Use of mitogenic cascade blockers for treatment of C-Raf induced lung adenoma in vivo: CI-1040 strongly reduces growth and improves lung structure.
Use of mitogenic cascade blockers for treatment of C-Raf induced lung adenoma in vivo: CI-1040 strongly reduces growth and improves lung structure.
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DOI：
10.1186/1471-2407-4-24
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发表时间：
2004-06-01
期刊：
影响因子：
3.8
通讯作者：
Rapp UR
中科院分区：
文献类型：
--
作者：
Kramer BW;Götz R;Rapp UR
促进细胞生长和增殖的信号网络在癌症中经常失调。肿瘤通常高度依赖此类信号传导途径，并且可能对这些信号级联内关键成分的下调变得高度敏感。经典的有丝分裂级联将生长因子受体的刺激通过 Ras、Raf、MEK 和 ERK 传递到细胞核，并为癌症治疗提供有吸引力的分子靶点。例如，Ras 和 Raf 激酶抑制剂已经进入多项正在进行的 II 期和 III 期临床试验。在本研究中，详细分析了 Raf 激酶抑制剂 BAY 43-9006 和 MEK 抑制剂 CI-1040 (PD184352) 对 Raf 依赖性肺肿瘤小鼠模型的影响。我们通过将组成型活性 C-Raf 激酶靶向肺部，建立了肺癌小鼠模型。这些小鼠在出生后 4 个月内就会出现腺瘤。此时，他们每天腹腔注射 100 mg/kg BAY 43-9006 或 CI-1040，持续 21 天。此后，分离肺并使用组织学和免疫组织化学分析以下参数：整体肺结构、腺瘤灶频率、增殖率、ERK活性、caspase-3激活和肺分化。使用灵敏的 Raf/MEK/ERK ELISA，两种抑制剂在体外同样有效。在体内，全身施用 MEK 抑制剂 CI-1040 将腺瘤形成减少到三分之一，并显着恢复肺结构。 CL-1040处理小鼠肺细胞增殖率下降，但对肺细胞分化没有明显影响。相反，Raf抑制剂BAY 43-9006不影响体内腺瘤形成。 MEK抑制剂CI-1040可用于治疗Ras和/或Raf依赖性人类恶性肿瘤。
Signaling networks promoting cell growth and proliferation are frequently deregulated in cancer. Tumors often are highly dependent on such signaling pathways and may become hypersensitive to downregulation of key components within these signaling cascades. The classical mitogenic cascade transmits stimuli from growth factor receptors via Ras, Raf, MEK and ERK to the cell nucleus and provides attractive molecular targets for cancer treatment. For example, Ras and Raf kinase inhibitors are already in a number of ongoing phase II and phase III clinical trials. In this study the effect of the Raf kinase inhibitor BAY 43-9006 and of the MEK inhibitor CI-1040 (PD184352) on a Raf dependent lung tumor mouse model was analyzed in detail. We have generated a lung cancer mouse model by targeting constitutively active C-Raf kinase to the lung. These mice develop adenomas within 4 months of life. At this time-point they received daily intraperitoneal injections of either 100 mg/kg BAY 43-9006 or CI-1040 for additional 21 days. Thereafter, lungs were isolated and the following parameters were analyzed using histology and immunohistochemistry: overall lung structure, frequency of adenoma foci, proliferation rate, ERK activity, caspase-3 activation, and lung differentiation. Both inhibitors were equally effective in vitro using a sensitive Raf/MEK/ERK ELISA. In vivo, the systemic administration of the MEK inhibitor CI-1040 reduced adenoma formation to a third and significantly restored lung structure. The proliferation rate of lung cells of mice treated with CL-1040 was decreased without any obvious effects on differentiation of pneumocytes. In contrast, the Raf inhibitor BAY 43-9006 did not influence adenoma formation in vivo. The MEK inhibitor CI-1040 may be used for the treatment of Ras and/or Raf-dependent human malignancies.
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影响因子：
8.8
作者：
Vonlanthen S;Heighway J;Altermatt HJ;Gugger M;Kappeler A;Borner MM;van Lohuizen M;Betticher DC
通讯作者：
Betticher DC
影响因子：
82.9
作者：
Sebolt-Leopold, JS;Dudley, DT;Saltiel, AR
通讯作者：
Saltiel, AR
影响因子：
11.4
作者：
Hüser, M;Luckett, J;Pritchard, C
通讯作者：
Pritchard, C
影响因子：
2.9
作者：
Mallon, R;Feldberg, LR;Kohler, C
通讯作者：
Kohler, C
影响因子：
64.8
作者：
KOLCH, W;HEIDECKER, G;RAPP, UR
通讯作者：
RAPP, UR