title: Pharmacodynamic modeling of combined chemotherapeutic effects predicts synergistic activity of gemcitabine and trabectedin in pancreatic cancer cells.
abstract: OBJECTIVE
  This study investigates the combined effects of gemcitabine and trabectedin (ecteinascidin 743) in two pancreatic cancer cell lines and proposes a pharmacodynamic (PD) model to quantify their pharmacological interactions.
  
  
  METHODS
  Effects of gemcitabine and trabectedin upon the pancreatic cancer cell lines MiaPaCa-2 and BxPC-3 were investigated using cell proliferation assays. Cells were exposed to a range of concentrations of the two drugs, alone and in combination. Viable cell numbers were obtained daily over 5 days. A model incorporating nonlinear cytotoxicity, transit compartments, and an interaction parameter ψ was used to quantify the effects of the individual drugs and combinations.
  
  
  RESULTS
  Simultaneous fitting of temporal cell growth profiles for all drug concentrations provided reasonable cytotoxicity parameter estimates (the cell killing rate constant K max and the sensitivity constant KC50) for each drug. The interaction parameter ψ was estimated as 0.806 for MiaPaCa-2 and 0.843 for BxPC-3 cells, suggesting that the two drugs exert modestly synergistic effects.
  
  
  CONCLUSIONS
  The proposed PD model enables quantification of the temporal profiles of drug combinations over a range of concentrations with drug-specific parameters. Based upon these in vitro studies, trabectedin may have augmented benefit in combination with gemcitabine. The PD model may have general relevance for the study of other cytotoxic drug combinations.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Miao
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Koch
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Straubinger
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA. wjjusko@buffalo.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004149:Dioxoles / Q000008:administration & dosage; D004357:Drug Synergism; D006801:Humans; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage; D000077606:Trabectedin; D000093542:Gemcitabine
chemical_list: D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D003841:Deoxycytidine; D000077606:Trabectedin; D000093542:Gemcitabine
keywords: Chemotherapeutic effect; Drug interaction; Gemcitabine; Pancreatic cancer; Pharmacodynamic modeling; Trabectedin