Mitoxantrone

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Mitoxantrone
Mitoxantrone skeletal.svg
Mitoxantrone ball-and-stick.png
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)
Legal status
  • (Prescription only)
Routes of
administration
Mainly intravenous
Pharmacokinetic data
Bioavailability n/a
Protein binding 78%
Metabolism Hepatic (CYP2E1)
Biological half-life 75 hours
Excretion Renal
Identifiers
CAS Registry Number 65271-80-9 YesY
ATC code L01DB07
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
Molecular mass 444.481 g/mol
 YesY (what is this?)  (verify)

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

Uses[edit]

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[edit]

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[edit]

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[edit]

References[edit]

  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.  edit
  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. 
  7. ^ Baron M, Giorgi-Renault S, Renault J et al. (1984). "Heterocycles with a quinone function.5.An abnormal reaction of butanedione with 1,2-diaminoanthraquinone - Crystalline structure obtained from naphto(2,3-f) quinoxaline-7,12 dione". Can. J. Chem. (in French) 62 (3): 526–530. doi:10.1139/v84-087.