Genetic variations within the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who are heterozygous or homozygous for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency. Those with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines; examples of toxicities include myelosuppression, neurotoxicity and hand-foot syndrome. Mechanism of action
5-FU acts in several ways, but principally as a thymidylate synthase (TS) inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidylate (dTMP), which is a nucleotide required for DNA replication. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to form thymidine monophosphate (dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via thymineless death. Calcium folinate provides an exogenous source of reduced folinates and hence stabilises the 5-FU-TS complex, hence enhancing 5-FUs cytotoxicity. History
In 1954, Abraham Cantarow and Karl Paschkis found liver tumors absorbed radioactive uracil more readily than did normal liver cells. Charles Heidelberger, who had earlier found that fluorine in fluoroacetic acid inhibited a vital enzyme, asked Robert Duschinsky and Robert Schnitzer at Hoffmann-La Roche to synthesize fluorouracil. Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice. The original 1957 report in Nature has Heidelberger as lead author, along with N. K. Chaudhuri, Peter Danneberg, Dorothy Mooren, Louis Griesbach, Robert Duschinsky, R. J. Schnitzer, E. Pleven, and J. Scheiner.
In 1958, Anthony R. Curreri, Fred J. Ansfield, Forde A. McIver, Harry A. Waisman, and Charles Heidelberger reported the first clinical findings of 5-FUs activity in cancer in humans. Natural analogues
In 2003, scientists isolated 5-fluorouracil derivatives, closely related compounds, from the marine sponge, Phakellia fusca collected around the Yongxing Island of the Xisha Islands in the South China Sea. This is significant because fluorine-containing organic compounds are rare in nature, and  also because manmade anticancer drugs are not frequently found to have analogues in nature. Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. Names
The name "fluorouracil" is the INN, USAN, USP name, and BAN. The form "5-fluorouracil" is often used; it shows that there is a fluorine atom on the 5th carbon of a uracil ring. References
Further reading
Dean L (2016). "Fluorouracil Therapy and DPYD Genotype". In Pratt VM, McLeod HL, Rubinstein WS,  et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520376. Bookshelf ID: NBK395610. Latchman, Jessica; Guastella, Ann; Tofthagen, Cindy (1 October 2014). "5-Fluorouracil Toxicity and Dihydropyrimidine Dehydrogenase Enzyme: Implications for Practice". Clinical Journal of Oncology Nursing. 18 (5): 581–585. doi:10.1188/14.CJON.581-585. PMC 5469441. PMID 25253112. External links
"Fluorouracil". Drug Information Portal. U.S. National Library of Medicine. "Fluorouracil Topical". MedlinePlus.