BioModelsapplication/xmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL2109140001?filename=biomodels.zipprimaryOK200Janina HesseNon-curatedordinary differential equation model3.6https://www.ebi.ac.uk/biomodels/MODEL2109140001falseBioModelsPythonModelsHesse2021 Interplay between core clock and cancer drug irinotecan pharmacokinetics and dynamics2021MODEL2109140001Janina Hesse, Julien Martinelli, Ouda Aboumanify, Annabelle Ballesta, Angela RelógioJanina Hesse10.1016/j.csbj.2021.08.051, Scheduling anticancer drug administration over 24 h may critically impact treatment success in a patient-specific manner. Here, we address personalization of treatment timing using a novel mathematical model of irinotecan cellular pharmacokinetics and -dynamics linked to a representation of the core clock and predict treatment toxicity in a colorectal cancer (CRC) cellular model. The mathematical model is fitted to three different scenarios: mouse liver, where the drug metabolism mainly occurs, and two human colorectal cancer cell lines representing an in vitro experimental system for human colorectal cancer progression. Our model successfully recapitulates quantitative circadian datasets of mRNA and protein expression together with timing-dependent irinotecan cytotoxicity data. The model also discriminates time-dependent toxicity between the different cells, suggesting that treatment can be optimized according to their cellular clock. Our results show that the time-dependent degradation of the protein mediating irinotecan activation, as well as an oscillation in the death rate may play an important role in the circadian variations of drug toxicity. In the future, this model can be used to support personalized treatment scheduling by predicting optimal drug timing based on the patient’s gene expression profile.. null, null. Institute for Systems Medicine, Department of Human Medicine, MSH Medical School Hamburg – University of Applied Sciences and Medical University, Hamburg 20457, Germany Institute for Theoretical Biology (ITB), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt - Universität zu Berlin, and Berlin Institute of Health, Berlin 10117, Germany INSERM U900, Saint-Cloud, France, Institut Curie, Saint Cloud, France, Paris Saclay University, France, MINES ParisTech, CBIO - Centre for Computational Biology, PSL Research University, Paris, France UPR ’Chronotherapy, Cancers and Transplantation’, Faculty of Medicine, Paris Saclay University, Campus CNRS, 7 rue Guy Moquet, 94800 Villejuif, France Lifeware Group, Inria Saclay Ile-de-France, Palaiseau 91120, France Molecular Cancer Research Center (MKFZ), Medical Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlinjanina.hesse@gmx.net10.1016/j.csbj.2021.08.051MSH Medical School HamburgfalseHesse2021 - Interplay between core-clock and cancer drug irinotecan pharmacokinetics and -dynamicsRefined quantitative core-clock model based on the model by Relógio et al. 2011. The translation-transcription network is extended by a set of irinotecan-relevant genes, which allows to connect the core clock to the irinotecan pharmacokinetics and -dynamics model by Ballesta et al. 2011. The original model by Ballesta et al. 2011 is extended by an explicit simulation of the number of living and dead cells.2021-09-142021-09-152021-09-14MODEL2109140001MODEL210914000110.1016/j.csbj.2021.08.051