Cyclophosphamide is the DNA Alkylating Agent
The correct answer is A. Cyclophosphamide. Cyclophosphamide is a DNA alkylating agent that forms cross-links with DNA through its metabolic activation, leading to cell death.
Mechanism of Action of Cyclophosphamide
Cyclophosphamide belongs to the class of alkylating agents that includes:
- DNA interstrand cross-linking agents (cyclophosphamide, ifosfamide, melphalan, busulfan, chlorambucil, thiotepa) 1
- Triazenes (procarbazine, dacarbazine, temozolomide)
- Nitrosoureas (carmustine, lomustine)
- Platinum agents
Cyclophosphamide specifically:
- Requires metabolic activation by liver microsomal enzymes to produce biologically active metabolites 2
- Forms DNA cross-links through its metabolites, particularly phosphoramide mustard 3
- Creates N,N-bis[2-(N7-guaninyl) ethyl] amine cross-links (G-NOR-G) that are strongly cytotoxic 3
- Alkylates the N-7 position of guanine in DNA 3
Comparison with Other Options
B. Vincristine
- Vincristine is not an alkylating agent
- It belongs to the vinca alkaloid class
- Mechanism: Inhibits microtubule polymerization, causing mitotic arrest
- Does not directly interact with DNA through alkylation
C. Methotrexate
- Methotrexate is not an alkylating agent
- It is an antimetabolite
- Mechanism: Inhibits dihydrofolate reductase, interfering with DNA synthesis
- Does not form covalent bonds with DNA
D. Doxorubicin
- Doxorubicin is not an alkylating agent
- It belongs to the anthracycline class
- Mechanism: Intercalates between DNA base pairs and inhibits topoisomerase II
- While it interacts with DNA, it does not alkylate DNA 1
Clinical Significance of Cyclophosphamide as an Alkylating Agent
Cyclophosphamide's alkylating properties have important clinical implications:
- Used in various malignancies including multiple myeloma, lymphomas, and solid tumors 1
- Can be used at different dosing schedules with varying effects:
- High dose: Primarily immunosuppressive (used in transplant conditioning)
- Metronomic (low) dose: Immunomodulatory effects 2
- Prolonged use can lead to myelodysplastic syndrome and secondary acute leukemia 1
- Can cause dose-dependent gonadotoxicity, contributing to premature ovarian insufficiency 1
Unlike some other alkylating agents (e.g., melphalan), cyclophosphamide is not toxic to stem cells, making it suitable for regimens where stem cell preservation is important 1.
The mechanism of DNA alkylation is fundamental to cyclophosphamide's cytotoxic effects and remains the basis for its continued use in modern chemotherapeutic regimens despite its potential toxicities.