## Cyclophosphamide: Classification and Mechanism **Key Point:** Cyclophosphamide is a nitrogen mustard alkylating agent that is a prodrug requiring hepatic activation to form active phosphoramide mustard, which then alkylates DNA by forming interstrand crosslinks. ### Nitrogen Mustards — Structural Class Nitrogen mustards are a subclass of alkylating agents characterized by: - Two chloroethyl groups attached to nitrogen - Ability to form stable aziridinium intermediates - Interstrand DNA crosslinking capability - Classic examples: cyclophosphamide, mechlorethamine, chlorambucil, melphalan ### Clinical Uses of Cyclophosphamide | Indication | Notes | | --- | --- | | Lymphomas (Hodgkin and non-Hodgkin) | Part of CHOP, CVAD regimens | | Leukemias | Acute and chronic myeloid leukemia | | Breast cancer | Adjuvant and metastatic disease | | Autoimmune diseases | SLE, vasculitis, rheumatoid arthritis | | Conditioning for stem cell transplant | High-dose use | **High-Yield:** Cyclophosphamide is a **prodrug** — it is inactive until metabolized by hepatic microsomal enzymes (CYP2C9, CYP3A4) to phosphoramide mustard, the actual DNA-alkylating species. ### Mechanism of DNA Damage 1. Hepatic activation → phosphoramide mustard 2. Spontaneous formation of aziridinium intermediate 3. Nucleophilic attack on N-7 of guanine (major groove) 4. Interstrand crosslink formation between two DNA strands 5. Replication fork collapse → cell death **Clinical Pearl:** Cyclophosphamide causes **hemorrhagic cystitis** due to acrolein (a toxic metabolite) accumulation in the bladder. Prevention requires aggressive hydration and mesna (a uroprotective agent that inactivates acrolein). **Mnemonic:** **CHOP** = **C**yclophosphamide, **H**ydroxydaunorubicin (doxorubicin), **O**ncovin (vincristine), **P**rednisone — the classic lymphoma regimen.
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