Effect of Nitroimidazole Sensitizers on In Vitro Glycolytic Metabolism of Hypoxic Squamous Cell Carcinoma

Abstract

Two nitroimidazole compounds, misonidazole (MISO) and nimorazole (NIMO), were evaluated for their potential to modify uptake of [5,6-³H] 2-fluoro-2-deoxy-D-glucose (³H-FDG) in the human squamous carcinoma cell line UT-SCC-5 exposed to increasing levels of hypoxia. UT-SCC-5 cells were incubated with 0-10 mM of MISO or NIMO under normal or reduced oxygen concentrations of 20%, 1.5%, or 0% with 5% CO₂ for 6 h, after which 74 KBq of ³H-FDG was added in media for 1 h. In the presence of normal concentrations of O₂, both sensitizers increased ³H-FDG uptake by up to 178% (MISO) or 84% (NIMO) when compared with untreated cells. In anoxia, MISO decreased ³H-FDG uptake to 35% of that of control whereas NIMO-treated cells showed a respective decrease in tracer uptake to 62%. Clonogenic assays clearly indicated that MISO was toxic and NIMO moderately toxic for hypoxic cells, whereas both sensitizers exerted only a very modest effect on survival of fully oxygenated cells. Our findings indicate that nitroimidazole treatment consistently increases ³H-FDG uptake into UT-SCC-5 cells under normal oxygen concentrations. In hypoxia, the observed decrease in tracer uptake is dependent on both the level of ambient oxygen and drug concentration and may reflect both direct toxicity and inhibition of glycolysis. The observations may be useful for further applications of ¹⁸F-FDG positron emission tomography (PET) to monitor effects of hypoxic cell radiosensitizers on tumor metabolism in vivo.