Thalidomide radiosensitizes tumors through early changes in the tumor microenvironment.
OBJECTIVE
The aim of this work was to study changes in the tumor microenvironment early after an antiangiogenic treatment using thalidomide (a promising angiogenesis inhibitor in a variety of cancers), with special focus on a possible "normalization" of the tumor vasculature that could be exploited to improve radiotherapy.


METHODS
Tumor oxygenation, perfusion, permeability, interstitial fluid pressure (IFP), and radiation sensitivity were studied in an FSAII tumor model. Mice were treated by daily i.p. injection of thalidomide at a dose of 200 mg/kg. Measurements of the partial pressure of oxygen (pO(2)) were carried out using electron paramagnetic resonance oximetry. Three complementary techniques were used to assess the blood flow inside the tumor: dynamic contrast-enhanced magnetic resonance imaging, Patent Blue staining, and laser Doppler imaging. IFP was measured by a "wick-in-needle" technique.


RESULTS
Our results show that thalidomide induces tumor reoxygenation within 2 days. This reoxygenation is correlated with a reduction in IFP and an increase in perfusion. These changes can be attributed to extensive vascular remodeling that we observed using CD31 labeling.


CONCLUSIONS
In summary, the microenvironmental changes induced by thalidomide were sufficient to radiosensitize tumors. The fact that thalidomide radiosensitization was not observed in vitro, and that in vivo radiosensitization occurred in a narrow time window, lead us to believe that initial vascular normalization by thalidomide accounts for tumor radiosensitization.
Ansiaux
Réginald
R
Laboratories of Biomedical Magnetic Resonance, Université Catholique de Louvain, Avenue E. Mounier 73-40, B-1200 Brussels, Belgium.
Baudelet
Christine
C
Jordan
Bénédicte F
BF
Beghein
Nelson
N
Sonveaux
Pierre
P
De Wever
Julie
J
Martinive
Philippe
P
Grégoire
Vincent
V
Feron
Olivier
O
Gallez
Bernard
B
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003287:Contrast Media; D004578:Electron Spin Resonance Spectroscopy; D005354:Fibrosarcoma / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D019786:Gadolinium DTPA; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009997:Osmotic Pressure / Q000528:radiation effects; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000528:radiation effects; D011836:Radiation Tolerance; D013792:Thalidomide / Q000627:therapeutic use*; D014965:X-Rays
D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D013792:Thalidomide; D019786:Gadolinium DTPA; D010100:Oxygen