alkylating agent
Summary
Alkylating agents are chemotherapeutic drugs that add alkyl groups to DNA (primarily at the N7 of guanine), causing DNA crosslinking, strand breaks, and mispairing, ultimately triggering apoptosis in rapidly dividing cells. They are cell cycle-independent and used to treat various cancers. Key examples include cyclophosphamide, nitrogen mustards, nitrosoureas, busulfan, and cisplatin (a related platinum compound).
Detail
Mechanism: Alkylating agents covalently transfer alkyl groups to nucleophilic sites on DNA, most commonly N7 of guanine. This causes intrastrand and interstrand crosslinks, DNA strand breakage, abnormal base pairing, and depurination, leading to mutations and inhibition of DNA replication/transcription. Because they damage DNA regardless of cell cycle phase, they are classified as cell cycle-nonspecific agents, though rapidly dividing cells (cancer cells) are most susceptible.
Key drugs and features: - Cyclophosphamide: prodrug activated by liver (CYP450) to phosphoramide mustard; used for lymphomas, leukemias, solid tumors, and as immunosuppressant (e.g., lupus nephritis, vasculitis). Toxicity: hemorrhagic cystitis (due to acrolein metabolite - prevented with mesna and hydration), myelosuppression, SIADH. - Nitrogen mustards (mechlorethamine): used in Hodgkin lymphoma (MOPP regimen). - Nitrosoureas (carmustine, lomustine): lipophilic, cross blood-brain barrier - used for brain tumors. Toxicity: CNS effects, pulmonary fibrosis. - Busulfan: used in CML and myeloablative conditioning for bone marrow transplant. Toxicity: pulmonary fibrosis, hyperpigmentation, adrenal insufficiency. - Cisplatin/carboplatin (platinum analogs, similar DNA crosslinking mechanism): used for testicular, ovarian, bladder, lung cancers. Toxicity: nephrotoxicity (amifostine protects), ototoxicity, peripheral neuropathy.
Clinical significance: Alkylating agents are associated with secondary malignancies (particularly acute myeloid leukemia) due to their mutagenic DNA damage - a critical long-term complication to know for boards. They also cause dose-limiting myelosuppression (bone marrow suppression) common to most alkylating agents. Understanding specific toxicities of each agent (e.g., hemorrhagic cystitis with cyclophosphamide, nephrotoxicity with cisplatin) is high-yield for Step 1 and Step 2 exams.
Sources
- Katzung's Basic and Clinical Pharmacology
- First Aid for the USMLE Step 1
- Goodman & Gilman's Pharmacological Basis of Therapeutics
Reviewed by AnkiBoss editorial — medical student review. Information here is for study reference only and is not medical advice. Spotted an error? Let us know.