Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Alkylating Agents (Continued)

  • Classification⁸

    • Non-Classical Agents (Nitrogen Mustard Compound):

      • Dacarbazine (DTIC):

        • 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 t_1/2 of about 20 min. with a slower second phase (terminal t_1/2) 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

        • Adverse Effects:

          • 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.