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DNA strand breakage by peroxidase-activated mitoxantrone
1Department of Pharmacy, Leicester Polytechnic, UK.
The Journal of Pharmacy and Pharmacology
|January 1, 1991
Summary
Horseradish peroxidase activates the anticancer drug mitoxantrone into a DNA-damaging free radical. This mitoxantrone-derived radical cross-links with plasmid DNA, potentially explaining its anti-tumor mechanism.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Mitoxantrone is an alkylaminoanthraquinone used as an anticancer agent.
- The precise mechanism of action for mitoxantrone, particularly its interaction with DNA, requires further elucidation.
Purpose of the Study:
- To investigate the interaction between mitoxantrone and horseradish peroxidase (HRP) in the presence of hydrogen peroxide.
- To characterize the resulting mitoxantrone-derived species and their effect on plasmid DNA.
Main Methods:
- Spectroscopic analysis was employed to detect and identify reaction products.
- The cross-linking of mitoxantrone-derived species with plasmid DNA was assessed.
- The concentration-dependent nature of the DNA cross-linking reaction was examined.
Main Results:
- Spectroscopic evidence confirmed that mitoxantrone is a substrate for HRP and hydrogen peroxide.
- The interaction yielded an air-stable mitoxantrone-derived free radical.
- These radicals, or their oxidation products, extensively cross-linked with plasmid DNA in a concentration-dependent manner.
Conclusions:
- Oxidative activation of mitoxantrone by HRP generates DNA-damaging species.
- This oxidative activation and subsequent DNA cross-linking may contribute to the antitumour activity of mitoxantrone.