DESCRIPTION
DACARBAZINE
Mechanism of Action
• Cell cycle–nonspecific drug.
• Initially developed as a purine antimetabolite, but its antitumor activity
is not mediated via inhibition of purine biosynthesis.
• Metabolic activation is required for antitumor activity.
• While the precise mechanism of cytotoxicity is unclear, this drug methylates
nucleic acids and inhibits DNA, RNA, and protein synthesis.
Mechanism of Resistance
Increased activity of DNA repair enzymes such as O6-alkylguanine-DNA
alkyltransferase (AGAT).
Absorption
Slow and variable oral absorption. For this reason, IV administration is
preferred.
Distribution
Volume of distribution exceeds total body water content, and drug is
widely distributed in body tissues. About 20% of drug is loosely bound to
plasma proteins.
D Metabolism
Metabolized in the liver by the microsomal P450 system to active metabolites
(MTIC, AIC). The elimination half-life of the drug is 5 hours. About
40%–50% of the parent drug is excreted unchanged in urine within 6 hours,
and tubular secretion appears to predominate. No specific guidelines for
dacarbazine dosing in the setting of hepatic and/or renal dysfunction.
However, dose modification should be considered in patients with moderately
severe hepatic and/or renal dysfunction.
Indications
1. Metastatic malignant melanoma.
2. Hodgkin’s lymphoma.
3. Soft tissue sarcomas.
4. Neuroblastoma.
Dosage Range
1. Hodgkin’s lymphoma—375 mg/m2 IV on days 1 and 15 every
28 days, as part of the ABVD regimen.
2. Melanoma—220 mg/m2 IV on days 1–3 and days 22–24 every 6 weeks,
as part of the Dartmouth regimen. As a single agent, 250 mg/m2 IV for
5 days or 800–1000 mg/m2 IV every 3 weeks.
Drug Interaction 1
Heparin, lidocaine, and hydrocortisone—Incompatible with dacarbazine.
Drug Interaction 2
Phenytoin, phenobarbital—Decreased efficacy of dacarbazine when administered
with phenytoin and phenobarbital as these drugs induce dacarbazine
metabolism by the liver P450 system.
Special Considerations
1. Dacarbazine is a potent vesicant, and it should be carefully administered
to avoid the risk of extravasation.
2. Dacarbazine is a highly emetogenic agent. Use of aggressive antiemetics
before drug administration to decrease risk of nausea and
vomiting.
3. Patients should avoid sun exposure for several days after dacarbazine
therapy.
4. Pregnancy category C. Breastfeeding should be avoided.
Toxicity 1
Myelosuppression is dose-limiting toxicity. Leukopenia and thrombocytopenia
are equally affected with nadir occurring at 21–25 days.
Toxicity 2
Nausea and vomiting can be severe, usually occurring within 1–3 hours
and lasting for up to 12 hours. Aggressive antiemetic therapy strongly recommended.
Anorexia is common, but diarrhea occurs rarely.
Toxicity 3
Flu-like syndrome in the form of fever, chills, malaise, myalgias, and
arthralgias. May last for several days after therapy.
Toxicity 4
Pain and/or burning at the site of injection.
Toxicity 5
CNS toxicity in the form of paresthesias, neuropathies, ataxia, lethargy,
headache, confusion, and seizures.
Toxicity 6
Increased risk of photosensitivity.
Toxicity 7
Teratogenic, mutagenic, and carcinogenic.
SPECIFICATION
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