The Pharmacodynamics of the p53-Mdm2 Targeting Drug Nutlin: The Role of Gene-Switching Noise

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.

本研究借助计算随机模型，探究携带野生型p53基因（wild-type p53 gene）的肿瘤细胞对药物Nutlin的响应机制——Nutlin是一种可干扰Mdm2介导的p53调控通路的小分子制剂。具体而言，本研究阐明了p53调控的随机基因开关可解释实验所得的剂量-响应曲线，即Nutlin作用下观测到的细胞活力的细胞间异质性。本研究提出的模型较为详细地刻画了p53的调控网络，涵盖Mdm2介导的负反馈环、PTEN介导的正反馈环，以及Nutlin结合引发的Mdm2可逆性抑制作用。本研究假设单个细胞的命运由核内磷酸化p53水平突破特定阈值所决定。此外，本研究开展了计算机模拟实验，以评估小鼠单次推注给药或分次给药后的剂量-响应曲线。研究结果表明，剂量分割策略在低剂量场景下可能无效，而在高剂量场景下则可发挥作用。这种复杂行为可归因于三方面因素的相互作用：p53水平触发细胞活性所需的阈值、推注剂量与活性p53峰值间的非线性关联，以及药物相对较快的体内清除速率。