Fig 1.
Schematic representation of PK, cellular and tumor growth inhibition (TGI) model.
(A) PK model; (B) Cellular and TGI model. A1:amount of 5-FU in central plasma; A2: amount of 5-FU in peripheral compartment; Cp(t): 5-FU concentration in central plasma. A3: amount of 5-FU in interstitial fluid; A4: amount of 5-FU in the intra-cellular domain; A5: amount of 5-FU anabolites; A6: incorporation of FUTP into RNA; A7: incorporation of FdUTP into DNA; A8: amount of dUMP;A9: amount of TS-FdUMP complex; TSf: amount of free TS; TStotal: amount of total TS; Nucp: extent of dNTP pool imbalance; NDSB: count of 5-FU induced DSBs; NDSB,deviation: deviation of 5-FU induced DSBs from baseline; P: amount of proliferating cells; D: amount of damaged cells. V: volumes of compartments; : Michaelis–Menten parameters; Q: clearance between neighboring compartments; k: rate constant; T: delaying parameters; G0: production rate of dUMP;; λd: death rate of tumor cells without 5-FU; fHRR: rate of repair of DSBs by HRR. EDSB: measure of contribution of DSBs in producing damaged cells.
Table 1.
Parameter estimates for PK and cellular model.
Fig 2.
Model simulation of 5-FU concentration in central and peripheral compartment.
Blue solid circle represents literature data; red solid curve, time profile of 5-FU in central plasma; yellow dash-dotted curve, the time profile of 5-FU in peripheral compartment. black dashed line: 0.7 credible regions of model simulation of central compartment; black dotted line: 0.7 credible regions of model simulation of peripheral compartment.
Table 2.
Literature data for the model variables.
Fig 3.
Time profiles of intermediate components in cellular model.
(A) 5-FU in interstitial fluid, (B) intra-cellular 5-FU, (C) 5-FU anabolites, (D) F-RNA, (E) F-DNA, (F) % Free TS, (G) dUMP, (H) dNTP pool imbalance, (I) double-strand break generation. Red curve, model simulation; solid blue circle, literature data points; and error bar represents standard errors. The shaded areas represent the 0.7 credible regions.
Fig 4.
Time-dependent outputs of the 9 TGI model using parameter estimates shown in Table 4.
Red line represents the time course of the control group; blue line represents the time course of colon tumor growth treated with corresponding dosage regimens shown in Table 3; triangle, literature data for the control group; circle, literature data for the treated group; error bar, standard errors; asterisk on x-axis represents injection time. The shaded areas in each panel represent the 0.7 credible intervals.
Table 3.
The nine different dosage regimens that are evaluated in our study.
Table 4.
Parameter estimates for the nine TGI models.
Table 5.
AUC and AUCe for 9 TGI models.
Table 6.
The range of variation for each parameter and their corresponding biological implication.
Table 7.
Values and fold change from the baseline of the 11 parameters considered in resistance analysis producing the simulations closest to the time course of resistant LS174T xenograft tumor.
Fig 5.
The simulation result of resistance analysis.
The first column is the time profiles of tumor volume; second column, 5-FU anabolites, third column: 5-FU induced DSB. Each row represents each aforementioned scenario. Red dash-dotted line, model simulation of resistant LS174T xenograft tumor; blue solid line: model simulation of sensitive LS174T xenograft tumor; yellow dashed line, the mean time course of 500 computed time courses; Θclosest denotes the parameter set associated with the time course of tumor volume closest to the tumor resistance response; purple dotted line: the time course generated by Θclosest.
Fig 6.
The simulation results associated with the four novel dosage regimens.
The regimens under consideration are (A) 100 mg/kg on day 1 of weeks 1 to 6 of a eight-week cycle, for a total of 4 cycles; (B) 50 mg/kg twice a week of weeks 1 to 6 of a eight-week cycle, for a total of 4 cycles; (C) 100 mg/kg on day 1 of weeks 1 to 3 followed by 50 mg/kg twice a week of weeks 4 to 6, for a total of 4 cycles (32 weeks); (D) 50 mg/kg twice a week of weeks 1 to 3 followed by 100 mg/kg on day 1 of weeks 4 to 6, for a total of 4 cycles (32 weeks). Red dash line: model simulation of control; blue solid line: simulation results associated with the four dosage regimens; purple diamond-shaped dot: time of injection of 100 mg/kg 5FU; green round dot: time of injection of 50 mg/kg 5FU.