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The pharmacodynamics of the p53-Mdm2 targeting drug Nutlin: the role of gene-switching noise.

Puszynski K, Gandolfi A, d'Onofrio A - PLoS Comput. Biol. (2014)

Bottom Line: The fate of the individual cell is assumed to be decided by the rising of nuclear-phosphorylated p53 over a certain threshold.Our results suggest that dose-splitting may be ineffective at low doses and effective at high doses.This complex behavior can be due to the interplay among the existence of a threshold on the p53 level for its cell activity, the nonlinearity of the relationship between the bolus dose and the peak of active p53, and the relatively fast elimination of the drug.

View Article: PubMed Central - PubMed

Affiliation: Silesian University of Technology, Institute of Automatic Control, Gliwice, Poland.

ABSTRACT
In this work we investigate, by means of a computational stochastic model, how tumor cells with wild-type p53 gene respond to the drug Nutlin, an agent that interferes with the Mdm2-mediated p53 regulation. In particular, we show how the stochastic gene-switching controlled by p53 can explain experimental dose-response curves, i.e., the observed inter-cell variability of the cell viability under Nutlin action. The proposed model describes in some detail the regulation network of p53, including the negative feedback loop mediated by Mdm2 and the positive loop mediated by PTEN, as well as the reversible inhibition of Mdm2 caused by Nutlin binding. The fate of the individual cell is assumed to be decided by the rising of nuclear-phosphorylated p53 over a certain threshold. We also performed in silico experiments to evaluate the dose-response curve after a single drug dose delivered in mice, or after its fractionated administration. Our results suggest that dose-splitting may be ineffective at low doses and effective at high doses. This complex behavior can be due to the interplay among the existence of a threshold on the p53 level for its cell activity, the nonlinearity of the relationship between the bolus dose and the peak of active p53, and the relatively fast elimination of the drug.

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Related in: MedlinePlus

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.
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pcbi-1003991-g005: 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.

Mentions: In Vassilev's experiments [6], the extra-cellular Nutlin concentration was maintained constant. This is not the case of in vivo delivery, when the drug is given as boli, i.e., computationally speaking, in impulsive doses. By fitting available data of Nutlin pharmacokinetics [58], we identified the parameters of the pharmacokinetic model (8) (see Fig. 5, panels A and B, and Table 3 of S3 Text). By means of that model, we have simulated realistic oral deliveries of Nutlin in mice.


The pharmacodynamics of the p53-Mdm2 targeting drug Nutlin: the role of gene-switching noise.

Puszynski K, Gandolfi A, d'Onofrio A - PLoS Comput. Biol. (2014)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263360&req=5

pcbi-1003991-g005: 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.
Mentions: In Vassilev's experiments [6], the extra-cellular Nutlin concentration was maintained constant. This is not the case of in vivo delivery, when the drug is given as boli, i.e., computationally speaking, in impulsive doses. By fitting available data of Nutlin pharmacokinetics [58], we identified the parameters of the pharmacokinetic model (8) (see Fig. 5, panels A and B, and Table 3 of S3 Text). By means of that model, we have simulated realistic oral deliveries of Nutlin in mice.

Bottom Line: The fate of the individual cell is assumed to be decided by the rising of nuclear-phosphorylated p53 over a certain threshold.Our results suggest that dose-splitting may be ineffective at low doses and effective at high doses.This complex behavior can be due to the interplay among the existence of a threshold on the p53 level for its cell activity, the nonlinearity of the relationship between the bolus dose and the peak of active p53, and the relatively fast elimination of the drug.

View Article: PubMed Central - PubMed

Affiliation: Silesian University of Technology, Institute of Automatic Control, Gliwice, Poland.

ABSTRACT
In this work we investigate, by means of a computational stochastic model, how tumor cells with wild-type p53 gene respond to the drug Nutlin, an agent that interferes with the Mdm2-mediated p53 regulation. In particular, we show how the stochastic gene-switching controlled by p53 can explain experimental dose-response curves, i.e., the observed inter-cell variability of the cell viability under Nutlin action. The proposed model describes in some detail the regulation network of p53, including the negative feedback loop mediated by Mdm2 and the positive loop mediated by PTEN, as well as the reversible inhibition of Mdm2 caused by Nutlin binding. The fate of the individual cell is assumed to be decided by the rising of nuclear-phosphorylated p53 over a certain threshold. We also performed in silico experiments to evaluate the dose-response curve after a single drug dose delivered in mice, or after its fractionated administration. Our results suggest that dose-splitting may be ineffective at low doses and effective at high doses. This complex behavior can be due to the interplay among the existence of a threshold on the p53 level for its cell activity, the nonlinearity of the relationship between the bolus dose and the peak of active p53, and the relatively fast elimination of the drug.

Show MeSH
Related in: MedlinePlus