Enhancement of the therapeutic efficacy of taxol by the mitogen-activated protein kinase kinase inhibitor CI-1040 in nude mice bearing human heterotransplants
Enhancement of the therapeutic efficacy of taxol by the mitogen-activated protein kinase kinase inhibitor CI-1040 in nude mice bearing human heterotransplants
复制标题
DOI：
10.1158/0008-5472.can-04-4391
复制
发表时间：
2005-04-01
期刊：
影响因子：
11.2
通讯作者：
Horwitz, SB
中科院分区：
文献类型：
--
作者：
McDaid, HM;Lopez-Barcons, L;Horwitz, SB
紫杉醇可能通过激活有丝分裂原激活的蛋白激酶(MEK)/细胞外信号调节激酶(ERK)细胞保护通路在人癌细胞系和肿瘤中参与内在的化疗耐药。我们之前已经在人类癌细胞系中证明了紫杉醇和MEK抑制剂U0126之间的可加性。在此，紫杉醇与口服生物可利用的MEK抑制剂CI-1040在人肺肿瘤异种移植到裸鼠体内的联合应用进行了评估。与异种移植模型不同的是，异种移植的肿瘤模型更具有临床意义。两种药物的联合治疗在所有模型中都能抑制肿瘤生长，在所测试的四个模型中有三个模型肿瘤消退，这支持了我们之前的观察，即紫杉醇的疗效因抑制MEK而增强。同时给药优于间歇给药。肿瘤的药效学评估表明，与单一药物相比，联合用药组抑制MEK与诱导S473磷酸化Akt和抑制增殖有关，此外还抑制成纤维细胞生长因子介导的血管生成和减少血管内皮生长因子的表达。这些发现具有重要意义，并表明这种组合可能在具有不同内在化疗敏感性的不同范围的肺肿瘤中具有广泛的治疗应用。
Taxol may contribute to intrinsic chemoresistance by activating the mitogen-activated protein kinase kinase (MEK)/ extracellular signal-regulated kinase (ERK) cytoprotective pathway in human cancer cell lines and tumors. We have previously shown additivity between Taxol and the MEK inhibitor, U0126 in human cancer cell lines. Here, the combination of Taxol with an orally bioavailable MEK inhibitor, CI-1040, was evaluated in human lung tumors heterotransplanted into nude mice. Unlike xenograft models that are derived from cells with multiple genetic alterations due to prolonged passage, heterotransplanted tumor models are more clinically relevant. Combined treatment with both drugs resulted in inhibition of tumor growth in all models and tumor regressions in three of four models tested, supporting our previous observation that Taxol's efficacy is potentiated by MEK inhibition. Concurrent administration was superior to intermittent dosing. Pharmacodynamic assessments of tumors indicated that suppression of MEK was associated with induction of S473 phosphorylated Akt and reduced proliferation in the combination groups relative to single agents, in addition to suppression of fibroblast growth factor-mediated angiogenesis and reduced expression of vascular endothelial growth factor. These findings are significant and indicate that this combination may have broad therapeutic applications in a diverse range of lung tumors with different intrinsic chemosensitivities.