Vertical VEGF targeting: A combination of ligand blockade with receptor tyrosine kinase inhibition

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 (2.5 mg/kg/day, p.o.), bevacizumab (5 mg/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 turnout 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 HIFI-alpha expression between 24 h and 192 h. 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. (C) 2008 Elsevier Ltd. All rights reserved.