Mechlorethamine

Mechlorethamine (nitrogen mustard; Mustargen), a derivative of the war gas sulfur mustard, is considered to be the first modern anticancer drug. In the early 1940s it was discovered to be effective in the treatment of human lymphomas.

Mechlorethamine in aqueous solution loses a chloride atom and forms a cyclic ethylenimmonium ion. This carbonium ion interacts with nucleophilic groups, such as the N7 and O6 of guanine, and leads to an interstrand cross-linking of DNA. Although there is great variation among normal and tumor tissues in their sensitivity to mechlorethamine, the drug is generally more toxic to proliferating cells than to resting or plateau cells. Mechlorethamine has a chemical and biological half-life in plasma of less than 10 minutes after intravenous injection. Little or no intact drug is excreted in urine.

The major indication for mechlorethamine is Hodgkin's disease; the drug is given in the MOPP regimen (mechlorethamine, vincristine, procarbazine, pred-nisone; see Chapter 55). Other less reactive nitrogen mustards are now preferred for the treatment of non-Hodgkin's lymphomas, leukemias, and various solid tumors.

The dose-limiting toxicity of mechlorethamine is myelosuppression; maximal leukopenia and thrombocytopenia occur 10 to 14 days after drug administration, and recovery is generally complete at 21 to 28 days. Lymphopenia and immunosuppression may lead to activation of latent herpes zoster infections, especially in patients with lymphomas. Mechlorethamine will affect rapidly proliferating normal tissues and cause alopecia, diarrhea, and oral ulcerations. Nausea and vomiting may occur 1 to 2 hours after injection and can last up to 24 hours. Since mechlorethamine is a potent blistering agent, care should be taken to avoid extravasation into subcutaneous tissues or even spillage onto the skin. Reproductive toxicity includes amenorrhea and inhibition of oogenesis and spermatogenesis. About half of premenopausal women and almost all men treated for 6 months with MOPP chemotherapy become permanently infertile. The drug is teratogenic and carcinogenic in experimental animals.

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