## Mechanism Comparison: 5-FU vs Methotrexate ### 5-Fluorouracil (5-FU) Mechanism **Key Point:** 5-FU is a **pyrimidine antimetabolite** that requires metabolic activation to its active forms: FdUMP and FUTP. 1. Converted to FdUMP (fluorodeoxyuridine monophosphate) via multiple enzymatic steps 2. FdUMP inhibits **thymidylate synthase** — the enzyme that converts dUMP to dTMP 3. This blocks DNA synthesis by depleting thymidine nucleotides 4. Also incorporates into RNA (FUTP form), disrupting transcription ### Methotrexate (MTX) Mechanism **Key Point:** Methotrexate is a **folate antagonist** that directly inhibits **dihydrofolate reductase (DHFR)**. 1. Binds competitively to DHFR with high affinity 2. Blocks conversion of dihydrofolate → tetrahydrofolate (THF) 3. Depletes the THF cofactor pool needed for one-carbon transfer reactions 4. Inhibits both purine and pyrimidine synthesis (broader effect) ### Discriminating Feature Table | Feature | 5-FU | Methotrexate | |---------|------|---------------| | **Primary Target** | Thymidylate synthase | Dihydrofolate reductase | | **Nucleotide Affected** | Pyrimidines (primarily dTMP) | Both purines and pyrimidines | | **Mechanism** | Inhibits dUMP → dTMP | Blocks THF regeneration | | **Activation Required** | Yes (multiple steps) | No (active as given) | | **Cell Cycle Phase** | S-phase dependent | All phases | **High-Yield:** The **thymidylate synthase inhibition** is the hallmark and distinguishing feature of 5-FU among antimetabolites. This is tested frequently because it explains why 5-FU causes selective DNA synthesis block. **Clinical Pearl:** 5-FU toxicity (mucositis, diarrhea) is often managed with **leucovorin (folinic acid)** rescue, which bypasses the DHFR block — this is why 5-FU is often given with leucovorin in clinical practice, despite having a different primary target than MTX. [cite:KD Tripathi 8e Ch 65]
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.