Combining radiotherapy with AZD2171, a potent inhibitor of vascular endothelial growth factor signaling: pathophysiologic effects and therapeutic benefit.
AZD2171 is a highly potent, orally active inhibitor of vascular endothelial growth factor receptor signaling. The potential for AZD2171 to enhance the antitumor effects of radiotherapy was investigated in lung (Calu-6) and colon (LoVo) human tumor xenograft models. Combined treatment resulted in a significantly enhanced growth delay compared with either modality alone. The enhancement was independent of whether chronic once daily AZD2171 treatment was given 2 h prior to each radiation fraction (2 Gy daily for 3 or 5 consecutive days), and daily thereafter, or commenced immediately following the course of radiotherapy. Histologic assessments revealed that 5 days of radiation (2 Gy) or AZD2171 (3 or 6 mg/kg/d) reduced vessel density and perfusion. Concomitant AZD2171 and radiation enhanced this effect and produced a significant increase in tumor hypoxia. Concomitant AZD2171 (6 mg/kg/d) was also found to reduce tumor growth significantly during the course of radiotherapy (5 x 2 Gy). However, the extent and duration of tumor regression observed postradiotherapy was similar to sequentially treated tumors, suggesting that preirradiated tumors were sensitized to AZD2171 treatment. An enhanced antivascular effect of administering AZD2171 postradiotherapy was observed in real-time in Calu-6 tumors grown in dorsal window chambers. Collectively, these data support the clinical development of AZD2171 in combination with radiotherapy.
Williams
Kaye J
KJ
Department of Pharmacy, University of Manchester, Coupland Street, Manchester M13 9PL, United Kingdom. kaye.williams@manchester.ac.uk
Telfer
Brian A
BA
Shannon
Aoife M
AM
Babur
Muhammad
M
Stratford
Ian J
IJ
Wedge
Stephen R
SR
D000818:Animals; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D051379:Mice; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011799:Quinazolines / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D042461:Vascular Endothelial Growth Factor A; C500926:cediranib; D007211:Indoles