Fluoropyrimidines and Anti-folates

Drug Mechanism of Action
5-fluorouracil (5-FU) Inhibits cell division by blocking DNA synthesis and RNA function
Capecitabine (orally available pro-drug of 5-FU) Inhibits cell division by blocking DNA synthesis
Pemetrexed Inhibits cell proliferation by interfering with folate-dependent enzymatic processes
1 2 3 4
  1. 5-FU binds to the TS-folate complex and inhibits production of the dTMP precursor for DNA synthesis. High levels of TS cannot be blocked by the 5-FU doses that can be safely administered, thereby leading to resistance. 5-FU is also incorporated into RNA thereby modifying its function (not illustrated).
  2. Capecitabine is a pro-drug of 5-FU that is metabolized in the liver to the first intermediate and to 5FU in the tumor to generate high local concentrations of 5-FU. High TP drives this conversion to 5-FU and leads to an increase in the pools of 5-FU in the tumor.
  3. DPD metabolizes 5-FU to an inactive metabolite.
  4. TS uses tetrahydrofolate as the methyl donor to generate dTMP from dUMP. Anti-folates like methotrexate and pemetrexed block TS activity as well as activity of other folate-requiring enzymes like DHFR (not illustrated).

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Green squares, sensitivity markers. Red squares, resistance markers