Interaction of the peroxidase-derived metabolite of mitoxantrone with nucleic acids. Evidence for covalent binding of 14C-labeled drug.
The antitumor agent mitoxantrone undergoes horseradish peroxidase-catalyzed oxidation by hydrogen peroxide to an identifiable cyclic metabolite which is a substituted hexahydronaphtho[2,3-f]-quinoxaline-7,12-dione. Binding of mitoxantrone to DNA inhibited enzymatic oxidation of the drug. The metabolite of mitoxantrone, derived from the action of the HRP/H2O2 system on the drug, bound non-covalently to DNA oligomers. Spectrophotometric analyses of such complexes showed formation of a new, blue-shifted, metachromatic absorption band which was observed when the DNA base pair to drug ratio was close to 1. Measurements of DNA unwinding angles suggest that the metabolite, in contrast to mitoxantrone, did not intercalate but rather bound externally to DNA. Experiments with 14C-labeled mitoxantrone confirmed that peroxidase-activated drug binds covalently to DNA.
Reszka
K
K
Department of Chemistry, University of Alberta, Edmonton, Canada.
Hartley
J A
JA
Kolodziejczyk
P
P
Lown
J W
JW
D001482:Base Composition; D001711:Biotransformation; D004247:DNA / Q000378:metabolism*; D006735:Horseradish Peroxidase / Q000378:metabolism*; D006861:Hydrogen Peroxide; D008942:Mitoxantrone / Q000378:metabolism*; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000378:metabolism*; D013053:Spectrophotometry
D004247:DNA; D006861:Hydrogen Peroxide; D008942:Mitoxantrone; D006735:Horseradish Peroxidase; D010544:Peroxidases