ZD6474, a potent inhibitor of vascular endothelial growth factor signaling, combined with radiotherapy: schedule-dependent enhancement of antitumor activity.
OBJECTIVE
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.


METHODS
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 x 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.
Williams
Kaye J
KJ
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom. kaye.williams@manchester.ac.uk
Telfer
Brian A
BA
Brave
Sandra
S
Kendrew
Jane
J
Whittaker
Lynsey
L
Stratford
Ian J
IJ
Wedge
Stephen R
SR
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D003131:Combined Modality Therapy; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D010100:Oxygen / Q000378:metabolism; D010880:Piperidines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D011878:Radiotherapy; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D010880:Piperidines; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077156:Gefitinib; D010100:Oxygen; C452423:vandetanib