Misonidazole increases the toxicity of BCNU for hypoxic cells

Abstract

Misonidazole (MISO) increased the toxicity of BCNU for hypoxic Chinese Hamster Ovary (CHO) cells in vitro, but had no effect on aerobic toxicity of BCNU. Survival was reduced by up to 10 −3 with an exposure to MISO (1mM x 4 hr) that had no direct toxicity for hypoxic cells. Preincubation of cells with MISO under hypoxic conditions followed by exposure to BCNU in air also resulted in increased toxicity. Related effects were observed when CHO cells were exposed to serum from mice that had received BCNU alone or BCNU + MISO: hypoxic (but not aerobic) cells were more sensitive to serum from mice that had received combined treatment. Studies showed that BCNU was more toxic in serum-free medium and that MISO had little or no effect on BCNU toxicity for hypoxic cells in the absence of serum. High performance liquid chromatography (HPLC) methods showed that BCNU decays with T 1 2 = 0.5 hr in the presence of 10 % fetal calf serum and T 1 2 = 1.0 hr in the absence of serum, but the decay curves were not influenced by hypoxia or by MISO. BCNU metabolism to active intermediates is known to be catabolized by albumen. The dependence of the interaction of BCNU and MISO on both serum and hypoxia is consistent with an effect of a hypoxic product off MISO metabolism to delay catabolism or excretion of protein-catalyzed active intermediates of BCNU.