The selective VEGFR1-3 inhibitor axitinib (AG-013736) shows antitumor activity in human neuroblastoma xenografts.
Tumor angiogenesis in childhood neuroblastoma is an important prognostic factor suggesting a potential role for antiangiogenic agents in the treatment of high-risk disease. Within the KidsCancerKinome project, we evaluated the new oral selective pan-VEGFR tyrosine kinase inhibitor axitinib (AG-013736) against neuroblastoma cell lines and the subcutaneous and orthotopic xenograft model IGR-N91 derived from a primary bone marrow metastasis. Axitinib reduced cell proliferation in a dose-dependent manner with IC(50) doses between 274 and >10,000 nmol/l. Oral treatment with 30 mg/kg BID for 2 weeks in advanced tumors yielded significant tumor growth delay, with a median time to reach five times initial tumor volume of 11.4 days compared to controls (p = 0.0006) and resulted in significant reduction in bioluminescence. Simultaneous inhibition of VEGFR downstream effector mTOR using rapamycin 20 mg/kg q2d×5 did not statistically enhance tumor growth delay compared to single agent activities. Axitinib downregulated VEGFR-2 phosphorylation resulting in significantly decreased microvessel density (MVD) and overall surface fraction of tumor vessels (OSFV) in all xenografts as measured by CD34 immunohistochemical staining (mean MVD ± SD and OSFV at 14 days 21.27 ± 10.03 in treated tumors vs. 48.79 ± 17.27 in controls and 0.56% vs. 1.29%; p = 0.0006, respectively). We further explored the effects of axitinib on circulating mature endothelial cells (CECs) and endothelial progenitor cells (CEPs) measured by flow cytometry. While only transient modification was observed for CECs, CEP counts were significantly reduced during and up to 14 days after end of treatment. Axitinib has potent antiangiogenic properties that may warrant further evaluation in neuroblastoma.
Rössler
Jochen
J
UPRES EA 3535, Pharmacology and New Anticancer Treatments, University Paris-Sud, Institut Gustave Roussy, Villejuif, France.
Monnet
Yann
Y
Farace
Francoise
F
Opolon
Paule
P
Daudigeos-Dubus
Estelle
E
Bourredjem
Abderrahmane
A
Vassal
Gilles
G
Geoerger
Birgit
B
D000818:Animals; D017209:Apoptosis; D000077784:Axitinib; D015153:Blotting, Western; D019046:Bone Marrow Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002648:Child; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007191:Indazoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009447:Neuroblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D020123:Sirolimus / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects; D014407:Tumor Cells, Cultured; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D007093:Imidazoles; D007191:Indazoles; D000077784:Axitinib; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; D020123:Sirolimus