title: Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126.
abstract: Current experimental and clinical knowledge supports the optimisation of endothelial cell targeting using a strategy combining anti-EGFR drugs with antivascular agents. The purpose of the present study was to examine the effects of the association of ZD6126, an antivascular microtubule-destabilising agent, with gefitinib and irradiation on the growth of six head and neck human cancer cell lines xenografted in nude mice and to study predictive and molecular factors responsible for antitumour effects. CAL33- and Hep-2-grafted cell lines were the most sensitive to ZD6126 treatment, with VEGF levels significantly higher (P=0.0336) in these tumour xenografts compared to Detroit 562- and CAL27-grafted cell lines with relatively low VEGF levels that were not sensitive to ZD6126. In contrast, neither IL8 levels nor EGFR expression was linked to the antitumour effects of ZD6126. ZD6126 in combination with gefitinib resulted in a synergistic cytotoxic interaction with greater antitumour effects than gefitinib alone. The synergistic interaction between ZD6126 and gefitinib was corroborated by a significant decrease in CD31 labelling. The present study may serve for future innovative clinical applications, as it suggests that VEGF tumour levels are possible predictors for ZD6126 antitumour efficacy. It also supports the notion of antitumour supra-additivity when combining gefitinib and ZD6126, and identifies neoangiogenesis as the main determinant of this synergistic combination.
authors.affiliation: Oncopharmacology Unit, Centre Antoine-Lacassagne, 33, Avenue de Valombrose, 06189 Nice Cedex 2, France.
authors.forename: A
authors.initials: A
authors.lastname: Bozec
authors.forename: S
authors.initials: S
authors.lastname: Lassalle
authors.forename: J
authors.initials: J
authors.lastname: Gugenheim
authors.forename: J-L
authors.initials: JL
authors.lastname: Fischel
authors.forename: P
authors.initials: P
authors.lastname: Formento
authors.forename: P
authors.initials: P
authors.lastname: Hofman
authors.forename: G
authors.initials: G
authors.lastname: Milano
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D004357:Drug Synergism; D005260:Female; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D012680:Sensitivity and Specificity; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C455219:N-acetylcochinol-O-phosphate; D009943:Organophosphorus Compounds; D011799:Quinazolines; D000077156:Gefitinib