Antitumor and antiangiogenic activity of cediranib in a preclinical model of renal cell carcinoma.
Cediranib is a highly potent and selective vascular endothelial growth factor (VEGF) signaling inhibitor with activity against all three VEGF receptors (VEGFRs) that inhibits angiogenesis and growth of human tumor xenografts in vivo. The present study evaluated the antitumor and antiangiogenic activity of cediranib in the clinically relevant, murine renal cell carcinoma (RENCA) model and its biological response using VEGF and sVEGFR-2 as biomarkers. Mice were treated with cediranib (5 mg/kg/d p.o.) or vehicle for 2, 8 or 12 days and tumor volumes, microvessel density (MVD) and VEGF and sVEGFR-2 plasma concentrations were determined. Cediranib treatment (8 and 12 days) led to a significant reduction in tumor size (42-50%) and a highly significant reduction in MVD (30-55%) versus controls. After 12 days' treatment, VEGF plasma concentration increased significantly in both cediranib-treated and control animals and this increase correlated with tumor size; the cediranib group showed a more pronounced increase in VEGF but a reduced tumor volume compared with control animals. Plasma concentrations of VEGF reached a plateau in the cediranib group after 17-21 days' treatment. sVEGFR-2 concentrations significantly decreased over 12 days in controls, whereas they remained stable in cediranib-treated mice. sVEGFR-2 did not correlate with tumor volume in controls; mice treated with cediranib had lower relative VEGFR-2 plasma concentrations and tumor burdens. In conclusion, cediranib showed potent antitumor and antiangiogenic efficacy in the RENCA model. sVEGFR-2 plasma concentrations can act as a surrogate marker for antitumor activity of VEGFR signaling inhibitors.
Medinger
Michael
M
Department of Medical Oncology, Tumor Biology Center at the Albert Ludwigs University, Freiburg, Germany. MedingerM@uhbs.ch
Esser
Norbert
N
Zirrgiebel
Ute
U
Ryan
Anderson
A
Jürgensmeier
Juliane M
JM
Drevs
Joachim
J
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D011799:Quinazolines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D007211:Indoles
D020533:Angiogenesis Inhibitors; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; C500926:cediranib; D007211:Indoles