A formal model for analyzing drug combination effects and its application in TNF-α-induced NFκB pathway

Abstract

BackgroundDrug combination therapy is commonly used in clinical practice. Many methods including Bliss independence method have been proposed for drug combination design based on simulations models or experiments. Although Bliss independence method can help to solve the drug combination design problem when there are only a small number of combinations, as the number of combinations increases, it may not be scalable. Exploration of system structure becomes important to reduce the complexity of the design problem.ResultsIn this paper, we deduced a mathematical model which can simplify the serial structure and parallel structure of biological pathway for synergy evaluation of drug combinations. We demonstrated in steady state the sign of the synergism assessment factor derivative of the original system can be predicted by the sign of its simplified system. In addition, we analyzed the influence of feedback structure on survival ratio of the serial structure. We provided a sufficient condition under which the combination effect could be maintained. Furthermore, we applied our method to find three synergistic drug combinations on tumor necrosis factor α-induced NFκB pathway and subsequently verified by the cell experiment.ConclusionsWe identified several structural properties underlying the Bliss independence criterion, and developed a systematic simplification framework for drug combiation desgin by combining simulation and system reaction network topology analysis. We hope that this work can provide insights to tackle the challenging problem of assessment of combinational drug therapy effect in a large scale signaling pathway. And hopefully in the future our method could be expanded to more general criteria.

Synergy of Silver Nanoparticles and Aztreonam against Pseudomonas aeruginosa PAO1 Biofilms

“…Once again, 10-nm and 20-nm AgNPs demonstrated more-significant reductions in biofilm recovery when combined with lower concentrations of aztreonam than did 40-nm and 60-nm nanoparticles. Next, we used the Bliss independence model (22,37,54) and FIC index (24,39,40) to calculate synergy between AgNPs and aztreonam in the inhibition of P. aeruginosa biofilm biomass ( Fig. 6 and Table 3), and we confirmed that 10 nm was the optimal AgNP size to use in the antimicrobial combination.…”

Targeting of β1 integrins impairs DNA repair for radiosensitization of head and neck cancer cells

“…Synergism and additivity were calculated as recently published using the following formula: S = r(a, b) -r(a0, b) × r(a, b0). 45,46 Foci assay For γH2AX/53BP1 and pDNA-PKcs T2609 foci assay 4 × 10 5 cells per well were grown in 3D lrECM for 24 h, then treated with antibodies (AIIB2 or IgG#1: 10 μg/ml) and inhibitor (Olaparib or DMSO: 1 μM; 24 h) and irradiated with 6 Gy or left unirradiated. Twenty-four hours after irradiation, cells were isolated using trypsin/EDTA, fixed with 3% formaldehyde/ phosphate-buffered saline (Merck, Darmstadt, Germany) and permeabilized with 0.25% Triton-X-100/phosphate-buffered saline (Roth, Karlsruhe, Germany).…”

Understanding synergy

“…A number of other supra-additive synergy models have been advanced (30,32,42,74,76,92,148,150,174). I briefly review four, the first three of which are closely related to Loewe additivity.…”

“…Bliss additivity is often used in the analysis of synergy in antimicrobiology, toxicology, radiation medicine, and other fields (20,39,60,64,123,124,152,174,177). According to Yeh et al (176), an advantage of Bliss additivity is that it is exactly analogous to the definition of epistasis used in molecular biology.…”