Banner
targets (2)
for drugs
Identification
Name Dexrazoxane
Accession Number DB00380 (APRD00090, DB02444)
Type small molecule
Groups approved
Description

An antimitotic agent with immunosuppressive properties. Dexrazoxane, the (+)-enantiomorph of razoxane, provides cardioprotection against anthracycline toxicity. It appears to inhibit formation of a toxic iron-anthracycline complex. [PubChem]
The Food and Drug Administration has designated dexrazoxane as an orphan drug for use in the prevention or reduction in the incidence and severity of anthracycline-induced cardiomyopathy.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Desrazoxane
Dexrazoxano [INN-Spanish]
Dexrazoxanum [INN-Latin]
Dextrorazoxane
Icrf-187
Razoxana [INN-Spanish]
Razoxanum [INN-Latin]
Salts Not Available
Brand names
Name Company
Cardioxane
Dyzoxane
Eucardion
Razoxane
Razoxin
Tepirone
Troxozone
Zinecard
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Immunosuppressive Agents
  • Cardiovascular Agents
  • Chelating Agents
CAS number 24584-09-6
Weight Average: 268.2691
Monoisotopic: 268.11715502
Chemical Formula C11H16N4O4
InChI Key InChIKey=BMKDZUISNHGIBY-ZETCQYMHSA-N
InChI
InChI=1S/C11H16N4O4/c1-7(15-5-10(18)13-11(19)6-15)2-14-3-8(16)12-9(17)4-14/h7H,2-6H2,1H3,(H,12,16,17)(H,13,18,19)/t7-/m0/s1
Plain Text
IUPAC Name
4-[(2S)-1-(3,5-dioxopiperazin-1-yl)propan-2-yl]piperazine-2,6-dione
SMILES
C[C@@H](CN1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Piperazines
Substructures
  • Carboxylic Acids and Derivatives
  • Amino Ketones
  • Piperazines
  • Aliphatic and Aryl Amines
  • Heterocyclic compounds
  • Carboxamides and Derivatives
Pharmacology
Indication For reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin hydrochloride dose of 300 mg/m^2 and would benefit from continued doxorubicin therapy. Also approved for the treatment of extravasation from intravenous anthracyclines.
Pharmacodynamics Dexrazoxane is a cardioprotective agent for use in conjunction with doxorubicin indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose. Patients receiving anthracycline-derivative antineoplastic agents may experience three types of cardiotoxicity: acute transient type; chronic, subacute type (related to cumulative dose and has a more indolent onset later on); and a late-onset type that manifests years after therapy, mainly in patients that have been exposed to the drug as a child. Although the exact mechanism of anthracycline-induced cardiotoxicity is not known, it has shown to exert a variety of actions that may result in the development of cardiotoxicity. In animals, anthracyclines cause a selective inhibition of cardiac muscle gene expression for α-actin, troponin, myosin light-chain 2, and the M isoform of creatine kinase. This may lead to myofibrillar loss associated with anthracycline-induced cardiotoxicity. Anthracyclines may also cause myocyte damage via calcium overload, altered myocardial adrenergic function, release of vasoactive amines, and proinflammatory cytokines. Furthermore, it has been suggested that the main cause of anthracycline-induced cardiotoxicity is associated with free-radical damage to DNA. The drugs intercalate DNA, chelate metal ions to produce drug-metal complexes, and generate superoxide radicals via oxidation-reduction reactions. Anthracyclines also contain a quinone structure that can undergo reduction via NADPH-dependent reactions to produce a semiquinone free radical that initiates a cascade of superoxide and hydroxide radical generation. Chelation of metal ions, particularly iron, by anthracyclines results in an anthracycline-metal complex that catalyzes the generation of reactive oxygen free radicals. This complex is a powerful oxidant that can initiate lipid peroxidation in the absence of oxygen free radicals. The toxicity induced by antrhacyclines may be exacerbated in cardiac cells, as these cells do not possess sufficient amounts of certain enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase) involved in detoxifying free radicals and protecting the cells from subsequent damage.
Mechanism of action The mechanism by which dexrazoxane exerts its cardioprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that readily penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane (a prodrug) is converted intracellularly to a ring-opened bidentate chelating agent that chelates to free iron and interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy. It should be noted that dexrazoxane may also be protective through its inhibitory effect on topoisomerase II.
Absorption IV administration results in complete bioavailability.
Volume of distribution
  • 9 to 22.6 L/m^2
Protein binding Very low (< 2%)
Metabolism
Dexrazoxane is hydrolysed by the enzyme dihydropyrimidine amidohydrolase in the liver and kidney to active metabolites that are capable of binding to metal ions.
Route of elimination Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of the 500 mg/m2 dose of dexrazoxane was excreted in the urine.
Half life 2.5 hours
Clearance
  • 7.88 L/h/m2 [dose of 50 mg/m2 Doxorubicin and 500 mg/m2 Dexrazoxane]
  • 6.25 L/h/m2 [dose of 60 mg/m2 Doxorubicin and 600 mg/m2 Dexrazoxane]
Toxicity Intraperitoneal, mouse LD10 = 500 mg/kg. Intravenous, dog LD10 = 2 gm/kg.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Bedford laboratories div ben venue laboratories inc
  • Topotarget as
  • Pharmacia and upjohn co
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Prices
Unit description Cost Unit
Zinecard 500 mg vial 517.18 USD vial
Dexrazoxane 500 mg vial 492.55 USD vial
Zinecard 250 mg vial 258.59 USD vial
Dexrazoxane 250 mg vial 246.28 USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 6727253 2000-03-13 2020-03-13
United States 5242901 1993-09-07 2010-09-07
Properties
State solid
Experimental Properties
Property Value Source
melting point 191-197 °C Not Available
water solubility Sparingly soluble Not Available
logP -2.6 Not Available
pKa 2.1 Not Available
Predicted Properties
Property Value Source
water solubility 1.04e+01 g/l ALOGPS
logP -1.1 ALOGPS
logP -2.7 ChemAxon
logS -1.4 ALOGPS
pKa (strongest acidic) 11.2 ChemAxon
pKa (strongest basic) 3.6 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 6 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 98.82 ChemAxon
rotatable bond count 3 ChemAxon
refractivity 64.25 ChemAxon
polarizability 26.12 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Hasinoff BB, Herman EH: Dexrazoxane: how it works in cardiac and tumor cells. Is it a prodrug or is it a drug? Cardiovasc Toxicol. 2007;7(2):140-4. Pubmed
  2. Hasinoff BB: The use of dexrazoxane for the prevention of anthracycline extravasation injury. Expert Opin Investig Drugs. 2008 Feb;17(2):217-23. Pubmed
  3. Kik K, Szmigiero L: [Dexrazoxane (ICRF-187)—a cardioprotectant and modulator of action of some anticancer drugs] Postepy Hig Med Dosw (Online). 2006;60:584-90. Pubmed
  4. Weiss G, Loyevsky M, Gordeuk VR: Dexrazoxane (ICRF-187). Gen Pharmacol. 1999 Jan;32(1):155-8. Pubmed
  5. Langer SW: Dexrazoxane for anthracycline extravasation. Expert Rev Anticancer Ther. 2007 Aug;7(8):1081-8. Pubmed
External Links
Resource Link
PubChem Compound 71384 Link_out
PubChem Substance 46505982 Link_out
ChemSpider 64479 Link_out
ChEBI 50223 Link_out
ChEMBL 50223 Link_out
Therapeutic Targets Database DAP000649 Link_out
PharmGKB PA449259 Link_out
HET CDX Link_out
Drug Product Database 2153440 Link_out
RxList http://www.rxlist.com/cgi/generic2/dexrazoxane.htm Link_out
Drugs.com http://www.drugs.com/cdi/dexrazoxane.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Dexrazoxane Link_out
ATC Codes
  • V03AF02
AHFS Codes Not Available
PDB Entries
FDA label show (162 KB)
MSDS show (161 KB)
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. DNA topoisomerase 2-alpha

Pharmacological action: yes
Actions: inhibitor

Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks

Organism class: human
UniProt ID: P11388 Link_out
Gene: TOP2A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hasinoff BB, Chee GL, Thampatty P, Allan WP, Yalowich JC: The cardioprotective and DNA topoisomerase II inhibitory agent dexrazoxane (ICRF-187) antagonizes camptothecin-mediated growth inhibition of Chinese hamster ovary cells by inhibition of DNA synthesis. Anticancer Drugs. 1999 Jan;10(1):47-54. Pubmed
  2. Hasinoff BB, Abram ME, Barnabe N, Khelifa T, Allan WP, Yalowich JC: The catalytic DNA topoisomerase II inhibitor dexrazoxane (ICRF-187) induces differentiation and apoptosis in human leukemia K562 cells. Mol Pharmacol. 2001 Mar;59(3):453-61. Pubmed
  3. Langer SW, Sehested M, Jensen PB: Dexrazoxane is a potent and specific inhibitor of anthracycline induced subcutaneous lesions in mice. Ann Oncol. 2001 Mar;12(3):405-10. Pubmed
  4. Hasinoff BB, Takeda K, Ferrans VJ, Yu ZX: The doxorubicin cardioprotective agent dexrazoxane (ICRF-187) induces endopolyploidy in rat neonatal myocytes through inhibition of DNA topoisomerase II. Anticancer Drugs. 2002 Mar;13(3):255-8. Pubmed
  5. Renodon-Corniere A, Jensen LH, Nitiss JL, Jensen PB, Sehested M: Analysis of bisdioxopiperazine dexrazoxane binding to human DNA topoisomerase II alpha: decreased binding as a mechanism of drug resistance. Biochemistry. 2003 Aug 19;42(32):9749-54. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Hasinoff BB, Herman EH: Dexrazoxane: how it works in cardiac and tumor cells. Is it a prodrug or is it a drug? Cardiovasc Toxicol. 2007;7(2):140-4. Pubmed
  8. Kik K, Szmigiero L: [Dexrazoxane (ICRF-187)—a cardioprotectant and modulator of action of some anticancer drugs] Postepy Hig Med Dosw (Online). 2006;60:584-90. Pubmed
  9. Hasinoff BB, Abram ME, Chee GL, Huebner E, Byard EH, Barnabe N, Ferrans VJ, Yu ZX, Yalowich JC: The catalytic DNA topoisomerase II inhibitor dexrazoxane (ICRF-187) induces endopolyploidy in Chinese hamster ovary cells. J Pharmacol Exp Ther. 2000 Nov;295(2):474-83. Pubmed

2. DNA topoisomerase 2-beta

Pharmacological action: unknown

Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks

Organism class: human
UniProt ID: Q02880 Link_out
Gene: TOP2B
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19