Mechlorethamine

• Class: Alkylating agent (nitrogen mustard derivative).
• Historical note: First anticancer chemotherapy drug (developed from WWI chemical warfare agents).

Mechanism of Action (MOA)

• Highly reactive bifunctional alkylating agent.
• Forms aziridinium ion intermediates that alkylate DNA at the N7 position of guanine.
• Results in intra- and inter-strand crosslinks → inhibition of DNA replication and transcription → apoptosis.
• Non–cell cycle specific.

Clinical Uses

• Historically in Hodgkin and non-Hodgkin lymphomas (part of the classic MOPP regimen: Mechlorethamine, Oncovin [vincristine], Procarbazine, Prednisone).
• Rarely used today due to toxicity and better alternatives.
• Topical mechlorethamine (Valchlor® gel, 0.016%) → used for cutaneous T-cell lymphoma (CTCL, e.g., mycosis fungoides).

Dosing

• IV (historical use in lymphoma): 0.4 mg/kg IV every 4 weeks (in MOPP regimen).
• Topical: 0.016% gel once daily to affected skin areas (Valchlor®).

Toxicities

• Severe myelosuppression (dose-limiting).
• Nausea/vomiting (very emetogenic).
• Alopecia, mucositis.
• Extravasation → severe local necrosis (highly vesicant).
• Secondary malignancies (especially leukemias).
• Topical: contact dermatitis, pruritus, erythema, skin ulceration.

Monitoring

• CBC (bone marrow suppression).
• Skin exam if topical (dermatitis, ulceration).
• Extravasation precautions with IV.

Summary

Mechlorethamine is the prototype nitrogen mustard alkylating agent. Rarely used IV now due to high toxicity, but still relevant topically in cutaneous T-cell lymphoma (Valchlor®). Main concerns: myelosuppression, vesicant injury, and secondary malignancies.