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.