Mitoxantrone

Mitoxantrone
Systematic (IUPAC) name
1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)
ethylamino]-anthracene-9,10-dione
Clinical data
Trade names Novantrone
AHFS/Drugs.com monograph
MedlinePlus a608019
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration		 Mainly intravenous
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability n/a
Protein binding 78%
Metabolism Hepatic (CYP2E1)
Biological half-life 75 hours
Excretion Renal
Identifiers
CAS Number 65271-80-9 YesY
ATC code L01DB07 (WHO)
PubChem CID 4212
IUPHAR/BPS 7242
DrugBank DB01204 YesY
ChemSpider 4067 YesY
UNII BZ114NVM5P YesY
KEGG D08224 YesY
ChEBI CHEBI:50729 YesY
ChEMBL CHEMBL58 YesY
PDB ligand ID MIX (PDBe, RCSB PDB)
Chemical data
Formula C22H28N4O6
Molar mass 444.481 g/mol
  (verify)

Mitoxantrone (INN, BAN, USAN; also known as Mitozantrone in Australia; trade name Novantrone) is an anthracenedione antineoplastic agent.

Uses

Mitoxantrone is used in the treatment of certain types of cancer, mostly metastatic breast cancer, acute myeloid leukemia, and non-Hodgkin's lymphoma. It was also shown to improve the survival rate of children suffering from first relapse of acute lymphoblastic leukemia.[1]

The combination of mitoxantrone and prednisone is approved as a second-line treatment for metastatic hormone-refractory prostate cancer. Until recently this combination has been the first line of treatment; however, a combination of docetaxel and prednisone has been shown to improve survival rates and lengthen the disease-free period.[2]

Mitoxantrone is also used to treat multiple sclerosis (MS), most notably the subset of the disease, known as secondary-progressive MS. As no cure for multiple sclerosis exists yet, it must be understood mitoxantrone will not cure the disease, but rather is effective in slowing the progression of secondary-progressive MS and extending the time between relapses in both relapsing-remitting MS and progressive-relapsing MS.[3]

Side effects

Mitoxantrone, as other drugs in its class, may cause several adverse reactions of varying severity, such as nausea, vomiting, hair loss, heart damage, and immunosuppression, which may also have a delayed onset. Cardiomyopathy is a particularly concerning effect as it is irreversible; thus regular monitoring with echocardiograms or MUGA scans is recommended for people taking mitoxantrone.

Because of the risk of cardiomyopathy, mitoxantrone carries a limit on the cumulative lifetime dose (based on body surface area) in patients with multiple sclerosis.[4]

Mechanism of action

Human topoisomerase iibeta in complex with DNA and mitoxantrone. PDB entry 4g0v.[5] Detail showing mitoxantrone (spheres) intercalated with DNA.

Mitoxantrone is a type II topoisomerase inhibitor; it disrupts DNA synthesis and DNA repair in both healthy cells and cancer cells by intercalation[6] between the DNA bases.

See also

References

  1. ↑ Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V (2010). "Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial". Lancet 376 (9757): 2009–2017. doi:10.1016/S0140-6736(10)62002-8. PMC 3010035. PMID 21131038.
  2. ↑ Katzung, Bertram G. (2006). "Cancer Chemotherapy". Basic and clinical pharmacology (10th ed.). New York: McGraw-Hill Medical Publishing Division. ISBN 0-07-145153-6. OCLC 157011367.
  3. ↑ Fox E (2006). "Management of worsening multiple sclerosis with mitoxantrone: a review". Clin Ther 28 (4): 461–74. doi:10.1016/j.clinthera.2006.04.013. PMID 16750460.
  4. ↑ "Mitoxantrone Hydrochloride (marketed as Novantrone and generics) - Healthcare Professional Sheet text version". U.S. Food and Drug Administration. Retrieved 19 September 2014.
  5. ↑ Wu, C. -C.; Li, Y. -C.; Wang, Y. -R.; Li, T. -K.; Chan, N. -L. (2013). "On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs". Nucleic Acids Research 41 (22): 10630–10640. doi:10.1093/nar/gkt828. PMID 24038465.
  6. ↑ Mazerski J, Martelli S, Borowski E (1998). "The geometry of intercalation complex of antitumor mitoxantrone and ametantrone with DNA: molecular dynamics simulations". Acta Biochim. Pol. 45 (1): 1–11. PMID 9701490.
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