Miao Xin, Koch Gilbert, Ait-Oudhia Sihem, Straubinger Robert M, Jusko William J
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York Buffalo, NY, USA.
Department of Pharmaceutical Sciences, University at Buffalo, State University of New YorkBuffalo, NY, USA; Pediatric Pharmacology and Pharmacometrics, University of Basel, Children's HospitalBasel, Switzerland.
Front Pharmacol. 2016 Nov 15;7:421. doi: 10.3389/fphar.2016.00421. eCollection 2016.
Combinations of gemcitabine and trabectedin exert modest synergistic cytotoxic effects on two pancreatic cancer cell lines. Here, systems pharmacodynamic (PD) models that integrate cellular response data and extend a prototype model framework were developed to characterize dynamic changes in cell cycle phases of cancer cell subpopulations in response to gemcitabine and trabectedin as single agents and in combination. Extensive experimental data were obtained for two pancreatic cancer cell lines (MiaPaCa-2 and BxPC-3), including cell proliferation rates over 0-120 h of drug exposure, and the fraction of cells in different cell cycle phases or apoptosis. Cell cycle analysis demonstrated that gemcitabine induced cell cycle arrest in phase, and trabectedin induced transient cell cycle arrest in phase that progressed to / phase. Over time, cells in the control group accumulated in / phase. Systems cell cycle models were developed based on observed mechanisms and were used to characterize both cell proliferation and cell numbers in the , /, , and / phases in the control and drug-treated groups. The proposed mathematical models captured well both single and joint effects of gemcitabine and trabectedin. Interaction parameters were applied to quantify unexplainable drug-drug interaction effects on cell cycle arrest in phase and in inducing apoptosis. The developed models were able to identify and quantify the different underlying interactions between gemcitabine and trabectedin, and captured well our large datasets in the dimensions of time, drug concentrations, and cellular subpopulations.
吉西他滨与曲贝替定联合使用对两种胰腺癌细胞系具有适度的协同细胞毒性作用。在此，开发了整合细胞反应数据并扩展原型模型框架的系统药效学（PD）模型，以表征癌细胞亚群细胞周期阶段的动态变化，这些变化是对吉西他滨和曲贝替定单药及联合用药的反应。获得了两种胰腺癌细胞系（MiaPaCa - 2和BxPC - 3）的大量实验数据，包括0 - 120小时药物暴露期间的细胞增殖率，以及处于不同细胞周期阶段或凋亡的细胞比例。细胞周期分析表明，吉西他滨诱导细胞周期停滞在S期，曲贝替定诱导短暂的细胞周期停滞在G2期，随后进展至M / G1期。随着时间的推移，对照组细胞积聚在G1 / S期。基于观察到的机制开发了系统细胞周期模型，用于表征对照组和药物处理组中G1、S / G2、G2 / M和M / G1期的细胞增殖和细胞数量。所提出的数学模型很好地捕捉了吉西他滨和曲贝替定的单药及联合效应。应用相互作用参数来量化吉西他滨和曲贝替定对G2期细胞周期停滞和诱导凋亡的无法解释的药物 - 药物相互作用效应。所开发的模型能够识别和量化吉西他滨和曲贝替定之间不同的潜在相互作用，并很好地捕捉了我们在时间、药物浓度和细胞亚群维度上的大型数据集。
