Mitoxantrone, More than Just Another Topoisomerase II Poison

  title={Mitoxantrone, More than Just Another Topoisomerase II Poison},
  author={Benny J. Evison and Brad E. Sleebs and Keith Geoffrey Watson and Don R. Phillips and Suzanne M. Cutts},
  journal={Medicinal Research Reviews},
Mitoxantrone is a synthetic anthracenedione originally developed to improve the therapeutic profile of the anthracyclines and is commonly applied in the treatment of breast and prostate cancers, lymphomas, and leukemias. A comprehensive overview of the drug's molecular, biochemical, and cellular pharmacology is presented here, beginning with the cardiotoxic nature of its predecessor doxorubicin and how these properties shaped the pharmacology of mitoxantrone itself. Although mitoxantrone is… 
Topoisomerase II inhibitors in AML: past, present, and future
The authors believe that small molecule inhibitors, such as venetoclax and possibly immunotherapy options could also be incorporated to the treatment paradigm in selected patients.
Anthracyclines are a clinically important class of antineoplastic agents used to treat a wide variety of solid and blood cancers. The first described anthracycline, daunorubicin, was first isolated
Intercalating TOP2 Poisons Attenuate Topoisomerase Action at Higher Concentrations
It is shown that anthracyclines and mitoxantrone act as topoisomerase II (TOP2) poisons at low concentration but attenuate TOP2 activity at higher concentration, both in cells and in in vitro cleavage experiments, suggesting that inhibition of TOP2B activity, rather than DNA damage resulting from TOP2 poisoning, may play a role in doxorubicin cardiotoxicity.
Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy
It is shown that myeloperoxidase activity leads to elevated accumulation of etoposide- and mitoxantrone-induced TOP2A and TOP2B-DNA covalent complexes in cells, which are converted to DNA double-strand breaks, a significant finding because TOP2 B has been linked to genetic damage associated with leukemic transformation.
Copper Complexes as Anticancer Agents Targeting Topoisomerases I and II
New emerging treatment aspects are depicted to encourage the expansion of this family of highly active anticancer drugs and to expend their use in clinical trials and future cancer therapy.
Myeloperoxidase enhances DNA damage induced by drugs targeting DNA topoisomerase II
Results show inhibition of myeloperoxidase could protect developing hematopoietic cells from TOP2 poison mediated damage without compromising the effectiveness of these drugs as antineoplastic agents.
Topoisomerase Inhibitors in Breast Cancer
Biology and molecular mechanics of the topoisomerase enzymes, and the effects of their inhibition in breast cancer, are discussed to explain and support the application of topoisomersase inhibitors in Breast cancer.
An evaluation of the interaction of pixantrone with formaldehyde-releasing drugs in cancer cells
The molecular nature of these lesions within cancer cells exposed to pixantrone and formaldehyde-releasing prodrugs was characterized along with the cellular responses to their formation, suggesting that pIXantrone-DNA adducts may promote a topoisomerase II-independent mechanism of cell death.
Topoisomerases as anticancer targets.
Topoisomerases remain as important therapeutic targets of anticancer agents and a possibility of designing isoform-specific human topoisomerase II poisons, which may be developed as safer anticancer drugs is suggested.


Mitoxantrone affects topoisomerase activities in human breast cancer cells.
Mitoxantrone: a new anticancer drug with significant clinical activity.
The drug has antiviral, antibacterial, antiprotozoal, immunomodulating, and antineoplastic properties and is mutagenic in some animal systems and is a promising new agent in the treatment of cancer.
NK314, a Topoisomerase II Inhibitor That Specifically Targets the α Isoform*
It is shown that NK314, a novel synthetic benzo[c]phenanthridine alkaloid, targets Top2α and not Top2β in vivo, and that a series of human knock-out cell lines are useful in assessing DNA damage and repair induced by potential topoisomerase-targeting agents.
Clinical applications of anticancer drugs targeted to topoisomerase II.
  • K. Hande
  • Medicine, Biology
    Biochimica et biophysica acta
  • 1998
Mitoxantrone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer.
Mitoxantrone is an effective and better tolerated alternative to the anthracyclines in most haematological malignancies, in breast cancer and in advanced hepatic or ovarian carcinoma, and synergy with other antineoplastic drugs has been demonstrated in murine tumour models.
The anthracyclines: will we ever find a better doxorubicin?
  • R. Weiss
  • Biology, Chemistry
    Seminars in oncology
  • 1992
Current studies are evaluating increased doses of epirubicin to improve anthracycline cytotoxicity, while limiting cardiotoxicity, but at present DOX still reigns in this drug class as the one having the most proven cancerocidal effect.
Pharmacokinetics and Metabolism of Mitoxantrone A Review
Mitoxantrone, a cytotoxic anthracenedione derivative, has given clinical evidence of beneficial activity in breast cancer, lymphoma and leukaemia and in peritoneal carcinosis; other regimens include continuous infusion, daily repeated doses or weekly administration.
Toxicity of the topoisomerase II inhibitors
  • K. Seiter
  • Medicine
    Expert opinion on drug safety
  • 2005
Toxicities of topoisomerase II inhibitors are discussed, including administration of these agents to patients with hepatic and/or renal insuffi-ciency, and the need for dose adjustments in selected patient populations.
Structural Basis of Type II Topoisomerase Inhibition by the Anticancer Drug Etoposide
The crystal structure of a large fragment of human TOP2β complexed to DNA and to the anticancer drug etoposide is presented to reveal structural details of drug-induced stabilization of a cleavage complex and the analysis of protein-drug interactions provides information applicable for developing an isoform-specific TOP2-targeting strategy.