Mechlorethamine is a nitrogen mustard and the prototype alkylating agent. It has been in clinical use for more than 60 years and is still used in the treatment of Hodgkin’s disease, chronic leukemias, lung cancer and polycythemia vera. The combination of mechlorethamine with other antineoplastic agents has been associated with low rates of serum enzyme elevations during therapy, but mechlorethamine has not been implicated specifically in cases of acute, clinically apparent injury.
Mechlorethamine (mek" lor eth' a meen), also known as chlormethine and mustine, is a nitrogen mustard and was the first alkylating agent developed for use as an antineoplastic agent in man. It remains the most reactive in this class of agents. Because it is irritating to local tissues and causes gastrointestinal intolerance, mechlorethamine is administered intravenously. Modifications of the chemical structure of mechlorethamine has led to similarly effective, but safer and better tolerated forms of alkylating agents, such as cyclophosphamide, ifosfamide, chlorambucil and melphalan. The alkylating agents act by causing modification and cross linking of DNA, thus triggering programmed cell death (apoptosis) and inhibiting DNA, RNA and protein synthesis in rapidly dividing cells. Mechlorethamine was approved for use in the United States in 1949. Its major use has been as therapy of Hodgkin’s disease and lymphomas in a regimen with vincristine, procarbazine and prednisone, commonly referred to as MOPP. In recent years, mechlorethamine has been replaced by more stable alkylating agents such as cyclophosphamide (COPP). Current indications include Hodgkin's disease, lymphosarcoma, chronic leukemias, polycytehemia vera, mycosis fungoides and lung cancer. Mechlorethamine is available in 10 mg vials generically and under the brand name Mustargen. The recommended dose varies with the indication, patient age and weight. Mechlorethamine is also available as a topic gel for treatment of cutaneous T-cell lymphomas and mycosis fungoides but requires special handling. Mechlorethamine shares common side effects with other alkylating agents, which include nausea, vomiting diarrhea, alopecia, pruritus, bone marrow suppression and rash.
Mild and transient elevations in serum aminotransferase levels are not uncommon during cycles of cancer chemotherapy, but the role of mechlorethamine in these abnormalities is unclear. The enzyme elevations are usually mild, transient and without symptoms, so that dose modification is rarely needed. Mechlorethamine has not been associated specifically with clinically apparent liver injury. Sinusoidal obstruction syndrome has been reported after MOPP therapy, but largely in patients with other risk factors for this complication, such as total body irradiation or previous courses of antineoplastic therapy.
Mechanism of Injury
The potential mechanism of hepatotoxicity from mechlorethamine is probably similar to that of other alkylating agents, a direct cytotoxic injury which is most specific to rapidly dividing cells, but in high doses can injury other cell types such as sinusoidal lining cells or hepatocytes.
Outcome and Management
Liver injury including sinusoidal obstruction syndrome are very rare after mechlorethamine therapy. The severity of sinusoidal obstruction syndrome varies considerably, from transient mild symptomatic liver injury to acute liver failure that is rapidly fatal. There is no known specific therapy for sinusoidal obstruction syndrome and management should focus on avoidance of further injury and supportive care. Rechallenge should not be done.
REPRESENTATIVE TRADE NAMES
Mechlorethamine – Mustargen®
Antineoplastic Agents, Alkylating
Product labeling at DailyMed, National Library of Medicine, NIH
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References Last Updated: 11 February 2014
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