Figure 5.

Transient gemcitabine‐induced cell cycle arrest and sequential drug exposure effects. Gemcitabine induced transient cell cycle arrest that was alleviated by delayed initiation of DNA repair. Panels show percentage of cells in S‐phase after incubation with 20 nM gemcitabine for different durations (24, 48, 72, and 96 hours) (a) measured by cell cycle analysis, or (b) predicted by the network model, and cell cycle arrest in S‐phase became insensitive to continuing gemcitabine exposure with ≥24 hours of treatment. Model‐based simulation of cell proliferation and cell cycle arrest with exposure to 20 nM gemcitabine and 200 nM birinapant initiated either simultaneously (solid/black) or sequentially (birinapant initiated 30 hours after gemcitabine; dashed/blue). (c) Sustained suppression of cell proliferation by sequenced exposure, and (d) percentage of cells in S phase with simultaneous vs. sequenced drug exposure. Model prediction recapitulated experimental data showing greater efficacy of gemcitabine/birinapant treatment with sequenced drug exposure.8