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Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells

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Abstract

Combination chemotherapy is standard treatment for pancreatic cancer. However, current drugs lack efficacy for most patients, and selection and evaluation of new combination regimens is empirical and time-consuming. The efficacy of gemcitabine, a standard-of-care agent, combined with birinapant, a pro-apoptotic antagonist of Inhibitor of Apoptosis Proteins (IAPs), was investigated in pancreatic cancer cells. PANC-1 cells were treated with vehicle, gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and combinations of the two drugs. Temporal changes in cell numbers, cell cycle distribution, and apoptosis were measured. A basic pharmacodynamic (PD) model based on cell numbers, and a mechanism-based PD model integrating all measurements, were developed. The basic PD model indicated that synergistic effects occurred in both cell proliferation and death processes. The mechanism-based model captured key features of drug action: temporary cell cycle arrest in S phase induced by gemcitabine alone, apoptosis induced by birinapant alone, and prolonged cell cycle arrest and enhanced apoptosis induced by the combination. A drug interaction term Ψ was employed in the models to signify interactions of the combination when data were limited. When more experimental information was utilized, Ψ values approaching 1 indicated that specific mechanisms of interactions were captured better. PD modeling identified the potential benefit of combining gemcitabine and birinapant, and characterized the key interaction pathways. An optimal treatment schedule of pretreatment with gemcitabine for 24–48 h was suggested based on model predictions and was verified experimentally. This approach provides a generalizable modeling platform for exploring combinations of cytostatic and cytotoxic agents in cancer cell culture studies.

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Acknowledgments

We thank Nancy Pyszczynski for excellent technical assistance and the Department of Flow Cytometry at Roswell Park Cancer Institute for technical consulting. We also thank Gilbert Koch for his suggestions in model development and manuscript revision. We are grateful to TetraLogic Pharmaceuticals Inc. for providing birinapant. This work was supported by Grants GM57980 and GM24211 from the National Institutes of Health.

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  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA

    Xu Zhu, Robert M. Straubinger & William J. Jusko

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Correspondence to William J. Jusko.

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Zhu, X., Straubinger, R.M. & Jusko, W.J. Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells. J Pharmacokinet Pharmacodyn 42, 477–496 (2015). https://doi.org/10.1007/s10928-015-9429-x

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