Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, 55455, USA.
AAPS J. 2012 Mar;14(1):1-9. doi: 10.1208/s12248-011-9308-3. Epub 2011 Nov 19.
Agents that block insulin-like growth factor (IGF) signaling are under investigation in clinical trials. Antitumor effects are likely to be enhanced when combined with other agents, but administration sequence effects on activity are not well-described. Three breast cancer cell lines (MCF-7, MDA-MB-231, and Hs-578T) were treated with Gemcitabine and small molecule receptor tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]1-(2-phenyl-quinolin-7-yl)-imidazo [1,5-a]pyrazin-8-ylamine (PQIP) as single agents and then in combination in the forward (Gemcitabine followed by PQIP) and reverse (PQIP followed by Gemcitabine) sequences. Antitumor effects were assessed longitudinally by Bayesian analysis using WinBUGS. The pharmacodynamic model adequately predicted the observed data. The differences in the cell-kill rate constants for the forward vs. reverse sequence ranged from 0.11 to 0.64 (day(-1)), and statistical significance was generally dependent on cell line and PQIP concentration. These data indicate that treatment with Gemcitabine first, followed by PQIP is superior to the reverse sequence in vitro.
目前正在临床试验中研究能够阻断胰岛素样生长因子 (IGF) 信号的药物。当与其他药物联合使用时，可能会增强抗肿瘤作用，但关于给药顺序对活性的影响尚未得到很好的描述。我们用吉西他滨和小分子受体酪氨酸激酶抑制剂 cis-3-[3-(4-甲基-哌嗪-1-基)-环丁基]-1-(2-苯基-喹啉-7-基)-咪唑并[1,5-a]吡嗪-8-基胺（PQIP）对三种乳腺癌细胞系（MCF-7、MDA-MB-231 和 Hs-578T）进行了单独处理，并以正向（先吉西他滨后 PQIP）和反向（先 PQIP 后吉西他滨）顺序进行了联合处理。我们采用贝叶斯分析（使用 WinBUGS）对肿瘤抑制效果进行了纵向评估。药效动力学模型可以很好地预测观察到的数据。与反向顺序相比，正向顺序的细胞杀伤率常数差异范围为 0.11 至 0.64（天(-1)），统计学意义通常取决于细胞系和 PQIP 浓度。这些数据表明，吉西他滨先处理，随后用 PQIP 处理的效果优于体外的反向顺序。
