formulated from different perspectives. During the last century, there has been an intensive debate on the suitability of these synergy models, both of which are theoretically justified and also in practice supported by different schools of scientists. More than 20 years ago, there was a community effort to make a consensus on the terminology one should use when claiming synergy. The agreement was formulated at a conference held in Saariselkä, Finland in 1992, stating that one should use the terms Bliss synergy or Loewe synergy to avoid ambiguity in the underlying models. We review the theoretical relationships between these models and argue that one should combine the advantages of both models to provide a more consistent definition of synergy and antagonism.

No MeSH data available.


Related in: MedlinePlus