Prior studies using pO(2)
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-cm(3)
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 RSR13-induced increase in
tumor oxygenation obtained using pO(2)
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.