Mitoxantrone

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

Mitoxantrone
Clinical data
Trade namesNovantrone
AHFS/Drugs.comMonograph
MedlinePlusa608019
Routes of
administration		Mainly intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailabilityn/a
Protein binding78%
MetabolismHepatic (CYP2E1)
Elimination half-life75 hours
ExcretionRenal
Identifiers
  • 1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)
    ethylamino]-anthracene-9,10-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC22H28N4O6
Molar mass444.488 g·mol−1
3D model (JSmol)
  • O=C2c1c(c(NCCNCCO)ccc1NCCNCCO)C(=O)c3c2c(O)ccc3O
  • InChI=1S/C22H28N4O6/c27-11-9-23-5-7-25-13-1-2-14(26-8-6-24-10-12-28)18-17(13)21(31)19-15(29)3-4-16(30)20(19)22(18)32/h1-4,23-30H,5-12H2 checkY
  • Key:KKZJGLLVHKMTCM-UHFFFAOYSA-N checkY
  (verify)

Uses

Mitoxantrone is used to treat certain types of cancer, mostly acute myeloid leukemia. It improves the survival rate of children suffering from acute lymphoblastic leukemia relapse.[1]

The combination of mitoxantrone and prednisone is approved as a second-line treatment for metastatic hormone-refractory prostate cancer. Until recently this combination was the first line of treatment; however, a combination of docetaxel and prednisone improves survival rates and lengthens 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. In the absence of a cure, mitoxantrone 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 with other drugs in its class, may cause adverse reactions of varying severity, including nausea, vomiting, hair loss, heart damage and immunosuppression, possibly with delayed onset. Cardiomyopathy is a particularly concerning effect as it is irreversible; thus regular monitoring with echocardiograms or MUGA scans is recommended for patients.

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

Mechanism of action

Mitoxantrone is a type II topoisomerase inhibitor; it disrupts DNA synthesis and DNA repair in both healthy cells and cancer cells by intercalation[5][6] between DNA bases. It is also classified as an antibiotic.[7]

Human topoisomerase II beta in complex with DNA and mitoxantrone. PDB entry 4g0v.[8] Detail showing mitoxantrone (spheres) intercalated with DNA.

See also

References
  1. Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, et al. (December 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 BG (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 EJ (April 2006). "Management of worsening multiple sclerosis with mitoxantrone: a review". Clinical Therapeutics. 28 (4): 461–474. 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. Mazerski J, Martelli S, Borowski E (1998). "The geometry of intercalation complex of antitumor mitoxantrone and ametantrone with DNA: molecular dynamics simulations". Acta Biochimica Polonica. 45 (1): 1–11. doi:10.18388/abp.1998_4280. PMID 9701490.
  6. Kapuscinski J, Darzynkiewicz Z (December 1985). "Interactions of antitumor agents Ametantrone and Mitoxantrone (Novatrone) with double-stranded DNA". Biochemical Pharmacology. 34 (24): 4203–4213. doi:10.1016/0006-2952(85)90275-8. PMID 4074383.
  7. "Mitoxantrone".
  8. Wu CC, Li YC, Wang YR, Li TK, Chan NL (December 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. PMC 3905874. PMID 24038465.
  • "Mitoxantrone". Drug Information Portal. U.S. National Library of Medicine.
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