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Home > D. General pathology > Therapy, Toxics and drugs > 5-FU


Friday 12 March 2004

5-FU is the most active anti-neoplastic agent in the treatment of advanced colorectal cancer. It acts through its conversion product - 5-fluoro-2’deoxy-5’monophosphate (FdUMP) - inhibiting thymidylate synthase and, subsequently, DNA synthesis.

5-FU is a prodrug and orotate phosphoribosyltransferase (OPRT) is the principal enzyme which directly converts 5-FU to an active anticancer metabolite, 5-fluoro-2’-deoxyuridine 5’-monophosphate.

Furthermore, OPRT is the key enzyme in the de novo DNA and RNA synthetic process, which converts orotic acid to orotidine 5’-phosphate.

It belongs to the family of drugs called antimetabolites. It is a pyrimidine analog. Its principal use is in colorectal cancer, in which it has been the established form of chemotherapy for decades (platinum-containing drugs are a recent addition).

As a pyrimidine analogue, it is transformed inside the cell into different cytotoxic metabolites which are then incorporated into DNA and RNA, finally inducing cell cycle arrest and apoptosis.

Capecitabine is a prodrug that is converted into 5-FU in the tissues. It can be administered orally.

- chemosensitization to 5-FU

An example of chemosensitization is the combined use of 5-fluorouracil (5-FU) and leucovorin (5’-formyltetrahydrofolate). A pure sensitizer should not really have innate cytotoxic properties, and leucovorin fulfills this criterion.

A folate cofactor can increase the stability and activity of 5-FU through the formation of a covalent ternary complex.

Resistance mechanisms against 5-FU include aberrations in its metabolism, alterations of thymidylate synthase - for instance, gene amplification - and altered kinetics with respect to nucleotides or folates.

Increasing intracellular levels of reduced folate methylenetetrahydrofolate (CH2THF) can improve the binding of FdUMP to thymidylate synthase and overcome some resistance against 5-FU.

Leucovorin has been used to expand the intracellular concentration of CH2THF and has been shown to increase the in vitro and in vivo toxicity of 5-FU by enhancing enzymatic binding in many cancer cell lines. Although leucovorin does not have antitumour activity on its own, 5-FU and leucovorin generated significantly superior response rates compared with bolus single-agent 5-FU (23% versus 11%); however, this did not result in significantly improved overall survival. In vitro, it seems that leucovorin sensitizes both tumour and normal cells to 5-FU.


- 5-FU induced hepatic veno-occlusive disease after intraarterial injection for metastatic colonic adenocarcinoma (2531719)

- 5-FU induced biliary sclerosis

  • Biliary sclerosis can result from intra-arterial infusion of 5-fluorodeoxyuridine (5-FU) for treatment of hepatic metastasis of colorectal carcinoma.

Ischaemic injury to the large intrahepatic and extrahepatic bile ducts can lead to strictures that resemble primary sclerosing cholangitis radiologically and histologically.


- Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003 May;3(5):330-8. PMID: 12724731