Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126

• Published in: British journal of cancer Vol. 95; no. 6; pp. 722 - 728
• Main Authors: BOZEC, A, LASSALLE, S, GUGENHEIM, J, FISCHEL, J.-L, FORMENTO, P, HOFMAN, P, MILANO, G
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 18.09.2006
• Subjects: Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Drug Synergism; Female; Gefitinib; Head and Neck Neoplasms - drug therapy; Humans; Medical sciences; Mice; Mice, Nude; Neoplasm Transplantation; Organophosphorus Compounds - pharmacology; Organophosphorus Compounds - therapeutic use; Quinazolines - pharmacology; Quinazolines - therapeutic use; Sensitivity and Specificity; Translational Therapeutics; Treatment Outcome; Tumors; Xenograft Model Antitumor Assays; Antineoplastic agent; ZD6126; Targeting; Enzyme; Quinazoline derivatives; Transferases; Enzyme inhibitor; Antivascular agent; antivascular agents; Epidermal growth factor receptor; Cancerology; Tumor; EGFR targeting; Antiangiogenic agent; Gefitinib; Protein-tyrosine kinase
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6603308

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.