Which of the following alkylating agents is a bifunctional agent that forms interstrand DNA crosslinks and is commonly used in ovarian cancer?

Explanation

## Cyclophosphamide: Bifunctional Alkylating Agent in Ovarian Cancer **Key Point:** Cyclophosphamide is a classical bifunctional alkylating agent (nitrogen mustard derivative) that forms interstrand and intrastrand DNA crosslinks, and has historically been a cornerstone of ovarian cancer chemotherapy. ### Mechanism of Action Cyclophosphamide is a prodrug activated by hepatic CYP2B6/CYP3A4 to its active metabolite **phosphoramide mustard**. This metabolite contains two reactive chloroethyl groups (hence "bifunctional"), each capable of alkylating the N-7 position of guanine on DNA strands. ### DNA Damage Pattern - **Interstrand crosslinks** — the most cytotoxic lesion; prevents strand separation during replication - **Intrastrand crosslinks** — also contribute to apoptosis - Crosslinks block DNA replication and transcription, triggering p53-mediated apoptosis ### Why Not the Other Options? | Agent | Class | Issue | |---|---|---| | **Cisplatin** | Platinum coordination complex | NOT a classical alkylating agent; forms adducts via coordinate covalent bonds, not alkylation; used in ovarian cancer but does not fit the strict definition | | **Mechlorethamine** | Nitrogen mustard (bifunctional) | Bifunctional alkylating agent, but NOT used in ovarian cancer; used in Hodgkin lymphoma (MOPP regimen) | | **Busulfan** | Alkyl sulfonate (bifunctional) | Bifunctional alkylating agent, but used in CML and conditioning for bone marrow transplant — NOT ovarian cancer | ### Clinical Use in Ovarian Cancer Cyclophosphamide was the **gold standard** for ovarian cancer chemotherapy (CAP regimen: Cyclophosphamide + Adriamycin + Cisplatin) before paclitaxel-based regimens became dominant. It remains used in recurrent/refractory settings and in combination regimens. **High-Yield (KD Tripathi / Goodman & Gilman):** Among the classical alkylating agents, cyclophosphamide is the most widely used clinically and is the prototypical bifunctional nitrogen mustard. Cisplatin, while forming DNA crosslinks, is classified as a **platinum coordination complex**, not an alkylating agent. **Clinical Pearl:** The key distinction — cisplatin acts via coordinate covalent bonding to DNA (not true alkylation), whereas cyclophosphamide alkylates DNA via reactive aziridinium intermediates. In pharmacology classification, only cyclophosphamide qualifies as a "bifunctional alkylating agent" among the options given.