Fluorouracil

Fluorouracil (5-FU, 5-fluorouracil), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer.^[3] By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer.^[3] As a cream it is used for actinic keratosis, basal cell carcinoma, and skin warts.^[4][5]

Fluorouracil

Clinical data
Pronunciation	/ˌflʊəroʊˈjʊərəsɪl/^[1]
Trade names	Adrucil, Carac, Efudex, others
AHFS/Drugs.com	Monograph
MedlinePlus	a682708
License data	US DailyMed: Fluorouracil US FDA: Fluorouracil
Pregnancy category	AU: D
Routes of administration	Intravenous, topical
ATC code	L01BC02 (WHO) L01BC52 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only^[2] UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	28 to 100%
Protein binding	8 to 12%
Metabolism	Intracellular and liver (CYP-mediated)
Elimination half-life	16 minutes
Excretion	Kidney
Identifiers
IUPAC name 5-Fluoro-1H,3H-pyrimidine-2,4-dione
CAS Number	51-21-8^Y
PubChem CID	3385
IUPHAR/BPS	4789
DrugBank	DB00544^Y
ChemSpider	3268^Y
UNII	U3P01618RT
KEGG	D00584^Y
ChEBI	CHEBI:46345^Y
ChEMBL	ChEMBL185^Y
CompTox Dashboard (EPA)	DTXSID2020634
ECHA InfoCard	100.000.078
Chemical and physical data
Formula	C4H3FN2O2
Molar mass	130.078 g·mol^−1
3D model (JSmol)	Interactive image
Melting point	282–283 °C (540–541 °F)
SMILES O=C1NC(=O)NC=C1F
InChI InChI=1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9)^Y Key:GHASVSINZRGABV-UHFFFAOYSA-N^Y
(verify)

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]

Fluorouracil was patented in 1956 and came into medical use in 1962.^[8] It is on the World Health Organization's List of Essential Medicines.^[9]

Medical uses

 

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 has been given systemically for anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers).^[10] It has also been given topically (on the skin) for actinic keratoses, skin cancers and Bowen's disease,^[10] and as eye drops for treatment of ocular surface squamous neoplasia.^[11] Other uses include ocular injections into a previously created trabeculectomy bleb to inhibit healing and cause scarring of tissue, thus allowing adequate aqueous humor flow to reduce intraocular pressure.

Contraindications

Fluorouracil is contraindicated in patients who are severely debilitated and in patients with bone marrow suppression due to either radiotherapy or chemotherapy.^[12] It is likewise contraindicated in pregnant or breastfeeding women.^[12] Non-topical use, i.e. administration by injection, should be avoided in patients who do not have malignant illnesses.^[12]

Adverse effects

Adverse effects by frequency include:^{[10][12][13][14][15]}

During systemic use

Common (> 1% frequency):

• Nausea
• Vomiting
• Diarrhea (see below for details)
• Mucositis
• Headache
• Hand-foot syndrome
• Myelosuppression (see below for details)
• Alopecia (hair loss)
• Photosensitivity
• Maculopapular eruption
• Itch
• Cardiotoxicity (see below for details)
• Persistent hiccups^[16]
• Mood disorders (irritability, anxiety, depression)

Uncommon (0.1–1% frequency):

• Oesophagitis
• GI ulceration and bleeding
• Proctitis
• Nail disorders
• Vein pigmentation
• Confusion
• Cerebellar syndrome
• Encephalopathy
• Visual changes
• Photophobia
• Lacrimation (the expulsion of tears without any emotional or physiologic reason)

Rare (< 0.1% frequency):

• Anaphylaxis
• Allergic reactions
• Fever without signs of infection
• Mania, reversible dementia^[17][18]

Diarrhea is severe and may be dose-limiting and is exacerbated by co-treatment with calcium folinate.^[10] Neutropenia tends to peak about 9–14 days after beginning treatment.^[10] Thrombocytopenia tends to peak about 7–17 days after the beginning of treatment and tends to recover about 10 days after its peak.^[10] 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.^[19] Life-threatening cardiotoxicity includes: arrhythmias, ventricular tachycardia and cardiac arrest, secondary to transmural ischaemia.^[19]

During topical use

Common (> 1% frequency):^[10][20]

• Local pain
• Itchiness
• Burning
• Stinging
• Crusting
• Weeping
• Dermatitis
• Photosensitivity

Uncommon (0.1–1% frequency):

• Hyper- or hypopigmentation
• Scarring

Neurological damage

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.^[21]

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.^[22][23][24] 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.^[22] 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).^{[25][26][27][28]} 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.^[25][26]

Numerous studies have found significant relationships between concentrations of 5-FU in blood plasma and both desirable or undesirable effects on patients.^[29][30] 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.^[25][31] 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.^[27][32][33]

Interactions

It may increase the INR and prothrombin times in people on warfarin.^[12] Fluorouracil's efficacy is decreased when used alongside allopurinol, which can be used to decrease fluorouracil induced stomatitis through use of allopurinol mouthwash.^[34]

Pharmacology

Pharmacogenetics

The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil, capecitabine, and tegafur.^[35] 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.^[35][36] 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.^[35][36]

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.^[37] Calcium folinate provides an exogenous source of reduced folinates and hence stabilises the 5-FU-TS complex, hence enhancing 5-FU's cytotoxicity.^[38]

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.^[39] Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.^[40] The original 1957 report^[41][42] 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.^[43]

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 organic compounds are rare in nature, and also because manmade anticancer drugs are not frequently found to have analogues in nature.^[44]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.^{[§ 1]}

[[File:

 

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

[[

]]

 

|alt=Fluorouracil (5-FU) Activity edit]]

Fluorouracil (5-FU) Activity edit

1. The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601".

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

1. "Fluorouracil – Definition and More from the Free Merriam-Webster Dictionary". from the original on 29 November 2014. Retrieved 19 November 2014.
2. "TOLAK : Fluorouracil Cream : 4% (w/w) fluorouracil (as fluorouracil sodium)" (PDF). Pdf.hres.ca. (PDF) from the original on 10 June 2022. Retrieved 8 June 2022.
3. "Fluorouracil". The American Society of Health-System Pharmacists. from the original on 20 December 2016. Retrieved 8 December 2016.
4. "Fluorouracil topical". The American Society of Health-System Pharmacists. from the original on 26 December 2016. Retrieved 8 December 2016.
5. 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. PMID 19954388. S2CID 218896998.
6. British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 590. ISBN 9780857111562.
7. Airley R (2009). Cancer Chemotherapy: Basic Science to the Clinic. John Wiley & Sons. p. 76. ISBN 9780470092569. from the original on 5 November 2017.
8. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 511. ISBN 9783527607495. from the original on 11 September 2017.
9. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
10. Rossi S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
11. Joag MG, Sise A, Murillo JC, Sayed-Ahmed IO, Wong JR, Mercado C, et al. (July 2016). "Topical 5-Fluorouracil 1% as Primary Treatment for Ocular Surface Squamous Neoplasia". Ophthalmology. 123 (7): 1442–1448. doi:10.1016/j.ophtha.2016.02.034. PMC 4921289. PMID 27030104.
12. "Fluorouracil 50 mg/ml Injection – Summary of Product Characteristics". electronic Medicines Compendium. Hospira UK Ltd. 24 August 2011. from the original on 1 February 2014. Retrieved 24 January 2014.
13. "DBL Fluorouracil Injection BP" (PDF). TGA eBusiness Services. Hospira Australia Pty Ltd. 21 June 2012. from the original on 28 January 2017. Retrieved 24 January 2014.
14. "ADRUCIL (fluorouracil) injection [Teva Parenteral Medicines, Inc.]". DailyMed. Teva Parenteral Medicines, Inc. August 2012. from the original on 1 February 2014. Retrieved 24 January 2014.
15. "Adrucil (fluorouracil) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. from the original on 2 February 2014. Retrieved 24 January 2014.
16. MedsFacts meta-analysis covering adverse side effect reports of 5fu(fluorouracil) patients who developed hiccups 5 September 2014 at the Wayback Machine at MedsFact, 2013
17. Ha JH, Hwang DY, Yu J, Park DH, Ryu SH (March 2011). "Onset of Manic Episode during Chemotherapy with 5-Fluorouracil". Psychiatry Investigation. 8 (1): 71–73. doi:10.4306/pi.2011.8.1.71. PMC 3079190. PMID 21519541.
18. 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.
19. Brayfield A, ed. (9 January 2017). "Fluorouracil: Martindale: The Complete Drug Reference". MedicinesComplete. London, UK: Pharmaceutical Press. from the original on 28 August 2021. Retrieved 14 August 2017.
20. "Efudex, Carac (fluorouracil topical) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. from the original on 2 February 2014. Retrieved 24 January 2014.
21. "Adrucil (Fluorouracil) Injection [TEVA Parenteral Medicines, Inc.]". from the original on 14 August 2014.
22. Gamelin 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. PMID 10439055.
23. 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. PMID 12175683.
24. Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens JH, Grochow LB, Sparreboom A (December 2002). "Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001". Journal of the National Cancer Institute. 94 (24): 1883–1888. doi:10.1093/jnci/94.24.1883. PMID 12488482.
25. Capitain 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. PMID 22683364.
26. Saam 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. PMID 21855044.
27. Beumer 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. PMID 19935361. S2CID 220558482.
28. Goldberg RM, Rothenberg ML, Van Cutsem E, Benson AB, Blanke CD, Diasio RB, et al. (January 2007). "The continuum of care: a paradigm for the management of metastatic colorectal cancer". The Oncologist. 12 (1): 38–50. doi:10.1634/theoncologist.12-1-38. PMID 17227899. S2CID 21638678.
29. Ploylearmsaeng SA, Fuhr U, Jetter A (2006). "How may anticancer chemotherapy with fluorouracil be individualised?". Clinical Pharmacokinetics. 45 (6): 567–592. doi:10.2165/00003088-200645060-00002. PMID 16719540. S2CID 36534309.
30. 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. PMID 23651027.
31. Gamelin E, Delva R, Jacob J, Merrouche Y, Raoul JL, Pezet D, et al. (May 2008). "Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer". Journal of Clinical Oncology. 26 (13): 2099–2105. doi:10.1200/jco.2007.13.3934. PMID 18445839. S2CID 9557055.
32. . MyCare Diagnostics. Archived from the original on 28 April 2014.
33. "A Brief History of BSA Dosing". MyCare Diagnostics. from the original on 28 April 2014.
34. 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. PMID 8192112. S2CID 26844431.
35. Caudle KE, Thorn CF, Klein TE, Swen JJ, McLeod HL, Diasio RB, Schwab M (December 2013). "Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing". Clinical Pharmacology and Therapeutics. 94 (6): 640–645. doi:10.1038/clpt.2013.172. PMC 3831181. PMID 23988873.
36. Amstutz 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. PMID 21919607.
37. Longley DB, Harkin DP, Johnston PG (May 2003). "5-fluorouracil: mechanisms of action and clinical strategies". Nature Reviews. Cancer. 3 (5): 330–338. doi:10.1038/nrc1074. PMID 12724731. S2CID 4357553.
38. Álvarez P, Marchal JA, Boulaiz H, Carrillo E, Vélez C, Rodríguez-Serrano F, et al. (February 2012). "5-Fluorouracil derivatives: a patent review". Expert Opinion on Therapeutic Patents. 22 (2): 107–123. doi:10.1517/13543776.2012.661413. PMID 22329541. S2CID 2793746.
39. Sneader W (June 2005). Drug discovery: a history. John Wiley & Sons. p. 255.
40. Cohen S (30 January 2008). "50 years ago in cell biology: A virologist recalls his work on cell growth inhibition". The Scientist. from the original on 19 September 2010.
41. Chu E (September 2007). "Ode to 5-Fluorouracil". Clinical Colorectal Cancer. 6 (9): 609. doi:10.3816/CCC.2007.n.029. Archived from the original on 14 July 2012.
42. Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Griesbach L, Duschinsky R, et al. (March 1957). "Fluorinated pyrimidines, a new class of tumour-inhibitory compounds". Nature. 179 (4561): 663–666. Bibcode:1957Natur.179..663H. doi:10.1038/179663a0. PMID 13418758. S2CID 4296069.
43. Jordan VC (February 2016). "A Retrospective: On Clinical Studies with 5-Fluorouracil". Cancer Research. American Association for Cancer Research. 76 (4): 767–768. doi:10.1158/0008-5472.CAN-16-0150. PMID 26880809. from the original on 28 August 2021. Retrieved 17 August 2019.
44. Xu XH, Yao GM, Li YM, Lu JH, Lin CJ, Wang X, Kong CH (February 2003). "5-Fluorouracil derivatives from the sponge Phakellia fusca". Journal of Natural Products. 66 (2): 285–288. doi:10.1021/np020034f. PMID 12608868.

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 J, Guastella A, Tofthagen C (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 Topical". MedlinePlus.