Enhancement of tumor oxygenation and radiation response by the allosteric effector of hemoglobin, RSR13

Prior studies using pO₂ microelectrodes have shown that RSR13, an allosteric modifier of hemoglobin, increases tissue oxygenation in vivo. Recently, measurements of tissue oxygenation have been performed by many investigators using blood oxygen level-dependent magnetic resonance imaging (BOLD MRI). In this study, we tested the hypothesis that the BOLD MRI signal ratio in tumors will change after administration of RSR13. NCI-H460 human lung carcinoma cells were used as a xenograft in athymic nude mice. Mice with 1-cm³ tumors in the flank were anesthetized and mounted on the MRI apparatus, and various doses of RSR13 were administered intraperitoneally (i.p.). MR images were then acquired at 10-min intervals for up to 60 min after injection. The effect of RSR13 on tumor response was studied using the same mouse xenograft model with tumor growth delay measurements. RSR13 increased the MRI signal ratio [Intensity(t)/Intensity(t = 0)] in a dose-dependent manner, with maximum increases occurring 30 min after RSR13 was administered. An RSR13 dose of 200 mg/kg proved to be optimum. Since the MRI signal ratio has been shown previously to be linearly related to tissue oxygenation, the changes in the MRI signal ratio can be attributed to changes in tumor oxygen levels. Using a 200-mg/kg dose of RSR13, with a 10-Gy dose of radiation administered to tumors 30 min later, enhancement of radiation-induced tumor growth delay by RSR13 was observed (enhancement factor = 2.8). Thus our MRI results support and verify the previously reported RSR13induced increase in tumor oxygenation obtained using pO₂ microelectrodes. Based upon these results and other previous studies, the mechanism of enhancement of the effect of radiation by RSR13 probably involves an increase in tumor oxygenation.