FIGURE 2 

Combination response shape models that describe many of the observed response morphologies. Each model (shown using the same colour scale as Figures 1 and 3) is used to calculate an expected combination effect I_model at any concentration X,Y, based on the single agent response curves. (A) HSA is a superposition of the X and Y single agent responses, calculated from the inhibitions I_X at X and I_Y at Y. (B) Loewe additivity (Loewe, 1928) is the drug-with-itself reference for synergy, where I_Loewe at X,Y yields additive doses relative to the components' effective concentrations X_I,Y_I at I_Loewe. (C) Bliss boosting describes combinations with a variable boost above E_max (the greater of the single agent limiting efficacies E_X,E_Y), at high combined concentrations. Useful reference levels for Bliss boosting are 'cancelling', 'suppressing', 'masking', 'multiplicative' corresponding to Bliss independence (Bliss, 1939), and 'saturating' (see Materials and methods). Finally, (D) potentiation can characterize responses similar to those of Bactrim^® (Figure 1), where one single agent's curve I_X(C) is shifted with a power-law slope p above an enhancer concentration Y_pot, and superposed on the enhancer's own activity. These models can be extended to higher-order combinations, and used in the same form (with adjustments to Bliss boosting) for any type of measurement, provided that the activities of both agents vary monotonically with concentration. Of these models, only Loewe additivity has an a priori mechanistic basis.