## Mechanism of Action Distinction **Key Point:** The fundamental difference between methotrexate and 5-fluorouracil lies in their target nucleotide pathways — methotrexate blocks folate metabolism (purine and pyrimidine synthesis), while 5-FU directly inhibits pyrimidine synthesis. ## Comparative Table | Feature | Methotrexate | 5-Fluorouracil | |---------|--------------|----------------| | **Drug Class** | Folate antagonist (DHFR inhibitor) | Pyrimidine antagonist | | **Target Enzyme** | Dihydrofolate reductase | Thymidylate synthase (via FdUMP) | | **Nucleotide Affected** | Purines + Pyrimidines | Pyrimidines only | | **Mechanism** | Blocks tetrahydrofolate cofactor | Inhibits dTMP synthesis | | **Activation** | Active form (MTX-polyglutamate) | Requires OPRT and other enzymes | | **Myelosuppression** | Yes (both drugs cause this) | Yes (both drugs cause this) | | **Dosing Schedule** | Weekly or high-dose IV | Continuous infusion or daily | **High-Yield:** Methotrexate's mechanism is **antimetabolite-by-cofactor-depletion** (blocks DHFR → ↓ THF → ↓ dNTP synthesis), whereas 5-FU is **antimetabolite-by-direct-inhibition** (FdUMP binds thymidylate synthase → ↓ dTMP). **Clinical Pearl:** This mechanistic difference explains why leucovorin (folinic acid) rescue is used with methotrexate but NOT with 5-FU — leucovorin bypasses the DHFR block in methotrexate toxicity. ## Why Other Options Are Incorrect - **Option 1 (Correct):** Captures the essential biochemical distinction. - **Option 2:** Both methotrexate AND 5-FU cause myelosuppression; this is NOT a discriminator. - **Option 3:** Both drugs require metabolic activation (methotrexate via polyglutamylation, 5-FU via OPRT); neither is "inactive" in the liver. - **Option 4:** While dosing schedules differ clinically, this is a consequence of pharmacokinetics, not the primary mechanistic distinction.
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.