Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts.
Antiangiogenic therapy can enhance radiation-induced tumor growth inhibition. However, the effects of combined antiangiogenic and radiation therapy on long-term tumor control and normal tissue response have not been reported. We treated mice bearing two different human tumor xenografts with anti-vascular endothelial growth factor receptor-2 antibody (DC101) and five dose fractions of local radiation and followed them for at least 6 months. DC101 significantly decreased the dose of radiation necessary to control 50% of tumors locally. The decrease was 1.7- and 1.3-fold for the moderately radiosensitive small cell lung carcinoma 54A and the highly radioresistant glioblastoma multiforme U87, respectively. In contrast to tumors, no increase in skin radiation reaction by the antibody was detected. Surprisingly, 44% of mice bearing 54A tumor developed clear ascites after DC101 treatment at its highest dose; this was fatal to 20% of mice. This adverse effect was seen only in mice that received whole-body irradiation 1 day before tumor implantation. The encouraging results on two human tumor xenografts suggest that vascular endothelial growth factor receptor-2 blockade merits further investigation to assess its potential as an enhancer of radiation therapy in the clinic.
Kozin
S V
SV
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Boucher
Y
Y
Hicklin
D J
DJ
Bohlen
P
P
Jain
R K
RK
Suit
H D
HD
D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000633:toxicity; D001835:Body Weight / Q000276:immunology / Q000528:radiation effects; D018288:Carcinoma, Small Cell / Q000098:blood supply / Q000532:radiotherapy / Q000628:therapy*; D002455:Cell Division / Q000276:immunology / Q000528:radiation effects; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D004306:Dose-Response Relationship, Immunologic; D004307:Dose-Response Relationship, Radiation; D005909:Glioblastoma / Q000098:blood supply / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D007410:Intestinal Diseases / Q000209:etiology / Q000276:immunology; D008175:Lung Neoplasms / Q000098:blood supply / Q000532:radiotherapy / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010100:Oxygen / Q000378:metabolism; D011836:Radiation Tolerance / Q000276:immunology / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology*; D040262:Receptors, Vascular Endothelial Growth Factor; D012867:Skin / Q000528:radiation effects; D014916:Whole-Body Irradiation / Q000009:adverse effects; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D017978:Receptors, Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D010100:Oxygen