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Thalidomide Radiosensitizes Tumors through Early Changes in the Tumor Microenvironment

Laboratories of ¹ Biomedical Magnetic Resonance, ² Medicinal Chemistry and Radiopharmacy, and ³ Pharmacology and Therapeutics and ⁴ Radiobiology and Radioprotection Unit, Université Catholique de Louvain, Brussels, Belgium

Requests for reprints: Bernard Gallez, CMFA/REMA Units, Université Catholique de Louvain, Avenue E. Mounier 73.40, B-1200 Brussels, Belgium. Phone: 32-2-7642792; Fax: 32-2-7642790; E-mail: Gallez{at}cmfa.ucl.ac.be.

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 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.

Key Words: antiangiogenic • oxygen • flow • interstitial fluid pressure • radiotherapy

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