Comparison of radiosensitizing effects of the mammalian target of rapamycin inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma.
Comparison of radiosensitizing effects of the mammalian target of rapamycin inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma.
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DOI：
10.1158/1535-7163.mct-08-1184
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发表时间：
2009-08
影响因子：
5.7
通讯作者：
Nathan CO
中科院分区：
文献类型：
--
作者：
Ekshyyan O;Rong Y;Rong X;Pattani KM;Abreo F;Caldito G;Chang JK;Ampil F;Glass J;Nathan CO
确定mTOR抑制剂CCI-779是否可以使头颈部鳞状细胞癌（HNSCC）对放射治疗（XRT）敏感，并将顺铂的放射增敏作用与其已知的相当大的毒性进行比较。CCI-779在体外对HNSCC细胞系的放射增敏作用进行了测定。在携带FaDu和SCC 40异种移植物的小鼠中评价CCI-779（5 mg/kg）、顺铂（1 mg/kg）和XRT（2戈伊）单独和组合的抗肿瘤活性。分析CCI-779对辐射诱导的Akt/mTOR途径活化的影响。CCI-779在体外对HNSCC细胞无放射增敏作用，但XRT联合CCI-779能显著增强XRT和CCI-779的体内抑瘤作用（P<0.05）。此外，CCI-779+XRT比顺铂+XRT更有效地抑制肿瘤生长（P<0.05）。在顺铂敏感的FaDu（P<0.01）和顺铂耐药的SCC 40异种移植小鼠（P<0.05）中，与单独的XRT相比，CCI-779+XRT显著改善了存活率。在CCI-779+XRT中添加顺铂没有额外的益处。CCI-779在FaDu异种移植物中显著减弱辐射诱导的mTOR通路的上调，增加细胞凋亡，并显示出有效的抗血管生成活性，其与放射治疗的组合进一步增强（P<0.05），这可以解释其在体内而不是体外的选择性放射增敏作用的机制。在HNSCC异种移植模型中，当与CCI-779组合时，放射治疗的抗肿瘤活性增强。CCI-779+XRT的抗肿瘤活性上级优于顺铂的常规放化疗。这些结果为利用CCI-779的分子靶向疗法与放射疗法组合治疗HNSCC的临床试验铺平了道路。
To determine if the mTOR inhibitor CCI-779 can sensitize head and neck squamous cell carcinoma (HNSCC) to radiotherapy (XRT) and compare the radiosensitizing effects to cisplatin with its known considerable toxicity. Radiosensitizing effects of CCI-779 were assayed on HNSCC cell lines in vitro. CCI-779 (5mg/kg), cisplatin (1 mg/kg) and XRT (2 Gy) alone and in combination were evaluated for antitumor activity in mice bearing FaDu and SCC40 xenografts. Effects of CCI-779 on radiation-induced activation of the Akt/mTOR pathway were analyzed. Although CCI-779 did not sensitize HNSCC cells to ionizing radiation in vitro, combination of CCI-779 and XRT significantly augmented the in vivo tumor growth inhibitory effects of XRT and CCI-779 (P<0.05). In addition CCI-779+XRT suppressed tumor growth more effectively than cisplatin+XRT (P<0.05). CCI-779+XRT significantly improved survival compared to XRT alone in both cisplatin-sensitive FaDu (P<0.01) and cisplatin-resistant SCC40 xenograft mice (P<0.05). There were no additional benefits of adding cisplatin to CCI-779+XRT. CCI-779 significantly attenuated irradiation-induced upregulation of the mTOR pathway, increased apoptosis and displayed potent antiangiogenic activity in FaDu xenografts that was further enhanced by its combination with radiotherapy (P<0.05) which may explain the mechanism of its selective radiosensitizing effects in vivo and not in vitro. Antitumor activity of radiotherapy was enhanced when combined with CCI-779 in HNSCC xenograft model. CCI-779+XRT showed antitumor activity superior to conventional chemoradiotherapy with cisplatin. These results pave the way for clinical trials utilizing molecular targeted therapy with CCI-779 in combination with radiotherapy for HNSCC treatment.