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Front Pharmacol. 2016 Nov 15;7:421. eCollection 2016.

Pharmacodynamic Modeling of Cell Cycle Effects for Gemcitabine and Trabectedin Combinations in Pancreatic Cancer Cells.

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Department of Pharmaceutical Sciences, University at Buffalo, State University of New York Buffalo, NY, USA.
Department of Pharmaceutical Sciences, University at Buffalo, State University of New YorkBuffalo, NY, USA; Pediatric Pharmacology and Pharmacometrics, University of Basel, Children's HospitalBasel, Switzerland.
Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology (Orlando), College of Pharmacy, University of Florida Orlando, FL, USA.


Combinations of gemcitabine and trabectedin exert modest synergistic cytotoxic effects on two pancreatic cancer cell lines. Here, systems pharmacodynamic (PD) models that integrate cellular response data and extend a prototype model framework were developed to characterize dynamic changes in cell cycle phases of cancer cell subpopulations in response to gemcitabine and trabectedin as single agents and in combination. Extensive experimental data were obtained for two pancreatic cancer cell lines (MiaPaCa-2 and BxPC-3), including cell proliferation rates over 0-120 h of drug exposure, and the fraction of cells in different cell cycle phases or apoptosis. Cell cycle analysis demonstrated that gemcitabine induced cell cycle arrest in S phase, and trabectedin induced transient cell cycle arrest in S phase that progressed to G2/M phase. Over time, cells in the control group accumulated in G0/G1 phase. Systems cell cycle models were developed based on observed mechanisms and were used to characterize both cell proliferation and cell numbers in the sub G1, G0/G1, S, and G2/M phases in the control and drug-treated groups. The proposed mathematical models captured well both single and joint effects of gemcitabine and trabectedin. Interaction parameters were applied to quantify unexplainable drug-drug interaction effects on cell cycle arrest in S phase and in inducing apoptosis. The developed models were able to identify and quantify the different underlying interactions between gemcitabine and trabectedin, and captured well our large datasets in the dimensions of time, drug concentrations, and cellular subpopulations.


cell cycle; drug combination; gemcitabine; pancreatic cancer; pharmacodynamic models; trabectedin

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