Paper Info
Title
The pharmacodynamics of the p53-Mdm2 targeting drug Nutlin: the role of gene-switching noise.
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.
Year
DOI
Venue
2014
10.1371/journal.pcbi.1003991
PLOS COMPUTATIONAL BIOLOGY
Keywords
Field
DocType
bioinformatics,biomedical research
PTEN,Biology,Nutlin,Pharmacokinetics,Mdm2,Negative feedback,Regulation of gene expression,Bioinformatics,Viability assay,Drug delivery
Journal
Volume
Issue
ISSN
10
12
1553-734X
Citations 
PageRank 
References 
3
0.85
2
Authors
3
Name
Order
Citations
PageRank
Krzysztof Puszyński1125.91
Alberto Gandolfi2144.75
Alberto d’Onofrio34512.31