alkylating agents
Summary
Alkylating agents are chemotherapeutic drugs that add alkyl groups to DNA (especially guanine N7), causing DNA cross-linking and strand breaks that trigger apoptosis. They are cell cycle-nonspecific and used in various cancers. Key examples include cyclophosphamide, nitrogen mustards, nitrosoureas, busulfan, and cisplatin (technically a platinum analog with similar mechanism).
Detail
Alkylating agents work by transferring alkyl groups to nucleophilic sites on DNA bases, most commonly the N7 position of guanine. This leads to intrastrand and interstrand DNA cross-links, DNA strand breakage, and mispairing during replication, ultimately triggering apoptosis in rapidly dividing cells. Because they act on DNA directly rather than targeting a specific phase of the cell cycle, they are classified as cell cycle-nonspecific agents, making them effective against both dividing and resting cells (useful in slow-growing tumors).
Key drugs and associations: - Cyclophosphamide: prodrug activated by liver P450 to acrolein (causes hemorrhagic cystitis, prevented by mesna and hydration); used in lymphomas, leukemias, and as immunosuppressant for autoimmune diseases (e.g., lupus nephritis, vasculitis). - Nitrogen mustards (mechlorethamine): used in Hodgkin lymphoma (MOPP regimen). - Nitrosoureas (carmustine, lomustine): cross blood-brain barrier, used for brain tumors; toxicity includes CNS effects. - Busulfan: used in CML and bone marrow ablation before transplant; causes pulmonary fibrosis and hyperpigmentation. - Cisplatin/carboplatin (platinum analogs): cross-link DNA similarly; used in testicular, ovarian, bladder cancers; toxicity includes nephrotoxicity, ototoxicity, peripheral neuropathy (prevented by amifostine and hydration). - Temozolomide: oral alkylator used for glioblastoma.
Common toxicities across the class: myelosuppression (dose-limiting), secondary malignancies (especially leukemia) due to mutagenic potential, and specific organ toxicities as above. These agents require monitoring of blood counts and, in cyclophosphamide's case, urinalysis for hematuria.
High-yield boards points: Know mechanism (DNA alkylation/cross-linking), cell cycle-nonspecific classification, unique toxicities of each drug, and mesna's role in preventing cyclophosphamide-induced hemorrhagic cystitis.
Sources
- First Aid for the USMLE Step 1
- Katzung's Basic and Clinical Pharmacology
- Goodman & Gilman's The 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.