Fluorouracil Explained

Fluorouracil (5-FU, 5-fluorouracil), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer.[1] As a cream it is used for actinic keratosis, basal cell carcinoma, and skin warts.[2] [3]

Side effects of use by injection are common.[1] They may include inflammation of the mouth, loss of appetite, low blood cell counts, hair loss, and inflammation of the skin.[1] When used as a cream, irritation at the site of application usually occurs.[2] Use of either form in pregnancy may harm the fetus.[1] Fluorouracil is in the antimetabolite and pyrimidine analog families of medications.[4] [5] 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.[1]

Fluorouracil was patented in 1956 and came into medical use in 1962.[6] It is on the World Health Organization's List of Essential Medicines.[7] In 2021, it was the 281st most commonly prescribed medication in the United States, with more than 800,000 prescriptions.[8] [9]

Medical uses

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] (a type of cutaneous squamous-cell carcinoma), 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. It is likewise contraindicated in pregnant or breastfeeding women. Non-topical use, i.e. administration by injection, should be avoided in patients who do not have malignant illnesses.

Adverse effects

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

During systemic use

Common (> 1% frequency):

Uncommon (0.1–1% frequency):

Rare (< 0.1% frequency):

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]

Uncommon (0.1–1% frequency):

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 natural products are extremely rare.[44]

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.

Further reading

External links

Notes and References

  1. Web site: Fluorouracil. The American Society of Health-System Pharmacists. 8 December 2016. live. https://web.archive.org/web/20161220192631/https://www.drugs.com/monograph/fluorouracil.html. 20 December 2016.
  2. Web site: Fluorouracil topical. The American Society of Health-System Pharmacists. 8 December 2016. live. https://web.archive.org/web/20161226054457/https://www.drugs.com/monograph/fluorouracil-topical.html. 26 December 2016.
  3. Moore AY . Clinical applications for topical 5-fluorouracil in the treatment of dermatological disorders . The Journal of Dermatological Treatment . 20 . 6 . 328–335 . 2009 . 19954388 . 10.3109/09546630902789326 . 218896998 .
  4. Book: British national formulary : BNF 69. 2015. British Medical Association. 9780857111562. 590. 69.
  5. Book: Airley R . Cancer Chemotherapy: Basic Science to the Clinic. 2009. John Wiley & Sons. 9780470092569. 76. en. live. https://web.archive.org/web/20171105200744/https://books.google.com/books?id=wjjYyYpfiQ8C&pg=PA76. 5 November 2017.
  6. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery. 2006. John Wiley & Sons. 9783527607495. 511. en. live. https://web.archive.org/web/20170911002644/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA511. 11 September 2017.
  7. Book: ((World Health Organization)) . The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) . 2023 . 10665/371090 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2023.02 . free .
  8. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  9. Web site: Fluorouracil - Drug Usage Statistics . ClinCalc . 14 January 2024.
  10. Book: Rossi S . 978-0-9805790-9-3 . Australian Medicines Handbook . Adelaide . The Australian Medicines Handbook Unit Trust . 2013 . 2013 .
  11. Joag MG, Sise A, Murillo JC, Sayed-Ahmed IO, Wong JR, Mercado C, Galor A, Karp CL . 6 . Topical 5-Fluorouracil 1% as Primary Treatment for Ocular Surface Squamous Neoplasia . Ophthalmology . 123 . 7 . 1442–1448 . July 2016 . 27030104 . 4921289 . 10.1016/j.ophtha.2016.02.034 .
  12. Web site: Fluorouracil 50 mg/ml Injection – Summary of Product Characteristics. electronic Medicines Compendium. Hospira UK Ltd. 24 August 2011. 24 January 2014. live. https://web.archive.org/web/20140201204538/http://www.medicines.org.uk/emc/medicine/636/SPC/Fluorouracil++50+mg+ml++Injection/. 1 February 2014.
  13. Web site: DBL Fluorouracil Injection BP. TGA eBusiness Services. Hospira Australia Pty Ltd. 21 June 2012. 24 January 2014. PDF. live. https://web.archive.org/web/20170128034658/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-02952-3. 28 January 2017.
  14. Web site: ADRUCIL (fluorouracil) injection [Teva Parenteral Medicines, Inc.]]. DailyMed. Teva Parenteral Medicines, Inc.. August 2012. 24 January 2014. live. https://web.archive.org/web/20140201231133/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=b90e0da7-f702-4f09-9488-74f2bb20e9ac. 1 February 2014.
  15. Web site: Adrucil (fluorouracil) dosing, indications, interactions, adverse effects, and more. Medscape Reference. WebMD. 24 January 2014. live. https://web.archive.org/web/20140202174903/http://reference.medscape.com/drug/adrucil-fluorouracil-342092#showall. 2 February 2014.
  16. http://medsfacts.com/study-5FU%28FLUOROURACIL%29-causing-HICCUPS.php MedsFacts meta-analysis covering adverse side effect reports of 5fu(fluorouracil) patients who developed hiccups
  17. Ha JH, Hwang DY, Yu J, Park DH, Ryu SH . Onset of Manic Episode during Chemotherapy with 5-Fluorouracil . Psychiatry Investigation . 8 . 1 . 71–73 . March 2011 . 21519541 . 3079190 . 10.4306/pi.2011.8.1.71 .
  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. Web site: Fluorouracil: Martindale: The Complete Drug Reference. 9 January 2017. 14 August 2017. Brayfield A . Pharmaceutical Press. MedicinesComplete. London, UK. 28 August 2021. https://web.archive.org/web/20210828090019/https://about.medicinescomplete.com/wp-content/plugins/revslider/public/assets/js/extensions/revolution.extension.slideanims.min.js?version=5.4.5. live.
  20. Web site: Efudex, Carac (fluorouracil topical) dosing, indications, interactions, adverse effects, and more. Medscape Reference. WebMD. 24 January 2014. live. https://web.archive.org/web/20140202174906/http://reference.medscape.com/drug/efudex-carac-fluorouracil-topical-343545#showall. 2 February 2014.
  21. Web site: Adrucil (Fluorouracil) Injection [TEVA Parenteral Medicines, Inc.]]. live. https://web.archive.org/web/20140814024152/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e0794add-67a7-4308-93e9-f889472716cc. 14 August 2014.
  22. Gamelin E, Boisdron-Celle M . 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 . March 1999 . 10439055 . 10.1016/s1040-8428(98)00036-5 .
  23. Felici A, Verweij J, Sparreboom A . Dosing strategies for anticancer drugs: the good, the bad and body-surface area . European Journal of Cancer . 38 . 13 . 1677–1684 . September 2002 . 12175683 . 10.1016/s0959-8049(02)00151-x .
  24. Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens JH, Grochow LB, Sparreboom A . 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 . December 2002 . 12488482 . 10.1093/jnci/94.24.1883 . free .
  25. Capitain O, Asevoaia A, Boisdron-Celle M, Poirier AL, Morel A, Gamelin E . 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 . December 2012 . 22683364 . 10.1016/j.clcc.2012.05.004 .
  26. Saam J, Critchfield GC, Hamilton SA, Roa BB, Wenstrup RJ, Kaldate RR . 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 . September 2011 . 21855044 . 10.1016/j.clcc.2011.03.015 .
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  34. Porta C, Moroni M, Nastasi G . Allopurinol mouthwashes in the treatment of 5-fluorouracil-induced stomatitis . American Journal of Clinical Oncology . 17 . 3 . 246–247 . June 1994 . 8192112 . 10.1097/00000421-199406000-00014 . 26844431 .
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