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.