Dacarbazine: Difference between revisions

Dacarbazine
Clinical data
Pronunciation	/dəˈkɑːrbəˌziːn/
Trade names	DTIC-Dome
AHFS/Drugs.com	Monograph
MedlinePlus	a682750
Routes of; administration	IV
ATC code	L01AX04 (WHO) ;
Legal status
Legal status	US: WARNING; In general: ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	100% (IV)
Metabolism	Extensive
Elimination half-life	5 hours
Excretion	Renal (40% as unchanged dacarbazine)
Identifiers
	IUPAC name 5-(3,3-Dimethyl-1-triazenyl)imidazole-4-carboxamide;
CAS Number	4342-03-4 ;
PubChem CID	2942;
DrugBank	DB00851 ;
ChemSpider	10481959 ;
UNII	7GR28W0FJI;
KEGG	C06936 ;
ChEBI	CHEBI:4305 ;
ChEMBL	ChEMBL476 ;
CompTox Dashboard (EPA)	DTXSID0020369 ;
ECHA InfoCard	100.022.179
Chemical and physical data
Formula	C6H10N6O
Molar mass	182.18 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CN(C)/N=N/c1ncnc1C(N)=O;
	InChI 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+ ; Key:FDKXTQMXEQVLRF-ZHACJKMWSA-N ;
	(what is this?) (verify)

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Revision as of 03:07, 23 April 2016

Dacarbazine (brand names DTIC, DTIC-Dome; also known as DIC or imidazole carboxamide) is an antineoplastic chemotherapy drug used in the treatment of various cancers, among them malignant melanoma, Hodgkin's lymphoma, sarcoma, and islet cell carcinoma of the pancreas.

Dacarbazine is a member of the class of alkylating agents, which destroy cancer cells by adding an alkyl group (C_nH_2n+1) to its DNA.

Dacarbazine is normally administered by intravenous infusion (IV) under the immediate supervision of a doctor or nurse. Dacarbazine is bioactivated in liver by demethylation to "MTIC" and then to diazomethane, which is an alkylating agent.

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.^[2]

Medical uses

As of mid-2006, dacarbazine is commonly used as a single agent in the treatment of metastatic melanoma, and as part of the ABVD chemotherapy regimen to treat Hodgkin's lymphoma, and in the MAID regimen for sarcoma. Dacarbazine was proven to be just as efficacious as procarbazine in the German trial for paediatric Hodgkin's lymphoma, without the teratogenic effects. Thus COPDAC has replaced the former COPP regime in children for TG2 & 3 following OEPA.

Side effects

Like many chemotherapy drugs, dacarbazine may have numerous serious side effects, because it interferes with normal cell growth as well as cancer cell growth. Among the most serious possible side effects are birth defects to children conceived or carried during treatment; sterility, possibly permanent; or immune suppression (reduced ability to fight infection or disease). Dacarbazine is considered to be highly emetogenic, and most patients will be pre-medicated with dexamethasone and antiemetic drugs like 5-HT₃ antagonist (e.g., ondansetron) and/or NK₁ receptor antagonist (e.g., aprepitant). Other significant side effects include headache, fatigue and occasionally diarrhea.

The Swedish National Board of Health and Welfare has sent out a black box warning and suggests avoiding dacarbazine due to liver problems.^[3]

Mechanism of action

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. Unfortunately however, some of the healthy cells will still be damaged.

Synthesis

Shealy et al., J. Org. Chem. 27, 2150 (1962); Hano et al., Gann 59, 207 (1968), C.A. 69, 42527g (1968).

History

Dacarbazine was developed by Y. Fulmer Shealy, Phd at Southern Research Institute in Birmingham, Alabama. Research was funded by a U.S. federal grant. Dacarbazine gained FDA approval in May 1975 as DTIC-Dome. The drug was initially marketed by Bayer.

Experimental use

The combination dacarbazine + oblimersen is in clinical trials for advanced melanoma.^[4]

Suppliers

Bayer continues to supply DTIC-Dome. There are also generic versions of dacarbazine available from APP, Bedford, Mayne Pharma (now Hospira) and Teva.

Notes

^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
^ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
^ "Archived copy". Archived from the original on October 1, 2011. Retrieved August 19, 2011. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)
^ Bedikian, AY; Garbe, C; Conry, R; Lebbe, C; Grob, JJ (June 2014). "Dacarbazine with or without Oblimersen (a Bcl-2 Antisense Oligonucleotide) in Chemotherapy-Naïve Patients with Advanced Melanoma and Low-Normal Serum Lactate Dehydrogenase: the AGENDA Trial". Melanoma Research. 24 (3): 237–43. PMID 24667300. {{cite journal}}: |access-date= requires |url= (help)

References

MedLine, U.S. National Institutes of Health, National Library of Medicine,[1]
Cancerweb,[2]
OncoLink,[3]
Swedish National Board of Health and Welfare,[4]

[FDA-AllBoxedWarnings-1] "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.

[WHO2015E-2] "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.

[3] "Archived copy". Archived from the original on October 1, 2011. Retrieved August 19, 2011. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)

[4] Bedikian, AY; Garbe, C; Conry, R; Lebbe, C; Grob, JJ (June 2014). "Dacarbazine with or without Oblimersen (a Bcl-2 Antisense Oligonucleotide) in Chemotherapy-Naïve Patients with Advanced Melanoma and Low-Normal Serum Lactate Dehydrogenase: the AGENDA Trial". Melanoma Research. 24 (3): 237–43. PMID 24667300. {{cite journal}}: |access-date= requires |url= (help)

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 Like many chemotherapy drugs, dacarbazine may have numerous serious side effects, because it interferes with normal cell growth as well as cancer cell growth.  Among the most serious possible side effects are birth defects to children conceived or carried during treatment; sterility, possibly permanent; or immune suppression (reduced ability to fight infection or disease). Dacarbazine is considered to be highly [[Chemotherapy-induced nausea and vomiting|emetogenic]], and most patients will be pre-medicated with [[dexamethasone]] and antiemetic drugs like [[5-HT3 antagonist|5-HT<sub>3</sub> antagonist]] (e.g., [[ondansetron]]) and/or [[NK1 receptor antagonist|NK<sub>1</sub> receptor antagonist]] (e.g., [[aprepitant]]). Other significant side effects include headache, fatigue and occasionally diarrhea.
-The Swedish National Board of Health and Welfare has sent out a [[Boxed warning|black box warning]] and suggests avoiding dacarbazine due to liver problems.<ref>http://www.fass.se/LIF/produktfakta/audit_page.jsp?_sourcePage=%2Fproduktfakta%2Fartikel_produkt.jsp&docType=7&nplId=19971212000080</ref>{{dl|date=April 2016}}
+The Swedish National Board of Health and Welfare has sent out a [[Boxed warning|black box warning]] and suggests avoiding dacarbazine due to liver problems.<ref>{{cite web|url=http://www.fass.se/LIF/produktfakta/audit_page.jsp?_sourcePage%3D%2Fproduktfakta%2Fartikel_produkt.jsp%26docType%3D7%26nplId%3D19971212000080 |title=Archived copy |accessdate=August 19, 2011 |deadurl=yes |archiveurl=http://web.archive.org/web/20111001011425/http://www.fass.se/LIF/produktfakta/audit_page.jsp?_sourcePage=%2Fproduktfakta%2Fartikel_produkt.jsp&docType=7&nplId=19971212000080 |archivedate=October 1, 2011 }}</ref>
 ==Mechanism of action==