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Details

Stereochemistry ACHIRAL
Molecular Formula C6H10N6O.C6H8O7
Molecular Weight 374.3067
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of DACARBAZINE CITRATE

SMILES

CN(C)\N=N\C1=C(N=CN1)C(N)=O.OC(=O)CC(O)(CC(O)=O)C(O)=O

InChI

InChIKey=UKLSKIDEWQXQJZ-ASTDGNLGSA-N
InChI=1S/C6H10N6O.C6H8O7/c1-12(2)11-10-6-4(5(7)13)8-3-9-6;7-3(8)1-6(13,5(11)12)2-4(9)10/h3H,1-2H3,(H2,7,13)(H,8,9);13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/b11-10+;

HIDE SMILES / InChI

Molecular Formula C6H10N6O
Molecular Weight 182.1832
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 1
Optical Activity NONE

Molecular Formula C6H8O7
Molecular Weight 192.1235
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Dacarbazine (DTIC), also known as imidazole carboxamide, is an antineoplastic agent, which is used in the treatment of metastatic malignant melanoma. In addition, this drug also is indicated for Hodgkin’s disease as a second-line therapy when used in combination with other effective agents. Dacarbazine works by methylating guanine at the O-6 and N-7 positions. Guanine is one of the four nucleotides that makes up DNA. The alkylated DNA strands stick together such that cell division becomes impossible. This affects cancer cells more than healthy cells because cancer cells divide faster. Dacarbazine is bioactivated in liver by demethylation to "MTIC" and then to diazomethane, which is an alkylating agent. Symptoms of anorexia, nausea, and vomiting are the most frequently noted of all toxic reactions. Over 90% of patients are affected with the initial few doses.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: CHEMBL2311221
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
DTIC-DOME

Approved Use

Dacarbazine for Injection USP is indicated in the treatment of metastatic malignant melanoma. In addition, Dacarbazine for Injection USP is also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other effective agents.

Launch Date

1.70380804E11
Primary
DTIC-DOME

Approved Use

Dacarbazine for Injection USP is indicated in the treatment of metastatic malignant melanoma. In addition, Dacarbazine for Injection USP is also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other effective agents.

Launch Date

1.70380804E11
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
6.2 μg/mL
750 mg/m² single, intravenous
dose: 750 mg/m²
route of administration: Intravenous
experiment type: SINGLE
co-administered:
DACARBAZINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
14.8 μM × min
750 mg/m² single, intravenous
dose: 750 mg/m²
route of administration: Intravenous
experiment type: SINGLE
co-administered:
DACARBAZINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
41.4 min
750 mg/m² single, intravenous
dose: 750 mg/m²
route of administration: Intravenous
experiment type: SINGLE
co-administered:
DACARBAZINE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
95%
DACARBAZINE plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
1000 mg/m2 1 times / 3 weeks multiple, intravenous
Highest studied dose
Dose: 1000 mg/m2, 1 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 1000 mg/m2, 1 times / 3 weeks
Co-administed with::
Lenalidomide, p.o(5 mg/day; 14 days)
Sources: Page: p.503, 504
unhealthy, 34–79
n = 3
Health Status: unhealthy
Condition: Malignant melanoma
Age Group: 34–79
Sex: M+F
Population Size: 3
Sources: Page: p.503, 504
Disc. AE: Cerebral ischemia...
AEs leading to
discontinuation/dose reduction:
Cerebral ischemia (grade 4, 33%)
Sources: Page: p.503, 504
800 mg/m2 1 times / 3 weeks multiple, intravenous
MTD
Dose: 800 mg/m2, 1 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 800 mg/m2, 1 times / 3 weeks
Co-administed with::
Lenalidomide, p.o(5 mg/day; 14 days)
Sources: Page: p.503
unhealthy, 34–79
n = 16
Health Status: unhealthy
Condition: Malignant melanoma
Age Group: 34–79
Sex: M+F
Population Size: 16
Sources: Page: p.503
DLT: Thrombocytopenia...
Disc. AE: Thrombocytopenia...
Dose limiting toxicities:
Thrombocytopenia (grade 2, 6.25%)
AEs leading to
discontinuation/dose reduction:
Thrombocytopenia (grade 1, 6.25%)
Sources: Page: p.503
1000 mg/m2 1 times / 3 weeks multiple, intravenous
Highest studied dose
Dose: 1000 mg/m2, 1 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 1000 mg/m2, 1 times / 3 weeks
Sources: Page: p.5
unhealthy, 40–65
n = 45
Health Status: unhealthy
Condition: Malignant melanoma
Age Group: 40–65
Sex: M+F
Population Size: 45
Sources: Page: p.5
Other AEs: Neutropenia, Fatigue...
Other AEs:
Neutropenia (grade 4, 2.2%)
Fatigue (grade 4, 2.2%)
Sources: Page: p.5
250 mg/m2 1 times / day multiple, intravenous
Recommended
Dose: 250 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 250 mg/m2, 1 times / day
Sources:
unhealthy
Disc. AE: Leukopenia, Thrombocytopenia...
AEs leading to
discontinuation/dose reduction:
Leukopenia (grade 3-5)
Thrombocytopenia (grade 3-5)
Anemia (sometimes)
Hematopoiesis impaired
Hepatotoxicity (grade 3-5, 0.01%)
Hepatic vein thrombosis (grade 3-5, 0.01%)
Necrosis hepatocellular (grade 3-5, 0.01%)
Anaphylaxis
Sources:
850 mg/m2 1 times / 3 weeks multiple, intravenous
Recommended
unhealthy
Disc. AE: Anemia, Leukopenia...
AEs leading to
discontinuation/dose reduction:
Anemia (mild)
Leukopenia (grade 3-5)
Thrombocytopenia (grade 3-5)
Hepatotoxicity (grade 3-5)
Hepatic vein thrombosis (grade 3-5)
Sources:
AEs

AEs

AESignificanceDosePopulation
Cerebral ischemia grade 4, 33%
Disc. AE
1000 mg/m2 1 times / 3 weeks multiple, intravenous
Highest studied dose
Dose: 1000 mg/m2, 1 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 1000 mg/m2, 1 times / 3 weeks
Co-administed with::
Lenalidomide, p.o(5 mg/day; 14 days)
Sources: Page: p.503, 504
unhealthy, 34–79
n = 3
Health Status: unhealthy
Condition: Malignant melanoma
Age Group: 34–79
Sex: M+F
Population Size: 3
Sources: Page: p.503, 504
Thrombocytopenia grade 1, 6.25%
Disc. AE
800 mg/m2 1 times / 3 weeks multiple, intravenous
MTD
Dose: 800 mg/m2, 1 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 800 mg/m2, 1 times / 3 weeks
Co-administed with::
Lenalidomide, p.o(5 mg/day; 14 days)
Sources: Page: p.503
unhealthy, 34–79
n = 16
Health Status: unhealthy
Condition: Malignant melanoma
Age Group: 34–79
Sex: M+F
Population Size: 16
Sources: Page: p.503
Thrombocytopenia grade 2, 6.25%
DLT
800 mg/m2 1 times / 3 weeks multiple, intravenous
MTD
Dose: 800 mg/m2, 1 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 800 mg/m2, 1 times / 3 weeks
Co-administed with::
Lenalidomide, p.o(5 mg/day; 14 days)
Sources: Page: p.503
unhealthy, 34–79
n = 16
Health Status: unhealthy
Condition: Malignant melanoma
Age Group: 34–79
Sex: M+F
Population Size: 16
Sources: Page: p.503
Fatigue grade 4, 2.2%
1000 mg/m2 1 times / 3 weeks multiple, intravenous
Highest studied dose
Dose: 1000 mg/m2, 1 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 1000 mg/m2, 1 times / 3 weeks
Sources: Page: p.5
unhealthy, 40–65
n = 45
Health Status: unhealthy
Condition: Malignant melanoma
Age Group: 40–65
Sex: M+F
Population Size: 45
Sources: Page: p.5
Neutropenia grade 4, 2.2%
1000 mg/m2 1 times / 3 weeks multiple, intravenous
Highest studied dose
Dose: 1000 mg/m2, 1 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 1000 mg/m2, 1 times / 3 weeks
Sources: Page: p.5
unhealthy, 40–65
n = 45
Health Status: unhealthy
Condition: Malignant melanoma
Age Group: 40–65
Sex: M+F
Population Size: 45
Sources: Page: p.5
Anaphylaxis Disc. AE
250 mg/m2 1 times / day multiple, intravenous
Recommended
Dose: 250 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 250 mg/m2, 1 times / day
Sources:
unhealthy
Hematopoiesis impaired Disc. AE
250 mg/m2 1 times / day multiple, intravenous
Recommended
Dose: 250 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 250 mg/m2, 1 times / day
Sources:
unhealthy
Hepatic vein thrombosis grade 3-5, 0.01%
Disc. AE
250 mg/m2 1 times / day multiple, intravenous
Recommended
Dose: 250 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 250 mg/m2, 1 times / day
Sources:
unhealthy
Hepatotoxicity grade 3-5, 0.01%
Disc. AE
250 mg/m2 1 times / day multiple, intravenous
Recommended
Dose: 250 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 250 mg/m2, 1 times / day
Sources:
unhealthy
Necrosis hepatocellular grade 3-5, 0.01%
Disc. AE
250 mg/m2 1 times / day multiple, intravenous
Recommended
Dose: 250 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 250 mg/m2, 1 times / day
Sources:
unhealthy
Leukopenia grade 3-5
Disc. AE
250 mg/m2 1 times / day multiple, intravenous
Recommended
Dose: 250 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 250 mg/m2, 1 times / day
Sources:
unhealthy
Thrombocytopenia grade 3-5
Disc. AE
250 mg/m2 1 times / day multiple, intravenous
Recommended
Dose: 250 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 250 mg/m2, 1 times / day
Sources:
unhealthy
Anemia sometimes
Disc. AE
250 mg/m2 1 times / day multiple, intravenous
Recommended
Dose: 250 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 250 mg/m2, 1 times / day
Sources:
unhealthy
Hepatic vein thrombosis grade 3-5
Disc. AE
850 mg/m2 1 times / 3 weeks multiple, intravenous
Recommended
unhealthy
Hepatotoxicity grade 3-5
Disc. AE
850 mg/m2 1 times / 3 weeks multiple, intravenous
Recommended
unhealthy
Leukopenia grade 3-5
Disc. AE
850 mg/m2 1 times / 3 weeks multiple, intravenous
Recommended
unhealthy
Thrombocytopenia grade 3-5
Disc. AE
850 mg/m2 1 times / 3 weeks multiple, intravenous
Recommended
unhealthy
Anemia mild
Disc. AE
850 mg/m2 1 times / 3 weeks multiple, intravenous
Recommended
unhealthy
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG


OverviewOther

Other InhibitorOther SubstrateOther Inducer




Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
Drug as victim
PubMed

PubMed

TitleDatePubMed
Carcinogenicity of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, and its metabolites in rats.
1975 Apr
Cardiomyopathy after widely separated courses of adriamycin exacerbated by actinomycin-D and mithramycin.
1975 Nov
[DTIC: effect on fibrinolysis and thrombocyte function].
1986 Oct
[Hepatic veno-occlusive disease caused by Deticene: a cause of acute hypovolemic shock].
1990
Inhibition of melanoma growth and metastasis by combination with (-)-epigallocatechin-3-gallate and dacarbazine in mice.
2001
Therapeutic implications of the kinetics of immunomodulation during single or combined treatment of melanoma patients with dacarbazine and interferon-alpha.
2001
Dacarbazine-induced carotid artery and deep venous thrombosis in a patient with leiomyosarcoma: case report.
2001 Apr
Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282.
2001 Aug
Role of cytochrome P450 isoenzymes in metabolism of O(6)-benzylguanine: implications for dacarbazine activation.
2001 Dec
Successful palliation of stenosing anorectal melanoma by intratumoral injections with natural interferon-beta.
2002 Aug
Phase I/II study of sequential chemoimmunotherapy (SCIT) for metastatic melanoma: outpatient treatment with dacarbazine, granulocyte-macrophage colony-stimulating factor, low-dose interleukin-2, and interferon-alpha.
2002 Dec
Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy.
2003 Aug
Pharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer.
2003 Feb 20
Survival with dacarbazine and fotemustine in newly diagnosed glioblastoma multiforme.
2003 Feb 24
Farnesyl thiosalicylic acid chemosensitizes human melanoma in vivo.
2003 Jan
Effect of a novel somatostatin analogue combined with cytotoxic drugs on human tumour xenografts and metastasis of B16 melanoma.
2003 Jan 13
O6-methylguanine-DNA-methyltransferase expression and gene polymorphisms in relation to chemotherapeutic response in metastatic melanoma.
2003 Oct 20
A humanized monoclonal antibody to carcinoembryonic antigen, labetuzumab, inhibits tumor growth and sensitizes human medullary thyroid cancer xenografts to dacarbazine chemotherapy.
2004 Dec
The prognostic role of CD4+ and CD8+ lymphocytes during chemoimmunotherapy in metastatic melanoma.
2004 Dec
Activity of irinotecan, cisplatin and dacarbazine (CPD) combination in previously treated patients with advanced colorectal carcinoma.
2004 Jun
Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo.
2004 Jun 1
Correspondence re: DC Lev et al., Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther, 2003;2(8):753-63.
2004 Mar
Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.
2004 Mar 15
Randomized trial of dacarbazine versus bleomycin, vincristine, lomustine and dacarbazine (BOLD) chemotherapy combined with natural or recombinant interferon-alpha in patients with advanced melanoma.
2005 Aug
Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281.
2005 Aug 1
Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) in human melanoma and identification of the therapeutic potential of resveratrol as an APE/Ref-1 inhibitor.
2005 Dec
Combined chemoimmunotherapy of metastatic melanoma: a single institution experience.
2005 Jun
Functional erythropoietin autocrine loop in melanoma.
2005 Mar
Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group.
2006 Oct 10
Interleukin-2-based biochemotherapy for patients with stage IV melanoma: long-term survivors outside a clinical trial setting.
2007
Serum VEGF-C is associated with metastatic site in patients with malignant melanoma.
2007
Chemoimmunotherapy for cutaneous melanoma with dacarbazine and epifocal contact sensitizers: results of a nationwide survey of the German Dermatologic Co-operative Oncology Group.
2007 Jul
Adjuvant chemotherapy with doxorubicin and dacarbazine has no effect in recurrence-free survival of malignant phyllodes tumors of the breast.
2007 Nov-Dec
Results of a multicenter randomized study to evaluate the safety and efficacy of combined immunotherapy with interleukin-2, interferon-{alpha}2b and histamine dihydrochloride versus dacarbazine in patients with stage IV melanoma.
2007 Oct
Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice.
2007 Oct
The management of desmoids in patients with familial adenomatous polyposis (FAP).
2008
Hodgkin lymphoma presenting with various immunologic abnormalities, including autoimmune hepatitis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, and immune thrombocytopenia.
2008 Feb
Glut-1 as a therapeutic target: increased chemoresistance and HIF-1-independent link with cell turnover is revealed through COMPARE analysis and metabolomic studies.
2008 Mar
Unexpected clinical outcome in a patient with liver and brain metastasis from melanoma.
2008 Mar-Apr
Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 Study Group.
2008 May 1
Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites.
2009 Jun
Glucocorticoid-dependent expression of O(6)-methylguanine-DNA methyltransferase gene modulates dacarbazine-induced hepatotoxicity in mice.
2010 Jun
A correlation between the in vitro drug toxicity of drugs to cell lines that express human P450s and their propensity to cause liver injury in humans.
2014 Jan
Patents

Sample Use Guides

Malignant Melanoma: the recommended dosage is 2 to 4.5 mg/kg/day for 10 days. Treatment may be repeated at 4 week intervals Hodgkin's Disease: The recommended dosage of Dacarbazine for Injection, USP in the treatment of Hodgkin’s disease is 150 mg/square meter body surface/day for 5 days, in combination with other effective drugs. Treatment may be repeated every 4 weeks.5 An alternative recommended dosage is 375 mg/square meter body surface on day 1, in combination with other effective drugs, to be repeated every 15 days
Route of Administration: Intravenous
The effect of alkyating agent dacarbazine (DTIC) and imexon, alone and in combination, was evaluated for growth inhibition (MTT), radiolabeled drug uptake, cellular thiol content (HPLC), and DNA strand breaks (Comet assay). Growth inhibition in vitro was additive with the two drugs. There was no effect on drug uptake or on the number of DNA strand breaks. There was a >75% reduction in cellular glutathione and cysteine with imexon but not DTIC. Co-administration of the two drugs in mice caused an increase in the area under the curve of both drugs, but the combination was not effective in reducing human A375 melanoma tumors in vivo.
Substance Class Chemical
Created
by admin
on Sat Dec 16 05:04:43 UTC 2023
Edited
by admin
on Sat Dec 16 05:04:43 UTC 2023
Record UNII
9UYU348NIF
Record Status Validated (UNII)
Record Version
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Name Type Language
DACARBAZINE CITRATE
WHO-DD  
Common Name English
Dacarbazine citrate [WHO-DD]
Common Name English
1H-IMIDAZOLE-4-CARBOXAMIDE, 5-(3,3-DIMETHYL-1-TRIAZEN-1-YL)-, 2-HYDROXY-1,2,3-PROPANETRICARBOXYLATE (1:1)
Systematic Name English
Code System Code Type Description
SMS_ID
100000092145
Created by admin on Sat Dec 16 05:04:44 UTC 2023 , Edited by admin on Sat Dec 16 05:04:44 UTC 2023
PRIMARY
EVMPD
SUB01547MIG
Created by admin on Sat Dec 16 05:04:44 UTC 2023 , Edited by admin on Sat Dec 16 05:04:44 UTC 2023
PRIMARY
FDA UNII
9UYU348NIF
Created by admin on Sat Dec 16 05:04:44 UTC 2023 , Edited by admin on Sat Dec 16 05:04:44 UTC 2023
PRIMARY
CAS
64038-56-8
Created by admin on Sat Dec 16 05:04:44 UTC 2023 , Edited by admin on Sat Dec 16 05:04:44 UTC 2023
PRIMARY
PUBCHEM
135565662
Created by admin on Sat Dec 16 05:04:44 UTC 2023 , Edited by admin on Sat Dec 16 05:04:44 UTC 2023
PRIMARY
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