Tumour control by whole brain irradiation of anti-VEGF-treated mice bearing intracerebral glioma.
OBJECTIVE
Tumour angiogenesis and invasion are key features of glioblastoma multiforme (GBM). Angiogenesis inhibitors increase progression-free survival (PFS) of recurrent GBM patients. VEGF inhibition controls the bulk tumour growth by inhibition of angiogenesis, but does not inhibit the invasive tumour component. We investigated if invasive tumour growth can be controlled by combining anti-VEGF treatment with irradiation of tumour plus surrounding brain in an orthotopic murine model for GBM.


METHODS
GBM cell line U251-NG2 was inoculated through a guide screw in the right frontal lobe of 53 athymic nude mice. Pegaptanib (a slow-releasing aptamer against VEGF) was injected in the tumour bed either or not followed by irradiation treatment with implanted I-125 seeds. Pegaptanib and/or irradiation were compared with sham-treated controls, resulting in four groups of 10-15 mice each. After 6 weeks of treatment, histological analysis was performed on all brains.


RESULTS
VEGF inhibition by locally deposited pegaptanib decreased tumour blood vessel density, and increased tumour hypoxia. Pegaptanib treatment still allowed the formation of tumour satellites. Irradiation decreased tumour size and suppressed formation of satellites. Combined pegaptanib plus irradiation further increased PFS. Tumour size directly correlated with PFS.


CONCLUSIONS
The anti-tumour effects of local VEGF inhibition are partially circumvented by the formation of invasive tumour satellites. Additional irradiation is effective in slowing down proliferation of these invasive tumour components.
Verhoeff
Joost J C
JJ
Department of Radiation Oncology, Academic Medical Center, Amsterdam, The Netherlands. j.j.verhoeff@amc.nl
Stalpers
Lukas J A
LJ
Claes
An
A
Hovinga
Koos E
KE
Musters
Gijsbert D
GD
Peter Vandertop
W
W
Richel
Dick J
DJ
Leenders
William P J
WP
van Furth
Wouter R
WR
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D052157:Aptamers, Nucleotide / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D052157:Aptamers, Nucleotide; D042461:Vascular Endothelial Growth Factor A; C495058:pegaptanib