Side effects of use by injection are common.[3] They may include inflammation of the mouth, loss of appetite, low blood cell counts, hair loss, and inflammation of the skin.[3] When used as a cream, irritation at the site of application usually occurs.[4] Use of either form in pregnancy may harm the fetus.[3] Fluorouracil is in the antimetabolite and pyrimidine analog families of medications.[6][7] How it works is not entirely clear, but it is believed to involve blocking the action of thymidylate synthase and thus stopping the production of DNA.[3]
Effect of topical skin treatment with 5-fluorouracil cream after a standard 30-day treatment, before commencement of the healing phase (months two and three)
Healed skin three+ years after treatment, showing some pigmentation loss
Fluorouracil is contraindicated in patients who are severely debilitated and in patients with bone marrow suppression due to either radiotherapy or chemotherapy.[14] It is likewise contraindicated in pregnant or breastfeeding women.[14] Non-topical use, i.e. administration by injection, should be avoided in patients who do not have malignant illnesses.[14]
Diarrhea is severe and may be dose-limiting and is exacerbated by co-treatment with calcium folinate.[12]Neutropenia tends to peak about 9–14 days after beginning treatment.[12]Thrombocytopenia tends to peak about 7–17 days after the beginning of treatment and tends to recover about 10 days after its peak.[12]Cardiotoxicity is a fairly common side effect, usually manifesting as angina or symptoms associated with coronary artery spasm, but about 0.55% of those receiving the drug will develop life-threatening cardiotoxicity.[21] Life-threatening cardiotoxicity includes: arrhythmias, ventricular tachycardia and cardiac arrest, secondary to transmural ischaemia.[21]
The United States package insert warns that acute cerebellar syndrome has been observed following injection of fluorouracil and may persist after cessation of treatment. Symptoms include ataxia, nystagmus, and dysmetria.[23]
Potential overdose
There is very little difference between the minimum effective dose and maximum tolerated dose of 5-FU, and the drug exhibits marked individual pharmacokinetic variability.[24][25][26] Therefore, an identical dose of 5-FU may result in a therapeutic response with acceptable toxicity in some patients and unacceptable and possibly life-threatening toxicity in others.[24] Both overdosing and underdosing are of concern with 5-FU, although several studies have shown that the majority of colorectal cancer patients treated with 5-FU are underdosed based on today's dosing standard, body surface area (BSA).[27][28][29][30] The limitations of BSA-based dosing prevent oncologists from being able to accurately titer the dosage of 5-FU for the majority of individual patients, which results in sub-optimal treatment efficacy or excessive toxicity.[27][28]
Numerous studies have found significant relationships between concentrations of 5-FU in blood plasma and both desirable or undesirable effects on patients.[31][32] Studies have also shown that dosing based on the concentration of 5-FU in plasma can greatly increase desirable outcomes while minimizing negative side effects of 5-FU therapy.[27][33] One such test that has been shown to successfully monitor 5-FU plasma levels and which "may contribute to improved efficacy and safety of commonly used 5-FU-based chemotherapies" is the My5-FU test.[29][34][35]
Interactions
It may increase the INR and prothrombin times in people on warfarin.[14] Fluorouracil's efficacy is decreased when used alongside allopurinol, which can be used to decrease fluorouracil induced stomatitis through use of allopurinol mouthwash.[36]
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.[39] Calcium folinate provides an exogenous source of reduced folinates and hence stabilises the 5-FU-TS complex, hence enhancing 5-FU's cytotoxicity.[40]
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.[41] Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.[42] The original 1957 report[43][44]
In 1958, Anthony R. Curreri, Fred J. Ansfield, Forde A. McIver, Harry A. Waisman, and Charles Heidelberger reported the first clinical findings of 5-FU's activity in cancer in humans.[45]
Natural analogues
In 2003, scientists isolated 5-fluorouracil derivatives, closely related compounds, from the marine sponge, Phakellia fusca, collected around Yongxing Island of the Xisha Islands in the South China Sea. This is significant because fluorine-containing natural products are extremely rare.[46]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
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.
^ abcdef"Fluorouracil". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
^ ab"Fluorouracil topical". The American Society of Health-System Pharmacists. Archived from the original on 26 December 2016. Retrieved 8 December 2016.
^Moore AY (2009). "Clinical applications for topical 5-fluorouracil in the treatment of dermatological disorders". The Journal of Dermatological Treatment. 20 (6): 328–335. doi:10.3109/09546630902789326. PMID19954388. S2CID218896998.
^British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 590. ISBN9780857111562.
^World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
^"DBL Fluorouracil Injection BP"(PDF). TGA eBusiness Services. Hospira Australia Pty Ltd. 21 June 2012. Archived from the original on 28 January 2017. Retrieved 24 January 2014.
^Park H. J., Choi Y. T., Kim I. H., Hah J. C.; A case of reversible dementia associated with depression in a patient on 5-FU or its analogue drugs. J. Korean Neuropsychiatr. Assoc. 1987;30:199–202.
^ abGamelin E, Boisdron-Celle M (March 1999). "Dose monitoring of 5-fluorouracil in patients with colorectal or head and neck cancer--status of the art". Critical Reviews in Oncology/Hematology. 30 (1): 71–79. doi:10.1016/s1040-8428(98)00036-5. PMID10439055.
^Felici A, Verweij J, Sparreboom A (September 2002). "Dosing strategies for anticancer drugs: the good, the bad and body-surface area". European Journal of Cancer. 38 (13): 1677–1684. doi:10.1016/s0959-8049(02)00151-x. PMID12175683.
^ abcCapitain O, Asevoaia A, Boisdron-Celle M, Poirier AL, Morel A, Gamelin E (December 2012). "Individual fluorouracil dose adjustment in FOLFOX based on pharmacokinetic follow-up compared with conventional body-area-surface dosing: a phase II, proof-of-concept study". Clinical Colorectal Cancer. 11 (4): 263–267. doi:10.1016/j.clcc.2012.05.004. PMID22683364.
^ abSaam J, Critchfield GC, Hamilton SA, Roa BB, Wenstrup RJ, Kaldate RR (September 2011). "Body surface area-based dosing of 5-fluoruracil results in extensive interindividual variability in 5-fluorouracil exposure in colorectal cancer patients on FOLFOX regimens". Clinical Colorectal Cancer. 10 (3): 203–206. doi:10.1016/j.clcc.2011.03.015. PMID21855044.
^ abBeumer JH, Boisdron-Celle M, Clarke W, Courtney JB, Egorin MJ, Gamelin E, et al. (December 2009). "Multicenter evaluation of a novel nanoparticle immunoassay for 5-fluorouracil on the Olympus AU400 analyzer". Therapeutic Drug Monitoring. 31 (6): 688–694. doi:10.1097/FTD.0b013e3181b9b8c0. PMID19935361. S2CID220558482.{{cite journal}}: CS1 maint: overridden setting (link)
^van Kuilenburg AB, Maring JG (May 2013). "Evaluation of 5-fluorouracil pharmacokinetic models and therapeutic drug monitoring in cancer patients". Pharmacogenomics. 14 (7): 799–811. doi:10.2217/pgs.13.54. PMID23651027.
^Porta C, Moroni M, Nastasi G (June 1994). "Allopurinol mouthwashes in the treatment of 5-fluorouracil-induced stomatitis". American Journal of Clinical Oncology. 17 (3): 246–247. doi:10.1097/00000421-199406000-00014. PMID8192112. S2CID26844431.
^ abAmstutz U, Froehlich TK, Largiadèr CR (September 2011). "Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity". Pharmacogenomics. 12 (9): 1321–1336. doi:10.2217/pgs.11.72. PMID21919607.
^Xu XH, Yao GM, Li YM, Lu JH, Lin CJ, Wang X, et al. (February 2003). "5-Fluorouracil derivatives from the sponge Phakellia fusca". Journal of Natural Products. 66 (2): 285–288. doi:10.1021/np020034f. PMID12608868.
