Neutrophil-mediated activation of mitoxantrone to metabolites which form adducts with DNA.
In this study we have shown that phorbol ester-stimulated human neutrophils are able to oxidatively activate mitoxantrone and result in covalent incorporation of the drug into cellular DNA. The use of the myeloperoxidase inhibitor sodium azide confirmed that the activation and covalent binding of mitoxantrone to cellular DNA was due to its metabolism by the haem enzyme myeloperoxidase. Phorbol ester-stimulated neutrophils were also able to oxidatively metabolise mitoxantrone and facilitate extracellular covalent binding of the drug to calf thymus DNA. These results suggest that myeloperoxidase may contribute to the mode of action of mitoxantrone.
Panousis
C
C
School of Biochemistry, La Trobe University, Bundoora, Victoria, Australia.
Kettle
A J
AJ
Phillips
D R
DR
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001386:Azides / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002417:Cattle; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008942:Mitoxantrone / Q000378:metabolism*; D018375:Neutrophil Activation / Q000187:drug effects / Q000502:physiology*; D016897:Respiratory Burst / Q000187:drug effects / Q000502:physiology; D019810:Sodium Azide; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000970:Antineoplastic Agents; D001386:Azides; D002273:Carcinogens; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D004247:DNA; D019810:Sodium Azide; D008942:Mitoxantrone; D013755:Tetradecanoylphorbol Acetate