title: Vertical VEGF targeting: A combination of ligand blockade with receptor tyrosine kinase inhibition.
abstract: The aim of this study was to examine the anti-tumour effects of dual vertical VEGF targeting consisting in the association between bevacizumab, a VEGF-depleting drug, and the VEGF receptor antityrosine kinase AZD2171. Mice bearing human head and neck CAL33 xenografted tumours were treated once daily for 11 d with either vehicle (controls), AZD2171 (2.5mg/kg/day, p.o.), bevacizumab (5mg/kg/day, i.p.) or the bevacizumab-AZD2171 combination. The AZD2171-bevacizumab combination produced additive effects on tumour growth and reduced the number of proliferating cells relative to control. Bevacizumab did not influence tumour vascular necrosis whilst AZD2171 (p=0.01) and the combination (p=0.01) increased it. The number of mature tumour cells decreased significantly with the combination treatment only (p=0.001), which induced the largest increase in the Bax/Bcl2 ratio (up to 25-fold) and a progressive 3-fold decrease in HIF1-alpha expression between 24h and 192h. The present data indicate that there is no redundancy in targeting the same angiogenic pathway with the presently tested clinically applicable drugs. The study provides a strong rationale for future clinical trials.
authors.affiliation: Oncopharmacology Unit - EA3836, Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice Cedex 2, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bozec
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Gros
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.forename: Patricia
authors.initials: P
authors.lastname: Formento
authors.forename: Anne
authors.initials: A
authors.lastname: Cayre
authors.forename: Clélia
authors.initials: C
authors.lastname: Dental
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne-Grimaldi
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Fischel
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D000068258:Bevacizumab; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011799:Quinazolines / Q000627:therapeutic use*; D014062:Tongue Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D004338:Drug Combinations; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C500926:cediranib; D007211:Indoles