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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 (ImM 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 of MISO metabolism to delay catabolism or excretion of protein-catalyzed active intermediates of BCNU.
Insights
Misonidazole (MISO) enhances BCNU chemotherapy for hypoxic cells by increasing its toxicity, showing potential for combined cancer treatment strategies. This effect is dependent on both hypoxia and serum presence.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- BCNU (Carmustine) is a chemotherapy drug with known toxicity.
- Hypoxia is a common characteristic of solid tumors.
- Misonidazole (MISO) is a radiosensitizer investigated for cancer therapy.
Purpose of the Study:
- To investigate the combined effect of Misonidazole (MISO) and BCNU on Chinese Hamster Ovary (CHO) cells under varying oxygen conditions.
- To explore the role of serum and hypoxia in the interaction between MISO and BCNU.
Main Methods:
- In vitro exposure of CHO cells to MISO and BCNU under hypoxic and aerobic conditions.
- Analysis of cell survival rates.
- Exposure of cells to mouse serum from animals treated with BCNU alone or in combination with MISO.
- High-performance liquid chromatography (HPLC) to assess BCNU decay kinetics in the presence and absence of serum and MISO.
Main Results:
- MISO significantly increased BCNU toxicity in hypoxic CHO cells, reducing survival by up to 10(-3), with no effect on aerobic cells.
- Preincubation with MISO under hypoxia followed by BCNU exposure enhanced toxicity.
- Hypoxic cells showed increased sensitivity to serum from mice treated with combined BCNU + MISO.
- BCNU toxicity was higher in serum-free medium, and MISO had minimal effect on BCNU toxicity in hypoxic cells without serum.
- HPLC showed BCNU decay was faster in serum, but not influenced by hypoxia or MISO.
Conclusions:
- The observed interaction between MISO and BCNU is dependent on both serum and hypoxia.
- A hypoxic metabolite of MISO may delay the catabolism or excretion of protein-catalyzed active BCNU intermediates.
- This suggests a potential therapeutic strategy of combining MISO with BCNU to enhance efficacy against hypoxic tumor regions.