title: Pharmacodynamic Modeling of Cell Cycle Effects for Gemcitabine and Trabectedin Combinations in Pancreatic Cancer Cells.
abstract: 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 inSphase, and trabectedin induced transient cell cycle arrest inSphase that progressed toG2/Mphase. Over time, cells in the control group accumulated inG0/G1phase. Systems cell cycle models were developed based on observed mechanisms and were used to characterize both cell proliferation and cell numbers in thesub G1,G0/G1,S, andG2/Mphases 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 inSphase 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.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York Buffalo, NY, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Miao
authors.affiliation: 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.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Koch
authors.affiliation: Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology (Orlando), College of Pharmacy, University of Florida Orlando, FL, USA.
authors.forename: Sihem
authors.initials: S
authors.lastname: Ait-Oudhia
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York Buffalo, NY, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Straubinger
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York Buffalo, NY, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
keywords: cell cycle; drug combination; gemcitabine; pancreatic cancer; pharmacodynamic models; trabectedin