Arsenic trioxide (As₂O₃) is an effective therapeutic against acute promyelocytic leukemia and certain solid tumors. Because As₂O₃ inhibits mitochondrial respiration in leukemia cells, we hypothesized that As₂O₃ might enhance the radiosensitivity of solid tumors by increasing tumor oxygenation [partial pressure of oxygen (pO₂)] via a decrease in oxygen consumption. Two murine models of radioresistant hypoxic cancer were used to study the effects of As₂O₃. We measured pO₂ and the oxygen consumption rate in vivo by electron paramagnetic resonance oximetry and ¹⁹fluorine-MRI relaxometry. Tumor perfusion was assessed by Patent blue staining. In both models, As₂O₃ inhibited mitochondrial respiration, leading to a rapid increase in pO₂. The decrease in oxygen consumption could be explained by an observed decrease in glutathione in As₂O₃-treated cells, as this could increase intracellular reactive oxygen species that can disrupt mitochondrial membrane potential. When tumors were irradiated during periods of As₂O₃-induced augmented oxygenation, radiosensitivity increased by 2.2-fold compared with control mice. Notably, this effect was abolished when temporarily clamped tumors were irradiated. Together, our findings show that As₂O₃ acutely increases oxygen consumption and radiosensitizes tumors, providing a new rationale for clinical investigations of As₂O₃ in irradiation protocols to treat solid tumors. Cancer Res; 72(2); 482–90. ©2011 AACR.

Hexafluorobenzene (HFB) and perfluoro‐15‐crown‐5‐ether (15C5) were compared as fluorine reporter probes of tissue oxygenation using ¹⁹F MRI for dynamic assessment of muscle oxygenation, with special focus on muscle tissue toxicity of the probes, and consecutive alteration of animal behavior. The latter were also compared in terms of sensitivity to changes in oxygenation as well as of signal‐to‐noise ratio for accurate pO₂ measurements. For that purpose, mouse muscles were imaged at 11.7 T, at 2‐ and 36‐h after intramuscular injection of HFB or 15C5. Histological analysis of the muscle tissue revealed a lack of toxicity for 15C5 from 2 up to 36‐h postinjection, whereas HFB induced tissue necrosis, blood clots and thrombosis as soon as 24‐h postinjection. This muscle toxicity led to a limitation in mice mobility 24‐h after injection of HFB as evidenced by behavioral testing (open‐field, grip strength, and catwalk tests), which was not the case after 15C5 intramuscular injection. Finally, pO₂ measurements assessed 2‐h postinjection showed consistent values with both probes, evidencing cross‐validation of the ¹⁹F MRI oximetry technique for acute measurements. However, the measurement at 36‐h was hampered for HFB, which showed significant lower values of muscle pO₂, whereas 15C5 was able to reliably assess muscle pO₂ at 36‐h postinjection. Magn Reson Med, 2013.