title: Vandetanib restores head and neck squamous cell carcinoma cells' sensitivity to cisplatin and radiation in vivo and in vitro.
abstract: OBJECTIVE
  We investigated whether vandetanib, an inhibitor of the tyrosine kinase activities of vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET), could augment the antitumor activity of radiation with or without cisplatin in preclinical in vitro and in vivo models of human head and neck squamous cell carcinoma (HNSCC).
  
  
  METHODS
  OSC-19 and HN5 HNSCC cells that were cisplatin and radioresistant were treated with vandetanib, cisplatin, and radiation alone or in combination in vitro and in vivo using an orthotopic nude mouse model. Treatment effects were assessed using clonogenic survival assay, tumor volume, bioluminescence imaging, tumor growth delay, survival, microvessel density, tumor and endothelial cell apoptosis, and EGFR and Akt phosphorylation data.
  
  
  RESULTS
  Vandetanib plus cisplatin radiosensitized HNSCC cells in vitro and in vivo. The combination treatment with vandetanib, cisplatin, and radiation was superior to the rest of treatments (including the double combinations) in antitumoral effects, prolonging survival, decreasing cervical lymph node metastases in vivo. It also increased both tumor and tumor-associated endothelial cell apoptosis and decreased microvessel density in vivo. An analysis of tumor growth delay data revealed that vandetanib plus cisplatin enhanced radioresponse in vivo. All vandetanib-containing treatments inhibited EGFR and Akt phosphorylation in vitro and in vivo.
  
  
  CONCLUSIONS
  The addition of vandetanib to combination therapy with cisplatin and radiation was able to effectively overcome cisplatin and radioresistance in in vitro and in vivo models of HNSCC. Further study of this regimen in clinical trials may be warranted.
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sano
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsumoto
authors.forename: David R
authors.initials: DR
authors.lastname: Valdecanas
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.forename: David P
authors.initials: DP
authors.lastname: Molkentine
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Ehab Y
authors.initials: EY
authors.lastname: Hanna
authors.forename: Vali
authors.initials: V
authors.lastname: Papadimitrakopoulou
authors.forename: John
authors.initials: J
authors.lastname: Heymach
authors.forename: Luka
authors.initials: L
authors.lastname: Milas
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology*; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D002945:Cisplatin; C452423:vandetanib