Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, Texas, USA.
Livestrong Cancer Institutes, The University of Texas at Austin, Austin, Texas, USA.
Sci Rep. 2019 Sep 6;9(1):12830. doi: 10.1038/s41598-019-49073-5.
The goal of this study is to experimentally and computationally investigate combination trastuzumab-paclitaxel therapies and identify potential synergistic effects due to sequencing of the therapies with in vitro imaging and mathematical modeling. Longitudinal alterations in cell confluence are reported for an in vitro model of BT474 HER2+ breast cancer cells following various dosages and timings of paclitaxel and trastuzumab combination regimens. Results of combination drug regimens are evaluated for drug interaction relationships based on order, timing, and quantity of dose of the drugs. Altering the order of treatments, with the same total therapeutic dose, provided significant changes in overall cell confluence (p < 0.001). Two mathematical models are introduced that are constrained by the in vitro data to simulate the tumor cell response to the individual therapies. A collective model merging the two individual drug response models was designed to investigate the potential mechanisms of synergy for paclitaxel-trastuzumab combinations. This collective model shows increased synergy for regimens where trastuzumab is administered prior to paclitaxel and suggests trastuzumab accelerates the cytotoxic effects of paclitaxel. The synergy derived from the model is found to be in agreement with the combination index, where both indicate a spectrum of additive and synergistic interactions between the two drugs dependent on their dose order. The combined in vitro results and development of a mathematical model of drug synergy has potential to evaluate and improve standard-of-care combination therapies in cancer.
本研究的目的是通过体外成像和数学建模实验和计算研究曲妥珠单抗-紫杉醇联合治疗，并确定由于治疗顺序而产生的潜在协同作用。报告了 BT474 HER2+乳腺癌细胞体外模型在不同紫杉醇和曲妥珠单抗联合方案剂量和时间的作用下细胞汇合的纵向变化。根据药物的顺序、时间和剂量来评估联合药物方案的药物相互作用关系。改变治疗顺序，相同的总治疗剂量，提供了细胞汇合的整体变化显著（p < 0.001）。介绍了两种数学模型，它们受到体外数据的限制，以模拟肿瘤细胞对单独治疗的反应。合并两种个体药物反应模型的集合模型被设计用于研究紫杉醇-曲妥珠单抗联合治疗的潜在协同作用机制。该集合模型显示，在曲妥珠单抗先于紫杉醇给药的方案中协同作用增加，并表明曲妥珠单抗加速了紫杉醇的细胞毒性作用。从模型中得出的协同作用与组合指数一致，两者都表明两种药物之间存在一系列相加和协同作用，取决于它们的剂量顺序。联合的体外结果和药物协同作用的数学模型的发展有可能评估和改善癌症的标准护理联合治疗。
