Why did Merck Develop a Screening Paradigm for Combination Therapies?

Sometimes two drugs are better than one. Combinations of therapies can be more effective than just one in isolation, thus a lower doses of each can be administered. The authors cite and test in this paper antiinfectives and cancer chemotherapeutics as models amenable to combination therapy.

How are combination therapies currently discovered?

The hypothesis-driven approach to combination therapies might utilize drugs that have a similar target. But this approach does not uncover unexpected interactions and sometimes cannot be empirically confirmed. An unbiased combinatorial screen where thousand drugs are screened pairwise is exhaustive, where 1000 compounds results in about a half million different combinations that must be tested. Merck came up with a more efficient method.

How did Merck develop a screening for synergistic drugs?

The authors took 11 compounds that they were aware had synergistic effects and probed them using an eight-point dose-response assay on a colorectal cancer cell line (HCT116). They made assumptions based on the frequency of interactions, dosing, and false negative rates. The 11 compounds were then tested with 89 background compounds (100 total) to see if they could be deconvulted. They screened the drugs using a 1536-well platform to test the compounds and then processed the interactions using Bliss independence criterion for selection. Bliss independence criterion and Loewe additivity models are used in co-exposure experiments to measure additivity, synergism, and antagonism in toxicology. They looked for a specific threshold of synergy and claimed to be successful.

How did the authors expand the testing of synergistic drug interactions?

To further their experiment, greater than 1000 compounds were tested against a THP-1 monocytic cell line were exposed to lipopolysaccharide-interferon γ. Compounds that synergistically inhibit the acute phase response were tested by IL-6 secretion assay. They note that there was no need for robotics with 22×1536-well plates. Drugs needed to be synergistic at more than one dose.

How is pooled synergistic drug affects more broadly applicable?

This could be a tool for chemical genomics. Single compound studies are limiting in scope, thus this method could open up the study of far more and complex interactions.

Article based on:

Severyn, Bryan, et al. “Parsimonious discovery of synergistic drug combinations.” ACS chemical biology 6.12 (2011): 1391-1398.


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