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Pyrimidine analogues and fluoropyrimidinesIn useRational design

Fluorouracil (5-FU)

Also known as Fluorouracil, 5-fluorouracil, 5-FU

A fluorine-substituted form of the pyrimidine base uracil, given by injection. It was developed in the 1950s from laboratory findings on uracil use by tumour cells, and its 2016 US label lists colorectal, breast, gastric and pancreatic adenocarcinoma.

From discovery to approval

  1. 1957 · First described

    A 1957 Nature paper by Heidelberger and colleagues, titled as describing fluorinated pyrimidines as a new class of tumour-inhibitory compounds, is the paper a 2009 meeting report cites for 5-fluorouracil appearing the most active halogen-substituted uracil. Duschinsky, Pleven and Heidelberger published the synthesis of 5-fluoropyrimidines the same year.[2][3][4][5][6][7][1][8]

  2. 1962-04-25 · FDA regular · 5 years after first description

    Original approval (ORIG-1) of NDA 012209, classed as a Type 1 new molecular entity with priority review in the Drugs@FDA history. The original letter and label are not available there, so the indication at approval is not stated here; the 2016 label lists adenocarcinoma of the colon and rectum, breast, stomach and pancreas. The type regular is an inference: no accelerated-approval wording was found.[9]

How it works

A nucleoside metabolic inhibitor that interferes with DNA synthesis and, to a lesser extent, RNA formation. Its metabolites include FdUMP, which inhibits thymidylate synthase, FUTP, which is incorporated into RNA, and FdUTP, which is incorporated into DNA.[1]

Where it came from and why

A 2009 meeting report says 5-fluorouracil was developed from 1950s findings that cancer cells incorporated more of the uracil base into DNA than normal cells did, citing a 1954 paper on uracil catabolism and a 1957 paper on uracil use by rat liver, intestinal mucosa and a rat carcinoma. A 2009 review of S-1 instead credits Duschinsky and colleagues with finding that uracil and fluorouracil concentrate in tumour cells.

In the 1950s, laboratory work on how animal tissues used the base uracil pointed to a difference between tumour and normal cells. A 2009 meeting report states that 5-fluorouracil was developed on the basis of findings that cancer cells incorporated a larger amount of the uracil base into DNA than normal cells did [2]. The report cites a 1954 paper titled "The catabolism of uracil in vivo and in vitro" [5] and a 1957 paper whose title describes a comparison of uracil use by rat liver, intestinal mucosa and a rat carcinoma [4]. A 2009 review of S-1 gives a different attribution, crediting Duschinsky and colleagues with finding that uracil and fluorouracil concentrate in tumour cells [8].

Charles Heidelberger and colleagues described fluorinated pyrimidines as a new class of tumour-inhibitory compounds in Nature in 1957 [3]. The meeting report cites that paper when it says 5-fluorouracil appeared the most active and promising of the halogen-substituted uracils [2]. The synthesis of 5-fluoropyrimidines was published the same year by Robert Duschinsky, Edward Pleven and Heidelberger [6].

The meeting report adds that clinical studies were started immediately [2]; a paper titled "Clinical studies with 5-fluorouracil" appeared in Cancer Research in 1958 [7]. Heidelberger's group went on to recognise that the metabolite FdUMP is a very potent inhibitor of thymidylate synthase [2]. The US label gives 1962 as the year of initial approval [1].

Cancers

  • Colorectal cancer

    The 2016 US label lists adenocarcinoma of the colon and rectum; a 2009 meeting report says the drug was shown to be helpful in colorectal and breast cancers.[1]

  • Breast cancer

    The 2016 US label lists adenocarcinoma of the breast.[1]

  • Gastric cancer

    The 2016 US label lists gastric adenocarcinoma.[1]

  • Pancreatic cancer

    The 2016 US label lists pancreatic adenocarcinoma.[1]

Family and partners

Drugs derived from it: Tegafur, Carmofur, Doxifluridine, Capecitabine

Worth knowing

  • The 2016 US label gives 1962 as the year of initial US approval.[1]
  • A 2007 symposium in New York marked the 50th anniversary of Charles Heidelberger's patent for 5-fluorouracil.[2]
  • A 2002 review notes that single-agent response rates of 5-fluorouracil in epithelial cancers are 10 to 30 percent, and that fewer than one third of patients with colorectal cancer have an objective response.[10]
  • A 2009 meeting report says Heidelberger's group recognised that the metabolite FdUMP is a very potent inhibitor of thymidylate synthase.[2]

On this site

References

  1. U.S. Food and Drug Administration. Fluorouracil injection, prescribing information (NDA 012209, supplement 040, revised 07/2016). The label states that it may not be the latest approved by FDA. Source
  2. Muggia FM, Peters GJ, Landolph JR Jr. XIII International Charles Heidelberger Symposium and 50 Years of Fluoropyrimidines in Cancer Therapy Held on september 6 to 8, 2007 at New York University Cancer Institute, Smilow Conference Center. Mol Cancer Ther. 2009;8(5):992-9. PubMedDOI
  3. HEIDELBERGER C, CHAUDHURI NK, DANNEBERG P, MOOREN D, GRIESBACH L, DUSCHINSKY R, et al. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature. 1957;179(4561):663-6. PubMedDOI
  4. HEIDELBERGER C, LEIBMAN KC, HARBERS E, BHARGAVA PM. The comparative utilization of uracil-2-C14 by liver, intestinal mucosa, and Flexner-Jobling carcinoma in the rat. Cancer Res. 1957;17(5):399-404. PubMed
  5. RUTMAN RJ, CANTAROW A, PASCHKIS KE. The catabolism of uracil in vivo and in vitro. J Biol Chem. 1954;210(1):321-9. PubMed
  6. Duschinsky R, Pleven E, Heidelberger C. The synthesis of 5-fluoropyrimidines. J Am Chem Soc. 1957;79(16):4559-60. DOI
  7. CURRERI AR, ANSFIELD FJ, McIVER FA, WAISMAN HA, HEIDELBERGER C. Clinical studies with 5-fluorouracil. Cancer Res. 1958;18(4):478-84. PubMed
  8. Shirasaka T. Development history and concept of an oral anticancer agent S-1 (TS-1): its clinical usefulness and future vistas. Jpn J Clin Oncol. 2009;39(1):2-15. PubMedDOI
  9. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, letters, labels, reviews for NDA 012209 (fluorouracil). Page read 2026-10-26. Source
  10. Malet-Martino M, Martino R. Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S-1): a review. Oncologist. 2002;7(4):288-323. PubMedDOI
  11. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330-8. PubMedDOI