LOW CONCENTRATIONS OF NITROIMIDAZOLES - E FFECTIVE RADIOSENSITIZERS AT LOW-DOSES

Purpose: There have been various reports that nitroimidazole radiosens itizers are less effective modifiers of radiation response in the clin ically relevant x-ray dose regions (0-4 Gy) than they are at doses use d in classical in vitro experiments. Our studies at low concentrations of etanidazole led us to question this generalization, and our purpos e was to further investigate low concentrations at low doses, using th e microscopic location of cells to facilitate these experiments. The o bservations are compared with data on these drugs in the literature us ing other methods and systems. Methods and Materials: Survival of V79 cells after irradiation in hypoxia +/- drug at various concentrations was assessed using the Cell Analyser (DMIPS) for low doses, in compari son with the standard clonogenic assay (higher doses). Enhancement rat ios (ERs) were calculated at 80% and 2% survival, respectively.Results : Etanidazole (SR-2508) consistently gave higher ERs at low doses (mea sured at 80% survival) than at high doses (survival 2%), when cells we re exposed to drug concentrations below similar to 2 mM (e.g., at 1 mM , ER(80%) = 2.2, ER(2%) = 1.8 in CHO cells after 1 h preincubation at 37 degrees C). Preincubation of cells for 1 h or 15 min at 37 degrees C with etanidazole prior to irradiation increased the ERs at high and low doses but did not change the ''cross-over'' behavior (ER(80%) > ER (2%) at low concentrations, ER(2%) > ER(80%) above 2 mM, regardless of pretreatment at 37 degrees C or cell line, CHO and V79 cells), wherea s the 5-nitroimidazole nimorazole consistently gave the same ERs wheth er determined at high or low radiation doses (e.g., at 1 mM, 1 h prein cubation at 37 degrees C ER(80%) = ER(2%) = 1.3). This crossover behav ior also occurred after irradiation/preincubation at 0 degrees C. The 2-nitroimidazole predecessor, misonidazole, shows the same cross-over behavior. Conclusion: Two nitroimidazoles at low concentrations appear to be as effective sensitizers (or better) at low doses (80% S); at h igh doses (2% S).