ZD6474, a Potent Inhibitor of Vascular Endothelial Growth Factor Signaling, Combined With Radiotherapy

Abstract

Purpose: Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis and acts as a radiation survival factor for endothelial cells. ZD6474 (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-quinazolin-4-amine) is a potent VEGF receptor 2 (KDR) tyrosine kinase inhibitor (TKI) that has additional activity versus the epidermal growth factor receptor. This study was designed to determine the efficacy of combining ZD6474 and radiotherapy in vivo.Experimental Design: The Calu-6 (non-small-cell lung cancer) tumor model was selected because it was found to be unresponsive to treatment with a selective epidermal growth factor receptor TKI but responds significantly to treatment with selective VEGF receptor TKIs. Tumor-bearing mice received either vehicle or ZD6474 (50 mg/kg, by mouth, once daily) for the duration of the experiment, with or without radiotherapy (3 ؋ 2 Gy, days 1-3). Two combination schedules were examined: (a) ZD6474 given before each dose of radiation (concurrent schedule); and (b) ZD6474 given 30 minutes after the last dose of radiotherapy (sequential schedule).Results: The growth delay induced using the concurrent schedule was greater than that induced by ZD6474 or radiation treatment alone (22 ؎ 1 versus 9 ؎ 1 and 17 ؎ 2 days, respectively; P ‫؍‬ 0.03 versus radiation alone). When administered sequentially, the growth delay was markedly enhanced (36 ؎ 1 days; P < 0.001 versus radiation alone or the concurrent schedule). Intravenous administration of Hoechst 33342 showed a trend toward reduced tumor perfusion after ZD6474 treatment, and a pairwise comparison (versus control) was significant after three doses of ZD6474 (P ‫؍‬ 0.05 by one-tailed t test). Thus, impaired reoxygenation between fractions in the concurrent protocol may be the causal basis for the schedule dependency of the radiopotentiation observed.Conclusions: ZD6474 may be a successful adjuvant to clinical radiotherapy, and scheduling of the treatments could be important to ensure optimal efficacy.

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma

“…Vandetanib is a tyrosine kinase inhibitor of both VEGFR-2 and EGFR, and preclinical studies have confirmed its anti-tumour effects in a range of cancer types (Wedge et al, 2002;Ciardiello et al, 2004;Taguchi et al, 2004;Williams et al, 2004;Yano et al, 2005). Phase III clinical studies are now underway with vandetanib in non-small-cell lung cancer following promising results in phase I and II studies (Holden et al, 2005;Natale et al, 2006;Tamura et al, 2006;Heymach et al, 2007a, b).…”

Combining radiotherapy with AZD2171, a potent inhibitor of vascular endothelial growth factor signaling: pathophysiologic effects and therapeutic benefit

“…One potential downside to this observation is that a substantial loss of the endothelial cell compartment has been associated with the induction of hypoxia (16,17), which could limit the effectiveness of radiotherapy in vivo. Indeed, compromised perfusion as a consequence of VEGF-inhibition during radiotherapy has been associated with suboptimal efficacy (7,8). Conversely, some studies have suggested that VEGFR-blockade can lead to a transient normalization of the vasculature, leading to a window of opportunity when perfusion, oxygenation, and consequently, radiation response may be improved (4,18,19).…”

Hypoxia modulation and radiosensitization by the novel dual EGFR and VEGFR inhibitor AEE788 in spontaneous and related allograft tumor models

“…A combined treatment modality with IR and ZD6474, another dual specific inhibitor of both VEGF and EGFR signaling, has previously been tested in xenografts of nonsmall cell lung cancer and glioblastoma (30,41). These studies focused on the antiangiogenic aspect of ZD6474, demonstrating reduced perfusion in the lung cancer model and reduced expression of VEGF in the glioblastoma model.…”