Miao Xin, Koch Gilbert, Straubinger Robert M, Jusko William J
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
Cancer Chemother Pharmacol. 2016 Jan;77(1):181-93. doi: 10.1007/s00280-015-2907-4. Epub 2015 Nov 25.
This study investigates the combined effects of gemcitabine and trabectedin (ecteinascidin 743) in two pancreatic cancer cell lines and proposes a pharmacodynamic (PD) model to quantify their pharmacological interactions.
Effects of gemcitabine and trabectedin upon the pancreatic cancer cell lines MiaPaCa-2 and BxPC-3 were investigated using cell proliferation assays. Cells were exposed to a range of concentrations of the two drugs, alone and in combination. Viable cell numbers were obtained daily over 5 days. A model incorporating nonlinear cytotoxicity, transit compartments, and an interaction parameter ψ was used to quantify the effects of the individual drugs and combinations.
Simultaneous fitting of temporal cell growth profiles for all drug concentrations provided reasonable cytotoxicity parameter estimates (the cell killing rate constant K max and the sensitivity constant KC50) for each drug. The interaction parameter ψ was estimated as 0.806 for MiaPaCa-2 and 0.843 for BxPC-3 cells, suggesting that the two drugs exert modestly synergistic effects.
The proposed PD model enables quantification of the temporal profiles of drug combinations over a range of concentrations with drug-specific parameters. Based upon these in vitro studies, trabectedin may have augmented benefit in combination with gemcitabine. The PD model may have general relevance for the study of other cytotoxic drug combinations.
本研究调查吉西他滨和曲贝替定（埃博霉素743）对两种胰腺癌细胞系的联合作用，并提出一种药效学（PD）模型以量化它们的药理相互作用。
使用细胞增殖试验研究吉西他滨和曲贝替定对胰腺癌细胞系MiaPaCa-2和BxPC-3的作用。细胞分别单独及联合暴露于两种药物的一系列浓度下。在5天内每天获取存活细胞数。使用一个包含非线性细胞毒性、转运室和相互作用参数ψ的模型来量化各药物及联合用药的效果。
对所有药物浓度的细胞生长时间曲线进行同时拟合，为每种药物提供了合理的细胞毒性参数估计值（细胞杀伤速率常数K max和敏感常数KC50）。MiaPaCa-2细胞的相互作用参数ψ估计为0.806，BxPC-3细胞的为0.843，表明这两种药物发挥适度的协同作用。
所提出的PD模型能够通过药物特异性参数量化一系列浓度下药物联合的时间曲线。基于这些体外研究，曲贝替定与吉西他滨联合使用可能具有更大的益处。该PD模型可能对其他细胞毒性药物联合的研究具有普遍意义。
