PMID- 19625495
OWN - NLM
STAT- MEDLINE
DCOM- 20100119
LR  - 20211203
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 8
IP  - 8
DP  - 2009 Aug
TI  - 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.
PG  - 2255-65
LID - 10.1158/1535-7163.MCT-08-1184 [doi]
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.
FAU - Ekshyyan, Oleksandr
AU  - Ekshyyan O
AD  - Department of Otolaryngology-Head and Neck Surgery, Louisiana State University 
      Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
FAU - Rong, Youhua
AU  - Rong Y
FAU - Rong, Xiaohua
AU  - Rong X
FAU - Pattani, Kavita M
AU  - Pattani KM
FAU - Abreo, Fleurette
AU  - Abreo F
FAU - Caldito, Gloria
AU  - Caldito G
FAU - Chang, John Kai Siung
AU  - Chang JK
FAU - Ampil, Federico
AU  - Ampil F
FAU - Glass, Jonathan
AU  - Glass J
FAU - Nathan, Cherie-Ann O
AU  - Nathan CO
LA  - eng
GR  - R01 CA102363/CA/NCI NIH HHS/United States
GR  - R01 CA102363-05/CA/NCI NIH HHS/United States
GR  - R01 CA 102363/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090722
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Radiation-Sensitizing Agents)
RN  - 624KN6GM2T (temsirolimus)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - Q20Q21Q62J (Cisplatin)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/therapeutic use
MH  - Apoptosis
MH  - Carcinoma, Squamous Cell/drug therapy/pathology/*radiotherapy
MH  - Cell Line, Tumor
MH  - Cisplatin/therapeutic use
MH  - Combined Modality Therapy
MH  - Head and Neck Neoplasms/drug therapy/pathology/*radiotherapy
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Protein Kinases/*metabolism
MH  - *Radiation-Sensitizing Agents
MH  - Sirolimus/*analogs & derivatives/therapeutic use
MH  - TOR Serine-Threonine Kinases
MH  - Xenograft Model Antitumor Assays
PMC - PMC2758817
MID - NIHMS130029
EDAT- 2009/07/25 09:00
MHDA- 2010/01/20 06:00
PMCR- 2010/08/01
CRDT- 2009/07/24 09:00
PHST- 2009/07/24 09:00 [entrez]
PHST- 2009/07/25 09:00 [pubmed]
PHST- 2010/01/20 06:00 [medline]
PHST- 2010/08/01 00:00 [pmc-release]
AID - 1535-7163.MCT-08-1184 [pii]
AID - 10.1158/1535-7163.MCT-08-1184 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2009 Aug;8(8):2255-65. doi: 10.1158/1535-7163.MCT-08-1184. Epub 
      2009 Jul 22.