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

• Published in: Molecular cancer therapeutics 2009-08, Vol.8 (8), p.2255-2265
• Main Authors: Ekshyyan, Oleksandr, Rong, Youhua, Rong, Xiaohua, Pattani, Kavita M, Abreo, Fleurette, Caldito, Gloria, Chang, John Kai Siung, Ampil, Federico, Glass, Jonathan, Nathan, Cherie-Ann O
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Apoptosis; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - radiotherapy; Cell Line, Tumor; Cisplatin - therapeutic use; Combined Modality Therapy; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - pathology; Head and Neck Neoplasms - radiotherapy; in vivo; Mice; Mice, Inbred Strains; mTOR; Protein Kinases - metabolism; Radiation-Sensitizing Agents; rapamycin analogues; Sirolimus - analogs & derivatives; Sirolimus - therapeutic use; temsirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-1184

To determine if the mammalian target of rapamycin (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 (5 mg/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 with XRT alone in both cisplatin-sensitive FaDu ( P < 0.01) and cisplatin-resistant SCC40 ( P < 0.05) xenograft mice. There were no additional benefits of adding cisplatin to CCI-779 + XRT. CCI-779 significantly attenuated irradiation-induced up-regulation of the mTOR pathway, increased apoptosis and displayed potent antiangiogenic activity in FaDu xenografts that was further enhanced by its combination with XRT ( P < 0.05), which may explain the mechanism of its selective radiosensitizing effects in vivo and not in vitro . Antitumor activity of XRT 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 using molecular targeted therapy with CCI-779 in combination with XRT for HNSCC treatment. [Mol Cancer Ther 2009;8(8):2255–65]