Myeloperoxidase oxidizes mitoxantrone to metabolites which bind covalently to DNA and RNA.
The anticancer agent mitoxantrone is readily oxidized by the human haem enzyme myeloperoxidase and hydrogen peroxide. Intercalation of mitoxantrone with DNA inhibited oxidation of the drug by myeloperoxidase. However, at a physiological ionic strength, significant oxidation of the drug was evident. At a H2O2:mitoxantrone ratio of 1.0, myeloperoxidase oxidized mitoxantrone to a metabolite (product B) which associated reversibly with DNA. At greater hydrogen peroxide concentrations, two further metabolites were produced (products C and D), neither of which associated reversibly with DNA, as indicated by the absence of any spectral change in the presence of DNA. Long exposure of the products derived from the oxidation of [14C]mitoxantrone by myeloperoxidase resulted in a time-dependent covalent binding of the activated drug to both DNA and RNA. The amount of DNA adduct increased linearly with the extent of oxidation of mitoxantrone (up to a H2O2:mitoxantrone ratio of 5.0). No adducts resulted from exposure of the oxidized product B to DNA, but adducts formed following further oxidation of B by myeloperoxidase. The myeloperoxidase-catalysed oxidation of mitoxantrone to products capable of interacting covalently and non-covalently with nucleic acids may represent an important mode of action of mitoxantrone against acute myeloid leukemias since these cells (including neutrophils, monocytes and their precursors) contain high levels of myeloperoxidase.
Panousis
C
C
School of Biochemistry, La Trobe University, Bundoora, Victoria, Australia.
Kettle
A J
AJ
Phillips
D R
DR
D000970:Antineoplastic Agents / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D006801:Humans; D008942:Mitoxantrone / Q000378:metabolism*; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism*
D000970:Antineoplastic Agents; D012313:RNA; D004247:DNA; D008942:Mitoxantrone; D009195:Peroxidase