Metabolic studies and neurotoxicity in tumors and brain of mice after hypoxic cell sensitizers

Abstract

Purpose : The effects of the radiosensitizers RK-28 and RP-170, both 2-nitroimidazole nucleoside analogues, and KU-2285, a fluorinated 2-nitroimidazole, as well as etanidazole (ETA) on glucose metabolism in mouse tumors and brain were studied to assess their degree of neurotoxicity. Methods and Materials : Adult male C57Bl mice received differing doses of the above sensitizers IP. Blood, brain, and tumor samples were removed at various times and the levels of glycolytic metabolites determined. Glucose uptake and phosphorylation in brain was measured by the 2-deoxyglucose method of Sokoloff et al. (6). Results : RP-170 showed neither signs of toxicity nor significant alterations in glucose metabolism in brain or tumor at doses up to 4 g/kg b.w. up to 4 h. By contrast, RK-28 was extremely neurotoxic at a dose of 1 g/kg b.w. with a high degree of lethality, resulting in a highly significant increase in the brain glucose level from 0.38 μmol/g to 2.20 μmol/g ( p < 0.001) 2 h after administration, whereas that in the tumor was decreased. KU-2285 and ETA were significantly ( p < 0.01) less toxic than RK-28 at this dose, as reflected in a lower increase in the brain glucose level (0.60 gmol/g), although KU-2285 approached that of RK-28 (1.43 μmol/g; p < 0.01) after 2 h following a dose of 2 g/kg b.w. However, in contrast to the other sensitizers, KU-2285 concomitantly also resulted in a highly significant continuous increase ( p < 0.01) in tumor glucose levels. Labeled 3H-2-deoxyglucose studies showed that RP-170 neither markedly affected the uptake of total radioactivity into the brain nor its degree of phosphorylation whereas, KU-2285 (2 g/kg) and RK-28 (1 g/kg) decreased uptake by ∼ 50% and phosphorylation approximately 3 and 4-fold, respectively. At doses of 1 g/kg, ETA and KU-2285 showed no significant changes in these parameters. This indicates a decreased level of neurotoxicity. Conclusion : Since the adult brain relies solely on glucose metabolism for its energy supply, interference to this pathway may be instrumental in the development of neurotoxicity, thus, underlining the need for such metabolic studies to assess the level of toxicity by radiosensitizers.