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DNA damage in normal and neoplastic mouse tissues after treatment with misonidazole in vivo
Abstract:
Alkaline elution has been used to examine the integrity of DNA isolated from various tissues from mice treated with misonidazole (MISO). High doses (1-3 mg/g) of MISO caused extensive DNA strand breakage in cells isolated from two fibrosarcoma tumors that were known to contain hypoxic cells, and also in cells from certain normal tissues (liver and kidney in particular). The incidence of strand breaks gives further support to the suggestion that MISO can be metabolically nitroreduced beyond the singly reduced nitro radical-anion in some normal tissues as well as in hypoxic tumor cells, generating DNA-reactive species. Nitroreductases must therefore be able to compete successfully with molecular oxygen for the MISO nitro radical-anion in such tissues.
Insights
High doses of misonidazole (MISO) caused significant DNA strand breaks in hypoxic tumor cells and normal tissues like liver and kidney. This suggests MISO generates DNA-reactive species through metabolic nitroreduction in these tissues.
Area of Science:
- Biochemistry
- Molecular Biology
- Toxicology
Background:
- Misonidazole (MISO) is a hypoxic cell radiosensitizer.
- Understanding MISO's metabolic fate and DNA interaction is crucial for its therapeutic application.
Purpose of the Study:
- To investigate the effect of misonidazole (MISO) on DNA integrity in various mouse tissues.
- To explore the metabolic activation of MISO and its DNA-damaging potential in both tumor and normal cells.
Main Methods:
- Alkaline elution technique was employed to assess DNA strand breakage.
- DNA was isolated from fibrosarcoma tumors and normal tissues (liver, kidney) of MISO-treated mice.
Main Results:
- High doses of MISO (1-3 mg/g) induced extensive DNA strand breaks in hypoxic fibrosarcoma cells.
- Significant DNA strand breakage was also observed in normal tissues, notably liver and kidney.
- These findings support the metabolic nitroreduction of MISO beyond the nitro radical-anion in normal tissues.
Conclusions:
- Misonidazole (MISO) treatment leads to DNA damage in hypoxic tumor cells and certain normal tissues.
- Metabolic nitroreduction of MISO generates DNA-reactive species, indicating potential toxicity in normal tissues.
- Nitroreductase activity and competition with oxygen influence MISO's DNA-damaging effects.