Which antimetabolite is a pyrimidine analog that undergoes activation to FdUMP and inhibits thymidylate synthase?

Explanation

## Mechanism of 5-Fluorouracil (5-FU) **Key Point:** 5-Fluorouracil is a pyrimidine antimetabolite that is converted to its active form FdUMP (fluorodeoxyuridine monophosphate), which irreversibly inhibits thymidylate synthase, blocking dTMP synthesis and DNA replication. ### Activation Pathway 1. 5-FU is converted to FUMP by orotate phosphoribosyltransferase 2. FUMP is converted to FdUMP by ribonucleotide reductase 3. FdUMP forms a covalent ternary complex with thymidylate synthase and methylenetetrahydrofolate 4. This blocks conversion of dUMP to dTMP, halting DNA synthesis ### Clinical Uses - Colorectal cancer (most common) - Gastric cancer - Breast cancer - Head and neck cancers **High-Yield:** 5-FU is a S-phase specific drug and is one of the most widely used chemotherapy agents in India and globally. It requires activation by cellular enzymes, making tumor cells with high metabolic activity preferentially sensitive. **Clinical Pearl:** Leucovorin (folinic acid) is often co-administered with 5-FU to enhance its effect by stabilizing the ternary complex and increasing FdUMP availability. ### Comparison with Other Antimetabolites | Drug | Class | Target | Mechanism | |------|-------|--------|----------| | 5-Fluorouracil | Pyrimidine | Thymidylate synthase | Inhibits dTMP synthesis | | Methotrexate | Folate analog | DHFR | Blocks folate metabolism | | 6-Mercaptopurine | Purine | HGPRT, IMPDH | Inhibits purine synthesis | | Cytarabine | Pyrimidine | DNA polymerase | Chain terminator |