DACARBAZINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C6H10N6O
Molecular Weight	182.1834
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN(C)/N=N/c1c(C(=O)N)nc[nH]1

InChI

InChIKey=FDKXTQMXEQVLRF-ZHACJKMWSA-N

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

HIDE SMILES / InChI

Molecular Formula	C6H10N6O
Molecular Weight	182.1834
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	1
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 229 Target ID: CHEMBL2311221 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24284332	Inhibitor 7701	Malignant melanoma Hodgkin's lymphoma

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	DNA	Approved 7997	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 170380800000
Hodgkin's lymphoma 34 Sources: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b6b97e41-5f15-498c-abfb-d8443ea4d216	Primary	DNA	Approved 7997	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 170380800000

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 Sources: https://pubmed.ncbi.nlm.nih.gov/20859231	unhealthy, 34–79 Health Status: unhealthy Age Group: 34–79 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/20859231	Disc. AE: Cerebral ischemia... AEs leading to discontinuation/dose reduction: Cerebral ischemia (grade 4, 33%) Sources: https://pubmed.ncbi.nlm.nih.gov/20859231
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 Sources: https://pubmed.ncbi.nlm.nih.gov/20859231	unhealthy, 34–79 Health Status: unhealthy Age Group: 34–79 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/20859231	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
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	unhealthy, 40–65 Health Status: unhealthy Age Group: 40–65 Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/23735514	Other AEs: Neutropenia, Fatigue... Other AEs: Neutropenia (grade 4, 2.2%) Fatigue (grade 4, 2.2%) Sources: https://pubmed.ncbi.nlm.nih.gov/23735514
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 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 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 1470	substrate 865

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1215	CYP1A2 892 CYP1A1 302 CYP2E1 567

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C19 1277	inhibitor 2614 Sources: https://www.jstage.jst.go.jp/article/sujms1989/14/3/14_3_207/_article/-char/ja/ Page: 208	no

Drug as victim

Target	Modality	Activity
CYP2C9 865	substrate 2752 Sources: https://clincancerres.aacrjournals.org/content/5/8/2192.short Page: 2195	no
CYP3A4 1470	substrate 2752 Sources: https://clincancerres.aacrjournals.org/content/5/8/2192.short Page: 2195	no
CYP1A1 302	substrate 2752 Sources: https://clincancerres.aacrjournals.org/content/5/8/2192.short Page: abstract	yes
CYP1A2 892	substrate 2752 Sources: https://clincancerres.aacrjournals.org/content/5/8/2192.short Page: abstract	yes
CYP2E1 567	substrate 2752 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

PubMed

Title	Date	PubMed
Cardiomyopathy after widely separated courses of adriamycin exacerbated by actinomycin-D and mithramycin.	1975 Nov	172214
Peripheral DTIC neurotoxicity: a case report.	1987	3028665
Fatal hepatic vascular toxicity of DTIC. Is it really a rare event?	1988 May 15	3359400
Hepatic vascular toxicity of dacarbazine (DTIC): not a rare complication.	1989 May	2707742
Dana-Farber Cancer Institute studies in advanced sarcoma.	1990 Feb	2106162
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
Toxicity, mutation frequency and mutation spectrum induced by dacarbazine in CHO cells expressing different levels of O(6)-methylguanine-DNA methyltransferase.	2000 Feb 14	10751609
Increased susceptibility to chemotherapeutic alkylating agents of mice deficient in DNA repair methyltransferase.	2000 Oct	11023546
Inhibition of melanoma growth and metastasis by combination with (-)-epigallocatechin-3-gallate and dacarbazine in mice.	2001	11746506
Therapeutic implications of the kinetics of immunomodulation during single or combined treatment of melanoma patients with dacarbazine and interferon-alpha.	2001	11583285
Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials.	2001 Feb	11254118
Docetaxel in combination with dacarbazine in patients with advanced melanoma.	2002	12417787
Phase II trial of Paclitaxel and Dacarbazine with filgrastim administration in advanced malignant melanoma.	2002	12025231
Chemoimmunohormonal therapy with carmustine, dacarbazine, cisplatin, tamoxifen, and interferon for metastatic melanoma: a prospective phase II study.	2002 Oct	12393984
IL-2-mediated augmentation of NK-cell activity and activation antigen expression on NK- and T-cell subsets in patients with metastatic melanoma treated with interferon-alpha and DTIC.	2003	14669796
On the effect of biochemotherapy in metastatic malignant melanoma: an immunopathological evaluation.	2003 Aug	12883367
Farnesyl thiosalicylic acid chemosensitizes human melanoma in vivo.	2003 Jan	12535206
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
Combined chemoimmunotherapy of metastatic melanoma: a single institution experience.	2005 Jun	15917704
Sarcomatoid renal cell carcinoma with a chromophobe component producing beta-human chorionic gonadotropin.	2005 Sep	16201981
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
Long-term survival in metastatic melanoma patients treated with sequential biochemotherapy: report of a Phase II study.	2006 Aug-Sep	16939954
Alkylating benzamides with melanoma cytotoxicity: experimental chemotherapy in a mouse melanoma model.	2006 Dec	17119449
Chemoimmunotherapy with dacarbazine, cisplatin, interferon-alpha2b and interleukin-2 versus two cycles of dacarbazine followed by chemoimmunotherapy in patients with metastatic melanoma: a randomised phase II study of the European Organization for Research and Treatment of Cancer Melanoma Group.	2006 Nov	17023156
Interleukin-2-based biochemotherapy for patients with stage IV melanoma: long-term survivors outside a clinical trial setting.	2007	18332650
Serum VEGF-C is associated with metastatic site in patients with malignant melanoma.	2007	17562445
Resection in the popliteal fossa for metastatic melanoma.	2007 Jan 19	17239242
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	17334785
Hemorrhagic cystitis in a patient receiving conventional doses of dacarbazine for metastatic malignant melanoma: case report and review of the literature.	2007 Jun	17692730
Combined treatment with Ad-hTRAIL and DTIC or SAHA is associated with increased mitochondrial-mediated apoptosis in human melanoma cell lines.	2007 Jun	17410615
CD69 on CD56+ NK cells and response to chemoimmunotherapy in metastatic melanoma.	2007 Nov	17973783
Adjuvant chemotherapy with doxorubicin and dacarbazine has no effect in recurrence-free survival of malignant phyllodes tumors of the breast.	2007 Nov-Dec	17983394
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
Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice.	2007 Oct	17508024
Durable complete responses with high-dose bolus interleukin-2 in patients with metastatic melanoma who have experienced progression after biochemotherapy.	2007 Sep 1	17761969
Biochemotherapy of metastatic melanoma in patients with or without recently diagnosed brain metastases.	2007 Sep 15	17623835
The management of desmoids in patients with familial adenomatous polyposis (FAP).	2008	19069698
Influence of therapy on the antioxidant status in patients with melanoma.	2008 Apr	18315784
The "old drug" dacarbazine as a second/third line chemotherapy in advanced soft tissue sarcomas.	2008 Apr	17898927
Hodgkin lymphoma presenting with various immunologic abnormalities, including autoimmune hepatitis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, and immune thrombocytopenia.	2008 Feb	18501091
Multicenter phase II study of chemoimmunotherapy in the treatment of metastatic melanoma.	2008 Feb	18176117
Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group.	2008 Feb 20	18281670
Meta-analysis of ifosfamide-based combination chemotherapy in advanced soft tissue sarcoma.	2008 Jun	18313854
Cerebellar dysfunction caused by procarbazine and consumption of excessive amount of bananas.	2008 Jun	18293384
Plitidepsin has a dual effect inhibiting cell cycle and inducing apoptosis via Rac1/c-Jun NH2-terminal kinase activation in human melanoma cells.	2008 Mar	18089842
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	17520257
Unexpected clinical outcome in a patient with liver and brain metastasis from melanoma.	2008 Mar-Apr	18505091
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	18445842
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	24085192

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

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 `Fri Jun 25 20:53:40 UTC 2021` Edited by `admin` on `Fri Jun 25 20:53:40 UTC 2021`
Record UNII	7GR28W0FJI
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

DACARBAZINE

Official Name

English

DACARBAZINE [WHO-IP]

Common Name

English

DIC

Common Name

English

DTIC

Common Name

English

DACARBAZINE [WHO-DD]

Common Name

English

DACARBASINE

Common Name

English

DACARBAZINE [INN]

Common Name

English

1H-IMIDAZOLE-4-CARBOXAMIDE, 5-(3,3-DIMETHYL-1-TRIAZENYL)-

Systematic Name

English

DACARBAZINE [ORANGE BOOK]

Common Name

English

DACARBAZINE [USP MONOGRAPH]

Common Name

English

DACARBAZINE [HSDB]

Common Name

English

DTIC-DOME

Brand Name

English

DACARBAZINE [USP-RS]

Common Name

English

DACARBAZINE [MI]

Common Name

English

DACARBAZINE [VANDF]

Common Name

English

NSC-45388

Code

English

NCI C04717

Code

English

DACARBAZINE [IARC]

Common Name

English

DACARBAZINE [EP MONOGRAPH]

Common Name

English

IMIDAZOLE CARBOXAMIDE

Systematic Name

English

DACARBAZINE [USAN]

Common Name

English

DACARBAZINE [MART.]

Common Name

English

DACARBAZINUM [WHO-IP LATIN]

Common Name

English

DACARBAZINE [JAN]

Common Name

English

5-(3,3-DIMETHYL-1-TRIAZENO)IMIDAZOLE-4-CARBOXAMIDE

Systematic Name

English

BIOCARBAZINE R

Common Name

English

DICARBAZINE

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C902