Mitoxantrone

Last updated
Mitoxantrone
Mitoxantrone skeletal.svg
Mitoxantrone ball-and-stick.png
Clinical data
Trade names Novantrone
AHFS/Drugs.com Monograph
MedlinePlus a608019
Routes of
administration
Mainly intravenous
ATC code
Legal status
Legal status
  • US: WARNING [1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability n/a
Protein binding 78%
Metabolism Hepatic (CYP2E1)
Elimination half-life 75 hours
Excretion Renal
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
Formula C22H28N4O6
Molar mass 444.488 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 Yes check.svgY
  • Key:KKZJGLLVHKMTCM-UHFFFAOYSA-N Yes check.svgY
   (verify)

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

Contents

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. [2]

The combination of mitoxantrone and prednisone is approved as a second-line treatment for metastatic hormone-refractory prostate cancer. This combination was once the first line of treatment; however, a combination of docetaxel and prednisone improves survival rates and lengthens the disease-free period. [3]

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. [4]

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. [5]

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 [6] [7] between DNA bases. It is also classified as an antibiotic. [8]

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

See also

Related Research Articles

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Pixantrone is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewer toxic effects on cardiac tissue. It acts as a topoisomerase II poison and intercalating agent. The code name BBR 2778 refers to pixantrone dimaleate, the actual substance commonly used in clinical trials.

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<span class="mw-page-title-main">Bisantrene</span> Chemical compound

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References

  1. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  2. 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.
  3. 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.
  4. 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.
  5. "Mitoxantrone Hydrochloride (marketed as Novantrone and generics) – Healthcare Professional Sheet text version". U.S. Food and Drug Administration. Retrieved 19 September 2014.
  6. 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.
  7. 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.
  8. "Mitoxantrone".
  9. 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.