Dacarbazine

Dacarbazine was first synthesized in 1959 and was approved for clinical use in 1975. Dacarbazine (aka DTIC: 4-(Dimethyltriazeno) imidazole-5-carboxamide) is a synthetic analog of naturally occurring purine precursor 5-amino-1H-imidazole-4-carboxamide. Dacarbazine (DTIC-Dome®) is an alkylating antineoplastic agent used in the treatment of a variety of cancers, primarily melanoma and Hodgkin's disease. It is a prodrug which exerts its action after bioactivation by liver CYP4501A1, CYP4501A2 and CYP2E1) via N-demethylation, which then acts on all phases of the cell cycle. The most prominent toxic effect of dacarbazine is DNA damage (via methylation) and subsequently secondary malignancy. Dacarbazine has also been associated with life threatening liver damage which typically arises during the second or third cycle of therapy and most likely represents severe acute sinusoidal obstruction syndrome. This compound may cause nausea, vomiting, bone marrow suppression, leukopenia, thrombocytopenia, hepatic vein thrombosis and cell necrosis. Other symptoms may include anemia, anaphylaxis, anorexia, diarrhea, and death. Dacarbazine has been reported to cause cardiovascular collapse, burning of the throat, abdominal pain, oliguria, anuria, delirium, fall of blood pressure, convulsions, muscular weakness with respiratory failure and collapse. High doses can cause gastrointestinal bleeding and occasionally alopecia, facial flushing, and a flu-like syndrome of fever, myalgias and malaise. Other side effects can be dermatological reactions and neurotoxicity. Ample research evidence shows dacarbazine is potentially a carcinogen, mutagen, teratogen, and immunosuppressive to humans and experimental animals. LD₅₀ dose (oral) of this drug is 2.15g/Kg in rats, and exposure should be avoided during pregnancy. There is no antidote for this drug. Withdrawal of the medication and/or reducing the dose along with good supportive medical care may resolve poisoning or overdose situations.