Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts.
Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts.
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DOI：
10.1186/1471-2407-10-515
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发表时间：
2010-09-28
期刊：
影响因子：
3.8
通讯作者：
Hedley DW
中科院分区：
文献类型：
--
作者：
Chang Q;Chapman MS;Miner JN;Hedley DW
将 MEK 抑制剂与其他信号通路抑制剂或常规细胞毒性药物相结合代表了一种有前景的抗癌新策略。 RDEA119/BAY 869766 是一种高效、选择性的 MEK1/2 抑制剂，正在进行 I 期人体临床试验。在原位生长的 3 个早期传代原发性胰腺癌异种移植物 OCIP19、21 和 23 中研究了 RDEA119/BAY 869766 作为单药以及与雷帕霉素联合使用的效果。在长期接触药物后，在不同的组中确定抗癌效果。分别通过流式细胞术和蛋白质印迹检查对细胞周期和下游信号传导的影响。测量血浆 RDEA119 浓度以监测体内药物蓄积。 RDEA119/BAY 869766 单独使用或与雷帕霉素联合使用，在所有 3 个模型中均显示出显着的生长抑制作用，S 期细胞百分比显着下降，同时溴脱氧尿苷标记大幅下降，细胞周期主要停滞在 G1 期。在所有三种模型中，联合治疗后 S6 核糖体蛋白均受到更大程度的抑制。血浆药代动力学分析表明，体内达到的 RDEA119 水平与体外产生靶标抑制和细胞周期停滞的水平相似。针对 ERK 和 mTOR 通路的药物在原发性异种移植物中具有抗癌活性，这些结果支持在胰腺癌患者中测试这种组合。
Combining MEK inhibitors with other signalling pathway inhibitors or conventional cytotoxic drugs represents a promising new strategy against cancer. RDEA119/BAY 869766 is a highly potent and selective MEK1/2 inhibitor undergoing phase I human clinical trials. The effects of RDEA119/BAY 869766 as a single agent and in combination with rapamycin were studied in 3 early passage primary pancreatic cancer xenografts, OCIP19, 21, and 23, grown orthotopically. Anti-cancer effects were determined in separate groups following chronic drug exposure. Effects on cell cycle and downstream signalling were examined by flow cytometry and western blot, respectively. Plasma RDEA119 concentrations were measured to monitor the drug accumulation in vivo. RDEA119/BAY 869766 alone or in combination with rapamycin showed significant growth inhibition in all the 3 models, with a significant decrease in the percentage of cells in S-phase, accompanied by a large decrease in bromodeoxyuridine labelling and cell cycle arrest predominantly in G1. The S6 ribosomal protein was inhibited to a greater extent with combination treatment in all the three models. Blood plasma pharmacokinetic analyses indicated that RDEA119 levels achieved in vivo are similar to those that produce target inhibition and cell cycle arrest in vitro. Agents targeting the ERK and mTOR pathway have anticancer activity in primary xenografts, and these results support testing this combination in pancreatic cancer patients.
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影响因子：
8.8
作者：
Cao, P.;Maira, S-M;Garcia-Echeverria, C.;Hedley, D. W.
通讯作者：
Hedley, D. W.
影响因子：
11.5
作者：
Ou, Da-Liang;Shen, Ying-Chun;Chen, Ann-Lii
通讯作者：
Chen, Ann-Lii
影响因子：
11.2
作者：
Yau, CYF;Wheeler, JJ;Hedley, DW
通讯作者：
Hedley, DW
影响因子：
11.2
作者：
McDaid, HM;Lopez-Barcons, L;Horwitz, SB
通讯作者：
Horwitz, SB
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA