Signal Transduction Laboratory, Ordway Research Institute, Albany, New York, United States of America.
PLoS Comput Biol. 2011 Feb 3;7(2):e1001073. doi: 10.1371/journal.pcbi.1001073.
Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin αvβ3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro-apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti-proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations.
未修饰的或作为聚[丙交酯-共-乙交酯]纳米颗粒的四碘甲状腺乙酸 (tetrac) 作用于人类癌细胞上的整合素 αvβ3 受体，以抑制肿瘤细胞增殖和异种移植物生长。为了在不存在和结合其他化疗药物的情况下研究 tetrac 制剂的体外药效学，我们开发了一种灌注波纹管细胞培养系统。将细胞生长在聚合物薄片上，并暴露于不同浓度的 tetrac、纳米 tetrac、白藜芦醇、西妥昔单抗或其组合中，最长可达 18 天。每隔一天或两天收获和计数细胞。NONMEM VI 和 S-ADAPT 中的精确蒙特卡罗参数期望最大化算法都用于数学建模。未修饰的 tetrac 抑制了癌细胞的增殖，并且在不同的细胞系中具有不同的效力。开发的基于机制的模型包括 tetrac 对细胞周期不同部分的两种作用，可以区分开来。对于人类乳腺癌细胞，建模表明对复制成功率的影响比生长率的影响具有更高的敏感性（更低的 IC50），而生长率的影响则具有更大的容量（Imax）。不进入细胞的纳米颗粒 tetrac（纳米 tetrac）具有更高的效力和更大的抗增殖作用比未修饰的 tetrac。收获细胞的荧光激活细胞分选分析显示 tetrac 和纳米 tetrac 诱导了浓度依赖性凋亡，这与促凋亡蛋白的表达相关，例如纳米 tetrac 中的 p53、p21、PIG3 和 BAD，而未修饰的 tetrac 则显示出不同的谱。发现 tetrac 和白藜芦醇、tetrac 和西妥昔单抗（Erbitux）以及纳米 tetrac 和西妥昔单抗的组合具有近似相加的抗增殖作用。我们的体外灌注癌细胞系统与数学建模一起成功地描述了 tetrac 和纳米 tetrac 随时间的抗增殖作用，可能有助于剂量发现和研究其他化疗药物或其组合的药效学。
