Medical Pharmacology Chapter 33-34: Anticancer Drugs
Alkylating Agents (Continued):
Non-Classical Agents (Nitrogen Mustard Compound):
Dacarbazine is classified as one of the "nonclassic alkylating agents."1,4
This agent is technically an "prodrug", requiring activation by oxidative N-demethylation in the liver.
A monomethyl metabolite is produced which then decomposes to diazomethane which in turn produces the cytotoxic methyl carbonium ion.1,4
The active agent is a monomethyl triazeno metabolite (MTIC).1
Two other drugs that require activation by the cytochrome P450 hepatic drug metabolizing system are ifosfamide and cyclophosphamide.5
Other cancer chemotherapy drugs belonging to the nitrosourea category require nonenzymatic activation.5
Resistance to dacarbazine may be related to the methylation from the O6-guanine bases in DNA by O6-methylguanine-DNA methyltransferase (MGMT).1
Absorption, Distribution, Metabolism, Excretion:
Dacarbazine is administered by the intravenous route of administration (IV).
A biphasic elimination curve consists of initial phase with a t1/2 of about 20 min. with a slower second phase (terminal t1/2) with a half-life of about 5 hours.
Factors that may extend the half-life includes hepatic or renal dysfunction.
About 40%-50% of dacarbazine is excreted as the parent compound.
Major urinary metabolites include the 5-aminoimidazole-4-carboxamide (AIC) which is a metabolites of the microsomal drug metabolizing system (cytochrome P450 CYP1A isoform(s)).
An AIC hydrolysis product, as a carboxylic acid represents another primary metabolite.1,2,6
Some Clinical Uses:
Major clinical uses for dacarbazine is in the management of Hodgkin's disease.1
Dacarbazine is administered in this setting in combination with other agents.
Dacarbazine is considered somewhat effective also in treating adult sarcomas and in managing malignant melanoma.
One example in treatment of Hodgkin's disease (nodular lymphocyte-predominant Hodgkin's lymphoma) with multiple drugs is the ABVD protocol which consists of doxorubicin, bleomycin, vinblastine and dacarbazine.3
NCCN guidelines (National Comprehensive Cancer Network) for nodular lymphocyte-predominant Hodgkin's lymphoma includes CVP (cyclophosphamide, vincristine, and prednisone), ABVD with or without rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone).
For favorable early-stage Hodgkin's lymphoma, treatment approaches continue to be assessed. One approach to standard therapy involves, however, ABVD along with radiation therapy.3
Most patients (> 90%) experience nausea and vomiting following dacarbazine administration.1
These effects develop soon after therapy initiation (1-3 hours) and may continue for as long as 12 hours.
Dacarbazine is a myelosuppressive agent producing thrombocytopenia and leukopenia which are typically reversible in 1-2 weeks.
Leukopenia and thrombocytopenia are considered among the most common side effects.2
Other less common side effects include alopecia, hepatotoxicity (including hepatocellular necrosis), neurotoxicity, facial flushing and skin reactions.