In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer
In vivo antitumor effect of the mTOR inhibitor CCI-779 and gemcitabine in xenograft models of human pancreatic cancer
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DOI：
10.1002/ijc.21532
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发表时间：
2006-05-01
影响因子：
6.4
通讯作者：
Doi, R
中科院分区：
文献类型：
--
作者：
Ito, D;Fujimoto, K;Doi, R
哺乳动物雷帕霉素靶点（mTOR）被认为是细胞生长和增殖的主要效应器，通过大量下游靶点控制蛋白质合成。我们研究了人胰腺癌和组织中磷脂酰肌醇3'-激酶（PI3K）/mTOR信号通路的表达，以及mTOR抑制剂CCI-779联合/不联合吉西他滨在人胰腺癌异种移植模型中的体内抗肿瘤作用。我们发现 PI3K/mTOR 信号通路中的 Akt、mTOR 和 p70 S6 激酶 (S6K1) 在所有检查的胰腺癌细胞系中均被激活。当检查手术切除的胰腺导管腺癌组织标本时，分别在 50%、55% 和 65% 的标本中检测到 Akt、mTOR 和 S6K1 磷酸化。尽管CCI-779在体外与吉西他滨联合使用时没有相加或协同的抗增殖作用，但在AsPC-1皮下异种移植模型中，无论是单药还是与吉西他滨联合使用，它都显示出显着的抗肿瘤活性。此外，在 Suit-2 腹膜播散异种移植模型中，与单独使用 CCI-779 或吉西他滨相比，这两种药物的组合取得了显着更好的生存率。这些结果表明 mTOR 抑制剂 CCI-779 对人类胰腺癌具有良好的活性，并表明 mTOR 信号传导的抑制可作为一种潜在的肿瘤选择性治疗策略。 (c) 2005 年 Wiley-Liss, Inc.
Mammalian target of rapamycin (mTOR) is considered to be a major effector of cell growth and proliferation that controls protein synthesis through a large number of downstream targets. We investigated the expression of the phosphatidylinositol 3'-kinase (PI3K)/mTOR signaling pathway in human pancreatic cancer Fells and tissues, and the in vivo antitumor effects of the mTOR inhibitor CCI-779 with/without gemcitabine in xenograft models of human pancreatic cancer. We found that the Akt, mTOR and p70 S6 kinase (S6K1) from the PI3K/mTOR signaling pathway were activated in all of the pancreatic cancer cell lines examined. When surgically resected tissue specimens of pancreatic ductal adenocarcinoma were examined, phosphorylation of Akt, mTOR and S6K1 was detected in 50, 55 and 65% of the specimens, respectively. Although CCI-779 had no additive or synergistic antiproliferative effect when combined with gemcitabine in vitro, it showed significant antitumor activity in the AsPC-1 subcutaneous xenograft model as both a single agent and in combination with gemictabine. Furthermore, in the Suit-2 peritoneal dissemination xenograft model, the combination of these 2 drugs achieved significantly better survival when compared with CCI-779 or gemcitabine alone. These results demonstrate promising activity of the mTOR inhibitor CCI-779 against human pancreatic cancer, and suggest that the inhibition of mTOR signaling can be exploited as a potentially tumor-selective therapeutic strategy. (c) 2005 Wiley-Liss, Inc.