title: Pharmacodynamic modeling of cell cycle and apoptotic effects of gemcitabine on pancreatic adenocarcinoma cells.
abstract: OBJECTIVE
  The standard of care for treating patients with pancreatic adenocarcinomas includes gemcitabine (2',2'-difluorodeoxycytidine). Gemcitabine primarily elicits its response by stalling the DNA replication forks of cells in the S phase of the cell cycle. To provide a quantitative framework for characterizing the cell cycle and apoptotic effects of gemcitabine, we developed a pharmacodynamic model in which the activation of cell cycle checkpoints or cell death is dependent on gemcitabine exposure.
  
  
  METHODS
  Three pancreatic adenocarcinoma cell lines (AsPC-1, BxPC-3, and MiaPaca-2) were exposed to varying concentrations (0-100,000 ng/mL) of gemcitabine over a period of 96 h in order to quantify proliferation kinetics and cell distributions among the cell cycle phases. The model assumes that the drug can inhibit cycle-phase transitioning in each of the 3 phases (G1, S, and G2/M) and can cause apoptosis of cells in G1 and G2/M phases. Fitting was performed using the ADAPT5 program.
  
  
  RESULTS
  The time course of gemcitabine effects was well described by the model, and parameters were estimated with good precision. Model predictions and experimental data show that gemcitabine induces cell cycle arrest in the S phase at low concentrations, whereas higher concentrations induce arrest in all cell cycle phases. Furthermore, apoptotic effects of gemcitabine appear to be minimal and take place at later time points.
  
  
  CONCLUSIONS
  The pharmacodynamic model developed provides a quantitative, mechanistic interpretation of gemcitabine efficacy in 3 pancreatic cancer cell lines, and provides useful insights for rational selection of chemotherapeutic agents for combination therapy.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Salaheldin S
authors.initials: SS
authors.lastname: Hamed
authors.forename: Robert M
authors.initials: RM
authors.lastname: Straubinger
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine