title: Impact of tumor cell VEGF expression on the in vivo efficacy of vandetanib (ZACTIMA; ZD6474).
abstract: VEGF is the key player in tumor angiogenesis. In the current study, the impact of VEGF expression on the response of tumors to the VEGFR2 associated tyrosine kinase inhibitor vandetanib was evaluated.
  
  
  METHODS
  Human colon carcinoma (HT29) and murine squamous carcinoma (SCCVII) clonal cell lines expressing varying levels of VEGF were established and their response to vandetanib was assessed in tissue culture and as solid tumors.
  
  
  RESULTS
  Vandetanib treatment had no effect on tumor cell clonogenic cell survival in vitro but doses >or=10 nM significantly reduced endothelial cell migration. In vivo, tumors derived from cell clones expressing high levels of VEGF displayed significantly enhanced angiogenesis and more aggressive growth. An intradermal angiogenesis assay was used to demonstrate that a 4-day treatment with vandetanib (50 mg/kg/day) was able to significantly inhibit blood vessel growth induced by both parental and high VEGF-expressing tumor cell clones. In the HT29 tumor model, treatment response to vandetanib (50 mg/kg/day, Monday-Friday for 2 weeks) was greatest in xenografts derived from the highest VEGF-expressing cell clones. A similar trend was noted in the SCCVII tumor model. The present findings indicate that vandetanib therapy effectively counteracted the aggressive feature of tumor growth resulting from VEGF over-expressing tumor cells and suggest that such tumors may be particularly well suited for anti-VEGF interventions.
authors.affiliation: Department of Radiation Oncology, University of Florida, Gainesville, Florida 32610, U.S.A. siemadw@ufl.edu
authors.forename: Dietmar W
authors.initials: DW
authors.lastname: Siemann
authors.forename: Christina M
authors.initials: CM
authors.lastname: Norris
authors.forename: Anderson
authors.initials: A
authors.lastname: Ryan
authors.forename: Wenyin
authors.initials: W
authors.lastname: Shi
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010880:Piperidines; D011799:Quinazolines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C452423:vandetanib