Hesse Janina, Martinelli Julien, Aboumanify Ouda, Ballesta Annabelle, Relógio Angela
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.
Comput Struct Biotechnol J. 2021 Sep 2;19:5170-5183. doi: 10.1016/j.csbj.2021.08.051. eCollection 2021.
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 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.
在24小时内安排抗癌药物给药可能会以患者特异性的方式严重影响治疗效果。在此，我们使用一种新型的伊立替康细胞药代动力学和药效学数学模型来解决治疗时间的个性化问题，该模型与核心时钟的表征相关联，并在结直肠癌（CRC）细胞模型中预测治疗毒性。该数学模型适用于三种不同的情况：药物代谢主要发生的小鼠肝脏，以及代表人类结直肠癌进展实验系统的两种人类结肠癌细胞系。我们的模型成功地概括了mRNA和蛋白质表达的定量昼夜节律数据集以及时间依赖性伊立替康细胞毒性数据。该模型还区分了不同细胞之间的时间依赖性毒性，表明可以根据它们的细胞时钟优化治疗。我们的结果表明，介导伊立替康激活的蛋白质的时间依赖性降解以及死亡率的振荡可能在药物毒性的昼夜节律变化中起重要作用。未来，该模型可用于通过基于患者基因表达谱预测最佳给药时间来支持个性化治疗方案的制定。
