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

Prior studies using pO(2) microelectrodes have shown that RSR13, an alloste ric modifier of hemoglobin, increases tissue oxygenation in vivo. Recently, measurements of tissue oxygenation have been performed by many investigato rs 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 carc inoma 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, a nd various doses of RSR13 were administered intraperitoneally (i.p.). MR im ages were then acquired at 10-min intervals for up to 60 min after injectio n. The effect of RSR13 on tumor response was studied using the same mouse x enograft model with tumor growth delay measurements. RSR13 increased the MR I signal ratio [Intensity(t)/Intensity(t = 0)] in a dose-dependent manner, with maximum increases occurring 30 min after RSR13 was administered. An RS R13 dose of 200 mg/kg proved to be optimum. Since the NM signal ratio has b een shown previously to be linearly related to tissue oxygenation, the chan ges in the MRI signal ratio can be attributed to changes in tumor oxygen le vels. Using a 200-mg/kg dose of RSR13, with a 10-Gy dose of radiation admin istered to tumors 30 min later, enhancement of radiation-induced tumor grow th delay by RSR13 was observed (enhancement factor = 2.8). Thus our MRI res ults support and verify the previously reported RSR13-induced increase in t umor oxygenation obtained using pO(2) microelectrodes. Based upon these res ults and other previous studies, the mechanism of enhancement of the effect of radiation by RSR13 probably involves an increase in tumor oxygenation. (C) 2001 by Radiation Research Society.