Alkylating agents
Alkylating agents are cell cycle nonspecific cytotoxic drugs that cross-link DNA strands, triggering apoptosis in dividing cells. They underpin regimens for lymphoma, leukemia, myeloma, and solid tumors, and are dosed by body surface area or fixed dose with mesna, hydration, and antiemetic prophylaxis to limit hemorrhagic cystitis, myelosuppression, and gonadal toxicity.
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What this article covers
- Overview
Alkylating agents attach an alkyl group to DNA, usually at guanine N7, cross-linking strands and triggering apoptosis regardless of cell cycle phase, so the class stays active against slowly dividing tumors.
- Epidemiology
Alkylating agents are among the oldest, most widely used cytotoxic classes, tracing to nitrogen mustard derivatives developed from chemical warfare agents.
- Risk factors
Preexisting renal impairment: platinum compounds and high-dose cyclophosphamide are renally cleared or toxic.
- Pathophysiology
Nitrogen mustards and nitrosoureas form a reactive alkyl intermediate that binds guanine N7 on opposite DNA strands; the resulting cross-link stalls the replication fork and triggers apoptosis.
- Clinical features
Class-wide myelosuppression: dose-limiting neutropenia and thrombocytopenia 7 to 14 days after dosing.
- Differential diagnosis
Antimetabolite (methotrexate, 5-fluorouracil, cytarabine): targets nucleotide synthesis, S-phase specific, lacking the cystitis and gonadotoxicity that define the oxazaphosphorines.
- Diagnosis
First, establish the indication by histologic diagnosis and staging (or biopsy-confirmed organ involvement with nephrotic-range proteinuria outside oncology), which sets the regimen and target dose.
- Management
First, confirm eligibility: neutrophil count above 1,500/microL, adequate renal function, and completed fertility counseling.
- Complications
Myelosuppression: neutrophil and platelet nadir at 7 to 14 days, raising febrile neutropenia risk.
- Prognosis
Efficacy is disease specific rather than class specific.
- Prevention
Cap cumulative dose where a threshold exists: stop cyclophosphamide for steroid-resistant glomerular disease after 8 to 12 weeks rather than continuing indefinitely.
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