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Tumor Radiosensitization by Antiinflammatory Drugs: Evidence for a New Mechanism Involving the Oxygen Effect

¹ Laboratory of Medicinal Chemistry and Radiopharmacy, ² Laboratory of Biomedical Magnetic Resonance, ³ Laboratory of Pharmacology and Therapeutics, ⁴ Laboratory of Molecular Imaging and Experimental Radiotherapy, Université Catholique de Louvain, Brussels, Belgium

Requests for reprints: Bernard Gallez, Laboratory of Biomedical Magnetic Resonance, Université Catholique de Louvain, CMFA/REMA Avenue Mounier 73.40, B-1200 Brussels, Belgium. Phone: 32-2764-2792; Fax: 32-2764-2790; E-mail: Gallez{at}cmfa.ucl.ac.be.

We hypothesized that nonsteroidal antiinflammatory drugs (NSAIDs) might enhance tumor radiosensitivity by increasing tumor oxygenation (pO₂), via either a decrease in the recruitment of macrophages or from inhibition of mitochondrial respiration. The effect of four NSAIDs (diclofenac, indomethacin, piroxicam, and NS-398) on pO₂ was studied in murine TLT liver tumors and FSaII fibrosarcomas. At the time of maximum pO₂ (t_max, 30 minutes after administration), perfusion, oxygen consumption, and radiation sensitivity were studied. Local pO₂ measurements were done using electron paramagnetic resonance. Tumor perfusion and permeability measurements were assessed by dynamic contrast-enhanced magnetic resonance imaging. The oxygen consumption rate of tumor cells after in vivo NSAID administration was measured using high-frequency electron paramagnetic resonance. Tumor-infiltrating macrophage localization was done with immunohistochemistry using CD11b antibody. All the NSAIDs tested caused a rapid increase in pO₂. At t_max, tumor perfusion decreased, indicating that the increase in pO₂ was not caused by an increase in oxygen supply. Also at t_max, global oxygen consumption decreased but the amount of tumor-infiltrating macrophages remained unchanged. Our study strongly indicates that the oxygen effect caused by NSAIDs is primarily mediated by an effect on mitochondrial respiration. When irradiation (18 Gy) was applied at t_max, the tumor radiosensitivity was enhanced (regrowth delay increased by a factor of 1.7). These results show the potential utility of an acute administration of NSAIDs for radiosensitizing tumors, and shed new light on the mechanisms of NSAID radiosensitization. These results also provide a new rationale for the treatment schedule when combining NSAIDs and radiotherapy.

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