RT Journal Article
SR Electronic
T1 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
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 2255
OP 2265
DO 10.1158/1535-7163.MCT-08-1184
VO 8
IS 8
A1 Ekshyyan, Oleksandr
A1 Rong, Youhua
A1 Rong, Xiaohua
A1 Pattani, Kavita M.
A1 Abreo, Fleurette
A1 Caldito, Gloria
A1 Chang, John Kai Siung
A1 Ampil, Federico
A1 Glass, Jonathan
A1 Nathan, Cherie-Ann O.
YR 2009
UL http://mct.aacrjournals.org/content/8/8/2255.abstract
AB 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]