In Silico Oncology: Quantification of the In Vivo Antitumor Efficacy of Cisplatin-Based Doublet Therapy in Non-Small Cell Lung Cancer (NSCLC) through a Multiscale Mechanistic Model
Fig 3
Results of the One-Factor-At-a-Time (OFAT) studies.
The effect of model input parameters on the estimation of sum of cisplatin and gemcitabine cell kill rates is studied by varying one input parameter at a time, while keeping the others at a baseline value. Two sets of baseline values have been considered (Table 5), corresponding to a SCC and an ADC representative case. The model parameters investigated are: (A) duration of cell cycle of stem cells, (B) duration of cell cycle of LIMP cells, (C) duration of cell cycle, when considered equal for both stem and LIMP cells, (D) residence time of stem cells in G0 phase, (E) residence time of LIMP cells in G0 phase, (F) residence time of cells in a G0 phase, when considered equal for both stem and LIMP cells, (G) fraction of stem cells that undergo symmetric division, (H) fraction of newborn cells that enter a quiescent state following mitosis, (I) fraction of stem cells that re-enter cell cycle from a quiescent state, fraction of LIMP cells that re-enter cell cycle from a quiescent state, fraction of cells that re-enter cell cycle from a quiescent state, the latter considered equal for both stem and LIMP cells, (J) number of mitoses performed by LIMP cells before becoming terminally differentiated, (K) number of stem and LIMP cells that enter the apoptotic pathway per hour, (L) number of DIFF cells that enter the necrotic pathway per hour, (M) number of DIFF cells that enter the apoptotic pathway per hour, (N) time between the onset of apoptosis and the removal of the apoptotic bodies, (O) time between the onset of necrosis and the removal of its products, (P) resistance of stem cells to chemotherapy, expressed as the ratio of the stem cell kill rate to the estimated drug cell kill rate and (R) assumed cell kill rate of gemcitabine. In (Q) the effect of the assumed cell kill rate of gemcitabine on the estimation of cisplatin’s cell kill rate is depicted. Abbreviations: ADC: Adenocarcinoma, SCC: Squamous cell carcinoma, cis-DDP: cisplatin, dFdC: gemcitabine, LIMP: LImited Mitotic Potential tumor cell (also called committed or restricted progenitor cell), DIFF: terminally DIFFerentiated tumor cell. G0: dormant, resting phase.