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MODEL1604270001 - Zhu2015 - combined gemcitabine and birinapant in pancreatic cancer cells - mechanistic PD model


The following model is part of the non-curated branch of BioModels Database. While the syntax of the model has been verified, its semantics remains unchecked. Any annotation present in the models is not a product of BioModels' annotators. We are doing our best to incorporate this model into the curated branch as soon as possible. In the meantime, we display only limited metadata here. For further information about the model, please download the SBML file.

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Reference Publication
Publication ID: 26252969
Zhu X, Straubinger RM, Jusko WJ.
Mechanism-based mathematical modeling of combined gemcitabine and birinapant in pancreatic cancer cells.
J Pharmacokinet Pharmacodyn 2015 Oct; 42(5): 477-496
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.  [more]
Original Model: MODEL1604270001.origin
Submitter: Vijayalakshmi Chelliah
Submission Date: 27 Apr 2016 14:54:18 UTC
Last Modification Date: 27 Apr 2016 17:37:54 UTC
Creation Date: 27 Apr 2016 17:37:54 UTC
Zhu2015 - combined gemcitabine and birinapant in pancreatic cancer cells - mechanistic PD model

This is a non-SBML model

This model is not available in SBML yet (the SBML file that is provided here is a dummy SBML model). However, the original ADAPT model code, obtained from the supplementary material of the article can be downloaded from the link below: The integrated mechanism-based pharmacodynamic (PD) model [Zhu2015_mechanistic_ADAPT5.txt].

This model is described in the article:

Zhu X, Straubinger RM, Jusko WJ.
J Pharmacokinet Pharmacodyn. 2015 Oct;42(5):477-96.


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.

This model is hosted on BioModels Database and identified by: MODEL1604270001.

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