DT-Web

DB00380 - Dexrazoxane


Identification
Name Dexrazoxane
Accession Number DB00380 (APRD00090, DB02444)
Type small molecule
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
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 268.2691
Groups approved
Monoisotopic Weight 268.11715502
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.
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.
Protein binding Very low (< 2%)
Biotransformation 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.
Toxicity Intraperitoneal, mouse LD10 = 500 mg/kg. Intravenous, dog LD10 = 2 gm/kg.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions Not Available
Food Interactions Not Available

Targets


DNA topoisomerase 2-alpha
Name DNA topoisomerase 2-alpha
Gene Name TOP2A
Pharmacological action yes
Actions inhibitor
References
  • 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
  • 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
  • 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
  • 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
  • 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
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
  • 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
  • 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
  • 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
DTHybrid score 0.4682
DNA topoisomerase 2-beta
Name DNA topoisomerase 2-beta
Gene Name TOP2B
Pharmacological action unknown
Actions Not Available
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • 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
  • 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
DTHybrid score 0.3885

Predictions


Id Partner name Gene Name Score
6875 Type-2 restriction enzyme EcoRV ecoRVR 0.1797
477 DNA topoisomerase 4 subunit A parC 0.1361
886 DNA topoisomerase 4 subunit A parC 0.1361
6226 DNA topoisomerase 4 subunit A parC 0.1361
404 DNA gyrase subunit A gyrA 0.1336
6224 DNA gyrase subunit A gyrA 0.1336
862 Multidrug resistance-associated protein 1 ABCC1 0.0527
4200 Cytochrome P450 1A2 CYP1A2 0.0502
1588 Multidrug resistance protein 1 ABCB1 0.0402
6137 Multidrug resistance-associated protein 6 ABCC6 0.0375
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.0361
4512 Cytochrome P450 3A4 CYP3A4 0.0337
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0332
4180 DNA-(apurinic or apyrimidinic site) lyase APEX1 0.0305
6148 Multidrug resistance-associated protein 7 ABCC10 0.0274
4118 Cytochrome P450 3A5 CYP3A5 0.0269
118 Organic cation/carnitine transporter 2 SLC22A5 0.0211
1353 DNA topoisomerase 1 TOP1 0.0202
3552 DNA topoisomerase 1 topA 0.0202
1898 Cytochrome P450 1B1 CYP1B1 0.0194
588 Chromodomain-helicase-DNA-binding protein 1 CHD1 0.0192
4120 NADPH--cytochrome P450 reductase POR 0.0168
4119 Cytochrome P450 2D6 CYP2D6 0.015
6144 Solute carrier family 22 member 2 SLC22A2 0.0144
3947 Xanthine dehydrogenase/oxidase XDH 0.0143
908 Glutathione S-transferase theta-1 GSTT1 0.0143
776 Bile salt export pump ABCB11 0.0129
2539 Tubulin alpha-1 chain TUBA4A 0.0126
6013 Cytochrome P450 2E1 CYP2E1 0.0126
6024 Cytochrome P450 1A1 CYP1A1 0.0125
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0122
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.012
904 Glutathione S-transferase P GSTP1 0.012
161 Tubulin beta chain TUBB 0.0117
312 Tubulin beta chain TUB2 0.0117
723 Cytosolic phospholipase A2 PLA2G4A 0.0114
4757 Cytochrome P450 2C9 CYP2C9 0.0112
1729 Solute carrier family 22 member 6 SLC22A6 0.0107
6016 Cytochrome P450 2C19 CYP2C19 0.0103
6022 UDP-glucuronosyltransferase 1-1 UGT1A1 0.0102
833 Organic cation/carnitine transporter 1 SLC22A4 0.0099
290 Prostaglandin G/H synthase 2 PTGS2 0.009
6178 UDP-glucuronosyltransferase 2B7 UGT2B7 0.0089
20 Prostaglandin G/H synthase 1 PTGS1 0.0084
3390 Aminoglycoside 3'-phosphotransferase aphA 0.0079
6029 Aminoglycoside 3'-phosphotransferase aphA1 0.0079
2282 Protein recA recA 0.0079
2315 Protein recA recA 0.0079
2332 Protein recA recA 0.0079
5263 Protein recA recA 0.0079
5265 FtsH ftsH 0.0079
5646 Galactokinase GALK1 0.0079
5302 TrwB trwB 0.0079
5645 DNA topoisomerase 4 subunit B parE 0.0078
6227 DNA topoisomerase 4 subunit B parE 0.0078
3794 Osmolarity sensor protein envZ envZ 0.0078
5649 Potassium-transporting ATPase B chain kdpB 0.0078
5643 General secretion pathway protein E epsE 0.0078
5641 Rod shape-determining protein MreB TM_0588 0.0078
4178 DNA repair protein RAD51 homolog 1 RAD51 0.0078
5642 Chaperone clpB clpB 0.0078
5290 ATP-dependent hsl protease ATP-binding subunit hslU hslU 0.0078
5638 ATP-dependent hsl protease ATP-binding subunit hslU hslU 0.0078
5644 Sensor protein phoQ phoQ 0.0078
4924 Cytochrome P450 2C8 CYP2C8 0.0072
6107 Cytochrome P450 3A7 CYP3A7 0.0072
5312 Kinesin-like protein KIF1A KIF1A 0.0069
6433 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 PFKFB4 0.0069
2867 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase ispE 0.0068
4751 Mitogen-activated protein kinase 12 MAPK12 0.0068
2397 Dihydroxyacetone kinase dhaK 0.0068
2852 DNA mismatch repair protein mutL mutL 0.0068
740 Argininosuccinate synthase ASS1 0.0068
865 Argininosuccinate synthase ASS1 0.0068
2680 Argininosuccinate synthase argG 0.0068
3194 Argininosuccinate synthase argG 0.0068
992 Protein tyrosine kinase 2 beta PTK2B 0.0064
1881 Hexokinase-1 HK1 0.0064
2950 Inositol-trisphosphate 3-kinase A ITPKA 0.0064
2615 Chemotaxis protein cheA cheA 0.0064
2371 Pantothenate kinase coaA 0.0064
2892 Acetylglutamate kinase argB 0.0064
3550 Acetylglutamate kinase argB 0.0064
825 Arsenical pump-driving ATPase ASNA1 0.0063
3435 Arsenical pump-driving ATPase arsA 0.0063
3231 Death-associated protein kinase 1 DAPK1 0.0063
2299 UDP-N-acetylmuramate--L-alanine ligase murC 0.0063
4373 Medium-chain-fatty-acid--CoA ligase Not Available 0.0062
6832 Serine/threonine-protein kinase SRPK2 SRPK2 0.0061
958 Insulin-like growth factor 1 receptor IGF1R 0.0061
2727 S-adenosylmethionine synthetase metK 0.006
887 DNA gyrase subunit B gyrB 0.0059
4150 DNA gyrase subunit B gyrB 0.0059
6225 DNA gyrase subunit B gyrB 0.0059
936 Ephrin type-A receptor 2 EPHA2 0.0059
2817 Phosphoribosylglycinamide formyltransferase 2 purT 0.0058
2184 Cystic fibrosis transmembrane conductance regulator CFTR 0.0052
2251 Thymidylate kinase tmk 0.0052
2254 Thymidylate kinase DTYMK 0.0052
3522 Thymidylate kinase tmk 0.0052
207 Glutathione synthetase GSS 0.0051
5269 Glutathione synthetase gshB 0.0051
3822 Actin, alpha skeletal muscle ACTA1 0.0047
937 Proto-oncogene tyrosine-protein kinase LCK LCK 0.0046
1836 Mitogen-activated protein kinase 10 MAPK10 0.0045
6228 Nuclear receptor coactivator 1 NCOA1 0.0044
1721 Glycogen synthase kinase-3 beta GSK3B 0.0043
6241 Nuclear receptor coactivator 2 NCOA2 0.0043
2347 Proto-oncogene serine/threonine-protein kinase Pim-1 PIM1 0.0043
2236 Casein kinase II subunit alpha CSNK2A1 0.0042
869 Estrogen receptor beta ESR2 0.0041
373 Transthyretin TTR 0.0038
6172 ATP-binding cassette sub-family B member 8, mitochondrial ABCB8 0.0036
136 Estrogen receptor ESR1 0.0035
5718 Cytochrome P450 2A6 CYP2A6 0.0034
337 NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial NDUFS7 0.0029
214 NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial NDUFS3 0.0029
803 NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial NDUFS2 0.0029
6168 Solute carrier family 22 member 16 SLC22A16 0.0029
6861 Alcohol dehydrogenase [NADP+] AKR1A1 0.0026
5251 Carbonyl reductase [NADPH] 1 CBR1 0.0022
650 Aldo-keto reductase family 1 member C3 AKR1C3 0.0021
2157 NAD(P)H dehydrogenase [quinone] 1 NQO1 0.0019
76 Nitric-oxide synthase, brain NOS1 0.0018
7 Nitric oxide synthase, inducible NOS2 0.0016
291 Nitric-oxide synthase, endothelial NOS3 0.0015
6030 Cytochrome P450 2B6 CYP2B6 0.0012
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