[en] Purpose: 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. Experimental Design: 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 (pO2) 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 radio-sensitize 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. [fr] OBJECTIF: L'objectif de ce travail était d'étudier les changements dans le microenvironnement de la tumeur après un début de traitement anti-angiogénique avec la thalidomide (un inhibiteur de l'angiogenèse prometteurs dans une variété de cancers), avec un accent particulier sur une éventuelle «normalisation» de la vascularisation des tumeurs qui pourraient être exploités pour améliorer la radiothérapie. EXPERIMENTAL DESIGN: Tumor oxygenation, perfusion, permeability, interstitial fluid pressure (IFP), and radiation sensitivity were studied in an FSAII tumor model. CONCEPTION EXPERIMENTALE: oxygénation tumorale, la perfusion, la perméabilité, la pression des fluides interstitiels (IFP), et la sensibilité aux rayons ont été étudiés dans un modèle de tumeur FSAII. Mice were treated by daily ip injection of thalidomide at a dose of 200 mg/kg. Les souris ont été traitées par injection ip quotidienne de la thalidomide à une dose de 200 mg / kg. Measurements of the partial pressure of oxygen (pO(2)) were carried out using electron paramagnetic resonance oximetry. Les mesures de la pression partielle d'oxygène (PO (2)) ont été effectuées en utilisant la résonance paramagnétique électronique oxymétrie. 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. Trois techniques complémentaires ont été utilisées pour évaluer le flux sanguin dans la tumeur: dynamique renforcée imagerie par résonance magnétique revanche, en matière de brevets coloration au bleu, et le laser Doppler. IFP a été mesurée par une "mèche en aiguille" technique. RESULTS: Our results show that thalidomide induces tumor reoxygenation within 2 days. Résultats: Nos résultats montrent que la thalidomide induit réoxygénation tumorale dans les 2 jours. This reoxygenation is correlated with a reduction in IFP and an increase in perfusion. Cette réoxygénation est corrélée avec une réduction de l'IFP et une augmentation de la perfusion. These changes can be attributed to extensive vascular remodeling that we observed using CD31 labeling. Ces changements peuvent être attribués à un remodelage vasculaire vaste que nous avons observé en utilisant un étiquetage CD31. CONCLUSIONS: In summary, the microenvironmental changes induced by thalidomide were sufficient to radiosensitize tumors. CONCLUSIONS: En résumé, les modifications du microenvironnement induites par la thalidomide ont été suffisantes pour radiosensitize tumeurs. 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. Le fait que radiosensibilisation thalidomide n'a pas été observé in vitro et in vivo que dans radiosensibilisation s'est produit dans une étroite fenêtre de temps, nous amènent à penser que la normalisation vasculaire initial par les comptes de la thalidomide pour radiosensibilisation tumorale.
Disciplines :
Oncology Radiology, nuclear medicine & imaging
Author, co-author :
ANSIAUX, Reginald; Université Catholique de Louvain - UCL > Laboratory of Biomedical Magnetic Resonance
BAUDELET, Christine; Université Catholique de Louvain - UCL > Laboratory of Biomedical Magnetic Resonance ; Laboratory of Medicinal Chemistry and Radiopharmacy
JORDAN, Bénédicte
BEGHEIN, Nelson; Université Catholique de Louvain - UCL > Laboratory of Biomedical Magnetic Resonance ; Laboratory of Medicinal Chemistry and Radiopharmacy
SONVEAUX, Pierre; Université Catholique de Louvain - UCL > Laboratory of Pharmacology and Therapeutics
DE WEVER, Julie; Université Catholique de Louvain - UCL > Laboratory of Pharmacology and Therapeutics
MARTINIVE, Philippe ; Université Catholique de Louvain - UCL > Laboratory of Pharmacology and Therapeutics
GREGOIRE, Vincent; Université Catholique de Louvain - UCL > Laboratory of BRadiobiology and Radioprotection Unit
FERON, Olivier; Université Catholique de Louvain - UCL > Laboratory of Pharmacology and Therapeutics
Gallez, Bernard
Language :
English
Title :
Thalidomide radiosensitizes tumors through early changes in the tumor microenvironment
Alternative titles :
[fr] Thalidomide radiosensitizes tumeurs grâce à des changements au début de la micro-environnement tumoral.
Publication date :
15 January 2005
Journal title :
Clinical Cancer Research
ISSN :
1078-0432
eISSN :
1557-3265
Publisher :
American Association for Cancer Research, Inc. (AACR), Birmingham, United States - Alabama
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