Info
5-Fluorouracil
- Activation of 5-fluorouracil to 5-FdUMP
- Complex formation with thymidylate synthase and folic acid → inhibition of
- thymidylate synthase → ↓ dTMP production → ↓ DNA synthesis
- Incorporation of pyrimidine analog into DNA and RNA → ↓ DNA and RNA synthesis
- Leucovorin enhances antineoplastic efficacy of 5-fluorouracil
Thymidylate Synthase
Mechanism of Action
- Vidoe: 5-FU (Fluorouracil); Mechanism of action - YouTube
- 5-FU is → a prodrug, after enter the cell, become 5-FdUMP, which will do the following works:
- 在uracil 第五個碳上加了一個F，去卡位，卡誰的 → thymiylate synthetase 的 → ∴ 所以 ✖ 無法再生成thymidylate ∴ 所以導致RNA ✖ 無法再繼續合成
- 作用在s phase，細胞在複製時，需要大量的 → RNA
- cf: Capecitabine (Xeloda)
Other Note
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A prodrug that undergoes a complex series of biotransformations to ribosyl and dexoxyribosyl nucleotide metabolites. One of these (FdUMP) forms a covalently bound ternary complex with thymidylate synthase and the reduced folate N5-N10-methylenetetrahydrofolate, a reaction critical for the synthesis of thymidylate.
- pyrimidine analog
- bioactivated to 5-FdUMP
- covalently complexes to folic acid
- complex inhibits thymidylate synthase
- ↓dTMP → ↓DNA & protein synthesis
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When combined with leucovorin (folinic acid), 5-FU forms a complex that inhibits “thymidylate” synthetase more effectively than 5-FU alone (Figure 1).
- Disrupting the synthesis of “thymidylate” results in an inhibition of DNA synthesis through a “thymineless death”
- 5-FU is → also converted to 5-FUTP, which is → incorporated into RNA, where it interferes with RNA processing & mRNA translation
- 5-FU is → also converted 5-FdUTP, which can be incorporated into DNA, resulting in inhibition of DNA synthesis & function
- Its cytotoxicity is → due to effects on both DNA- and RNA-mediated events
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from: Fluorouracil