DACARBAZINE CITRATE

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 Search

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

Description
Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b6b97e41-5f15-498c-abfb-d8443ea4d216 | https://www.ncbi.nlm.nih.gov/pubmed/3098406

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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA 278 Target ID: CHEMBL2311221 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24284332	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Malignant melanoma 22 Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b6b97e41-5f15-498c-abfb-d8443ea4d216	Primary		Approved 8429	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 1975
Hodgkin's lymphoma 34 Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b6b97e41-5f15-498c-abfb-d8443ea4d216	Primary		Approved 8429	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 1975

C_max

Value	Dose	Co-administered	Analyte	Population
6.2 μg/mL REVIEW https://www.ncbi.nlm.nih.gov/pubmed/26940170	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

Value	Dose	Co-administered	Analyte	Population
14.8 μM × min REVIEW https://www.ncbi.nlm.nih.gov/pubmed/26940170	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
41.4 min REVIEW https://www.ncbi.nlm.nih.gov/pubmed/26940170	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

F_unbound

Value	Dose	Co-administered	Analyte	Population
95% OTHER GOV https://www.medicines.org.uk/emc/product/7747/smpc			DACARBAZINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse 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: https://pubmed.ncbi.nlm.nih.gov/20859231 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: https://pubmed.ncbi.nlm.nih.gov/20859231 Page: p.503, 504	Disc. AE: Cerebral ischemia... AEs leading to discontinuation/dose reduction: Cerebral ischemia (grade 4, 33%) Sources: https://pubmed.ncbi.nlm.nih.gov/20859231 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: https://pubmed.ncbi.nlm.nih.gov/20859231 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: https://pubmed.ncbi.nlm.nih.gov/20859231 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: https://pubmed.ncbi.nlm.nih.gov/20859231 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: https://pubmed.ncbi.nlm.nih.gov/23735514 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: https://pubmed.ncbi.nlm.nih.gov/23735514 Page: p.5	Other AEs: Neutropenia, Fatigue... Other AEs: Neutropenia (grade 4, 2.2%) Fatigue (grade 4, 2.2%) Sources: https://pubmed.ncbi.nlm.nih.gov/23735514 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: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=b6b97e41-5f15-498c-abfb-d8443ea4d216&type=display	unhealthy Health Status: unhealthy Condition: Malignant melanoma Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=b6b97e41-5f15-498c-abfb-d8443ea4d216&type=display	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: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=b6b97e41-5f15-498c-abfb-d8443ea4d216&type=display
850 mg/m2 1 times / 3 weeks multiple, intravenous Recommended Dose: 850 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 850 mg/m2, 1 times / 3 weeks Sources: https://www.ema.europa.eu/en/documents/referral/summary-information-referral-opinion-following-arbitration-pursuant-article-29-directive-2001/83/ec-formerly-article-10-paragraph-2-directive-75/319/eec-20-may-1975-amended-dacarbazine-fauld_en.pdf	unhealthy Health Status: unhealthy Condition: Malignant melanoma Sources: https://www.ema.europa.eu/en/documents/referral/summary-information-referral-opinion-following-arbitration-pursuant-article-29-directive-2001/83/ec-formerly-article-10-paragraph-2-directive-75/319/eec-20-may-1975-amended-dacarbazine-fauld_en.pdf	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: https://www.ema.europa.eu/en/documents/referral/summary-information-referral-opinion-following-arbitration-pursuant-article-29-directive-2001/83/ec-formerly-article-10-paragraph-2-directive-75/319/eec-20-may-1975-amended-dacarbazine-fauld_en.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	substrate 1037

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1478	CYP1A2 1054 CYP1A1 349 CYP2E1 667

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C19 1553	inhibitor 3277 Sources: https://www.jstage.jst.go.jp/article/sujms1989/14/3/14_3_207/_article/-char/ja/ Page: 208.0	no

Drug as victim

Target	Modality	Activity
CYP2C9 1037	substrate 3367 Sources: https://clincancerres.aacrjournals.org/content/5/8/2192.short Page: 2195.0	no
CYP3A4 1737	substrate 3367 Sources: https://clincancerres.aacrjournals.org/content/5/8/2192.short Page: 2195.0	no
CYP1A1 349	substrate 3367 Sources: https://clincancerres.aacrjournals.org/content/5/8/2192.short Page: abstract	yes
CYP1A2 1054	substrate 3367 Sources: https://clincancerres.aacrjournals.org/content/5/8/2192.short Page: abstract	yes
CYP2E1 667	substrate 3367 Sources: https://clincancerres.aacrjournals.org/content/5/8/2192.short Page: abstract	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:4305	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:4305
MolPort	MolPort-044-723-991	https://www.molport.com/shop/molecule-link/MolPort-044-723-991
ZINC	ZINC000254748682	http://zinc15.docking.org/substances/ZINC000254748682
eMolecules	37036088	https://www.emolecules.com/cgi-bin/more?vid=37036088

PubMed

Title	Date	PubMed
Cisplatin, dacarbazine, and fotemustine plus interferon alpha in patients with advanced malignant melanoma. A multicenter phase II study of the Italian Cooperative Oncology Group.	2000 Dec 15	11135225
Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase.	2000 Oct	11023546
Docetaxel in combination with dacarbazine in patients with advanced melanoma.	2002	12417787
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	12439608
Chemoimmunotherapy for melanoma with dacarbazine and 2,4-dinitrochlorobenzene elicits a specific T cell-dependent immune response.	2002 Oct	12202904
Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy.	2003 Aug	12939465
Pharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer.	2003 Feb 20	12494480
Second-line chemotherapy with dacarbazine and fotemustine in nitrosourea-pretreated patients with recurrent glioblastoma multiforme.	2003 Jul	12853885
Mcl-1 antisense therapy chemosensitizes human melanoma in a SCID mouse xenotransplantation model.	2003 Jun	12787138
Isolated limb infusion with fotemustine after dacarbazine chemosensitisation for inoperable loco-regional melanoma recurrence.	2004 Dec	15522559
Activity of irinotecan, cisplatin and dacarbazine (CPD) combination in previously treated patients with advanced colorectal carcinoma.	2004 Jun	15273666
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	16373707
Long-term survival benefit after adjuvant treatment of cutaneous melanoma with dacarbazine and low dose natural interferon alpha: A controlled, randomised multicentre trial.	2006	16760174
Alkylating benzamides with melanoma cytotoxicity: experimental chemotherapy in a mouse melanoma model.	2006 Dec	17119449
Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group.	2006 Oct 10	16966688
Intralesional therapy of metastatic spreading melanoma with beta-interferon.	2006 Sep	16928243
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	17709802
Impairment of APE1 function enhances cellular sensitivity to clinically relevant alkylators and antimetabolites.	2009 Jun	19470598

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

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 GMT 2023` Edited by `admin` on `Sat Dec 16 05:04:43 GMT 2023`
Record UNII	9UYU348NIF
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

DACARBAZINE CITRATE

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