Figure 1.
Pictorial view of the p53-Mdm2-PTEN interactions in the presence of Nutlin.
Black solid arrows: chemical reactions; red solid arrows: chemical reactions involving Nutlin; green dashed arrows: induction of activities; blue solid arrows: translocations. P, phosphate group; u, ubiquitin; n, Nutlin; the symbol denotes degradation.
Figure 2.
Percentage of cells viable after exposure to different Nutlin concentrations.
Symbols: experimental data from Vassilev et al. [6]. Solid and dotted lines: models predictions. In the simulation, cell viability was evaluated 48 h after the start of exposure. The response of 500 cells was simulated for each Nutlin concentration.
Figure 3.
Time-courses of the phosphorylated nuclear p53 (green) and nuclear Mdm2 (red) in response to two different Nutlin extra-cellular concentrations in RKO and SJSA-1 cells.
Solid lines represent medians, and dotted lines first and third quartiles. The Nutlin exposure begins at . Left column: PTEN feedback loop is active; right column: PTEN feedback loop is inactive.
Figure 4.
Time-courses of the total (green) and free (red) intracellular Nutlin in response to two different Nutlin extra-cellular concentrations in RKO (left column) and SJSA-1 (right column) cells.
Extra-cellular concentrations: panels A and C, M; panels B and D,
M. Solid lines represent medians, and dotted lines first and third quartiles. The PTEN feedback loop is active.
Figure 5.
Nutlin pharmacokinetics: Data from Zhang et al. [58] (total Nutlin concentration in mouse retina after oral delivery, black dots), and fittings by the model (8).
Doses: panel A, 100 mg/Kg; panel B, 200 mg/Kg.
Figure 6.
Prediction of the percentage of cell viability after oral dosage in mice.
Filled symbols correspond to single dose delivery (in all panels), open symbols to the case in which the total dose was split into four equal doses given with 24 h breaks (panel A), 12 h breaks (panel B), and 6 h breaks (panel C). Cell viability was assessed 120 h after the first dose.
Figure 7.
Single-dose vs. split delivery of a total dose of 50 mg/kg of Nutlin: Effects on the RKO cell line.
Left panels: dynamics of Nutlin. Extra-cellular free concentration (blue, on the log scale), total intra-cellular amount (green), free intra-cellular amount (red). Right panels: time-course of p53 (green) and Mdm2 (red). Upper panels: single dose. Central panels: the dose is split in four doses delivered with an interval of 24 hours in between. Lower panels: again the dose is split in four doses, but here the time between two doses is 6 hours. Solid lines represent medians, and dotted lines first and third quartiles.
Figure 8.
Single-dose vs. split delivery of a total dose of 400 mg/kg of Nutlin: Effects on the RKO cell line.
Left panels: dynamics of Nutlin. Extra-cellular free concentration (blue, on the log scale), total intra-cellular amount (green), free intra-cellular amount (red). Right panels: time-course of p53 (green) and Mdm2 (red). Upper panels: single dose. Central panels: the dose is split in four doses delivered with an interval of 24 hours in between. Lower panels: again the dose is split in four doses, but here the time between two doses is 6 hours. Solid lines represent medians, and dotted lines first and third quartiles.