General Description
White to ivory microcrystals or off-white crystalline solid.
Reactivity Profile
DACARBAZINE(4342-03-4) decomposes explosively at its melting point (250°C). Decomposes in the presence of light. Sensitive to oxidation.
Air & Water Reactions
Insoluble in water.
Potential Exposure
Dacarbazine is used in cancer chemo-
therapy. Dacarbazine is used as an antineoplastic agent in
the treatment of certain skin cancers, and is occasionally
used in the therapy of other neoplastic diseases which have
become resistant to alternative treatment.br Health professionals who handle this drug (for example,
pharmacists, nurses, and physicians) may possibly be
exposed during drug preparation, administration, or cleanup;
however, the risks can be avoided through use of appropriate
containment equipment and work practices
.People
receiving dacarbazine in treatment are also exposed.
Fire Hazard
Flash point data for this chemical are not available. DACARBAZINE is probably combustible.
First aid
Skin Contact
: Flood all areas of body that have
contacted the substance with water. Don’t wait to remove
contaminated clothing; do it under the water stream. Use
soap to help assure removal. Isolate contaminated clothing
when removed to prevent contact by others. Eye Contact:
Remove any contact lenses at once. Flush eyes well with
copious quantities of water or normal saline for at least
20 30 minutes. Seek medical attention. Inhalation: Leave
contaminated area immediately; breathe fresh air. Proper
respiratory protection must be supplied to any rescuers. If
coughing, difficult breathing or any other symptoms develop,
seek medical attention at once, even if symptoms develop
many hours after exposure. Ingestion: If convulsions are not
present, give a glass or two of water or milk to dilute the substance. Assure that the person’s airway is unobstructed
and contact a hospital or poison center immediately for
advice on whether or not to induce vomiting.
Shipping
UN3249 Medicine, solid, toxic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials.
Incompatibilities
ncompatible with oxidizers (chlorates,
nitrates, peroxides, permanganates, perchlorates, chlorine,
bromine, fluorine, etc.); contact may cause fires or explo-
sions. Keep away from alkaline materials, strong bases,
strong acids, oxoacids, and epoxides. Explosive decom-
position reported @ 250℃
255℃
Description
Dacarbazine is nevertheless considered the first representative of the series of triazene
derivatives. It has been shown that it is an alkylating agent, and thus this drug inhibits RNA
and protein synthesis to a greater degree than DNA. Dacarbazine is used intravenously for
Hodgkin’s disease, soft-tissue sarcoma, and metastatic melanoma. A synonym of this drug
is diticene.
Waste Disposal
It is inappropriate and possi-
bly dangerous to the environment to dispose of expired or
waste drugs and pharmaceuticals by flushing them down
the toilet or discarding them to the trash. Household quanti-
ties of expired or waste pharmaceuticals may be mixed
with wet cat litter or coffee grounds, double-bagged in
plastic, discard in trash. Larger quantities shall carefully
take into consideration applicable DEA, EPA, and FDA
regulations. If possible return the pharmaceutical to the
manufacturer for proper disposal being careful to properly
label and securely package the material. Alternatively, the
waste pharmaceutical shall be labeled, securely packaged
and transported by a state licensed medical waste contractor
to dispose by burial in a licensed hazardous or toxic waste
landfill or incinerator.
Definition
ChEBI: A monocarboxylic acid amide that is 1H-imidazole-4-carboxamide which is substituted at position 5 by a 3,3-dimethyltriaz-1-en-1-yl group. It is used for the treatment of metastatic malignant melanoma, and in combination with other drugs
or the treatment of Hodgkin's disease and soft-tissue sarcoma.
Indications
Dacarbazine (DTIC-Dome) is activated by photodecomposition
and by enzymatic N-demethylation.
Eventual formation of a methyl carbonium ion results
in methylation of DNA and RNA and inhibition of nucleic
acid and protein synthesis. As with other alkylating
agents, cells in all phases of the cell cycle are susceptible
to dacarbazine.
The plasma half-life of dacarbazine is biphasic, with
a distribution phase of 19 minutes and an elimination
phase of 5 hours. The drug is not appreciably protein
bound, and it does not enter the central nervous system
(CNS). Urinary excretion of unchanged drug is by renal
tubular secretion. Dacarbazine metabolism and decomposition
is complex.
Dacarbazine is the most active agent used in metastatic
melanoma, producing a 20% remission rate. It is also
combined with doxorubicin and other agents in the treatment
of various sarcomas and Hodgkin’s disease.
Dacarbazine may cause severe nausea and vomiting.
Leukopenia and thrombocytopenia occur 2 weeks after
treatment, with recovery by 3 to 4 weeks. Less common
is a flulike syndrome of fever, myalgias, and malaise.
Alopecia and transient abnormalities in renal and hepatic
function also have been reported.
Biochem/physiol Actions
Dacarbazine is a purine analog of naturally occurring purine precursor 5-amino-1H-imidazole-4-carboxamide (AIC). It is a synthetic triazine antineoplastic agent that exerts cytotoxic effects by acting as an alkylating agent and by inhibiting DNA synthesis and inducing apoptosis. It is known to induce hepatotoxicity in mice. Dacarbazine is not cell cycle-phase specific.
Clinical Use
This DNA methylating agent is administered IV as a single agent in the treatment of malignant melanoma and in combination with other agents in the treatment of metastatic melanoma.
Synthesis
Dacarbazine, 5-(3,3-dimethyl-1-triazeno)imidazol-4-carboxamide (30.6.5),
is made by diazotation of 5-aminoimidazol-4-carboxamide with nitrous acid, which results
in the formation of 5-diazoimidazol-4-carboxamide (30.6.4). Reacting this with dimethylamine gives the desired dacarbazine (30.6.5)
Veterinary Drugs and Treatments
Dacarbazine has been used to treat relapsed canine lymphoma, soft
tissue sarcomas
and melanoma in dogs. In combination with doxorubicin,
dacarbazine has been evaluated to treat dogs with relapsed
lymphosarcoma. Ongoing studies evaluating various protocols are
ongoing for this indication.
Drug interactions
Potentially hazardous interactions with other drugs
Aldesleukin: avoid concomitant use.
Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis.
Environmental Fate
The exact mechanism of action of dacarbazine is unknown;
however, several proposed mechanisms have been made
including inhibition of DNA synthesis by acting as a purine
analog, alkylating agent, and interference with sulfhydryl
groups. It is most commonly classified as an alkylating agent in
the triazene group. While the active compound of dacarbazine,
DTIC, is structurally similar to purines, its primary mechanism
of action precludes the agent from being classified as an antimetabolite.
Dacarbazine is a synthetic compound that is
metabolically activated to the active alkylating metabolite
methyl-triazeno-imidazole-carboxamide (MTIC) via the cytochrome
P450 system, primarily CYP1A1, CYP1A2, and CYP
2E1. MTIC is rapidly tautomerized into an inactive derivative,
5-aminoimidazole-4-carboxamide (AIC), which is renally
excreted. The entire process of activating DTIC occurs within
15 min of intravenous infusion. DTIC exerts its actions
throughout all phases of the cellular cycle. The antitumor
effects of this compound are related to the induction of methyl
adducts to DNA. The 70% of alkylation occurs at the N7
position of guanine. The cytotoxic and mutagenic effects of
MTIC are manifested through alkylation of DNA at the O6
guanine position, accounting for 6–8% of methylated bases
formed. This is primarily a result of generation of incorrect base
pairing, leading to DNA double strand breaks and apoptosis.
Metabolism
Dacarbazine (DTIC) is assumed to be inactive.
Dacarbazine is extensively metabolised in the liver
by the cytochrome P450 isoenzymes CYP1A2 and
CYP2E1 (and possibly in the tissues by CYP1A1)
to its active metabolite 5-(3-methyl-triazen-1-yl)-
imidazole-4-carboxamide (MTIC), which spontaneously
decomposes to the major metabolite 5-amino-imidazole-
4-carboxamide (AIC). About half of a dose is excreted in
the urine by tubular secretion; 50% as unchanged DTIC
and approximately 50% as AIC.
storage
Color Code—Blue: Health Hazard/Poison: Storein a secure poison location. Prior to working with dacarbazine you should be trained on its proper handling and storage. Store in a refrigerator or a cool, dry place and protectfrom light. A regulated, marked area should be establishedwhere this chemical is stored in compliance with OSHAStandard 1910.1045.
Toxicity evaluation
Dacarbazine is a colorless to an ivory-colored crystalline solid
that must be reconstituted and administered as a parenteral
agent for intravenous injection. It is available as a dry powder in
100, 200, and 500mg vials that when reconstituted have
a standard concentration of 10 mg dacarbazine per 1 ml solution
and a pH of 3–4. Vials of dacarbazine should be refrigerated
(2–8°C) and protected from light. When exposed to light,
dacarbazine is rapidly decomposed to 4-diazoimidazole-5-carboxamide.
When exposed to high temperatures (250–255°C)
dacarbazine decomposes explosively. Dacarbazine is slightly
soluble in water. Dacarbazine may be diluted in either normal
saline or dextrose 5% water. Reconstituted solution is stable for
24 h at room temperature (20°C) and 96 h under refrigeration
(4°C); however, it is recommended by the manufacturer to
use the product within 8 and 72 h, respectively. Dacarbazine
should not be used if it turns pink, as this is a sign of
decomposition.
