Fluorouracil

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Fluorouracil
Fluorouracil2DACS.svg
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Clinical data
Pronunciation /ˌflʊəroʊˈjʊərəsɪl/ [1]
Trade names Adrucil, Carac, Efudex, others
AHFS/Drugs.com Monograph
MedlinePlus a682708
License data
Pregnancy
category
  • AU:D
Routes of
administration 		Intravenous, topical
ATC code
Legal status
Legal status
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
  • 5-Fluoro-1H,3H-pyrimidine-2,4-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.078 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C4H3FN2O2
Molar mass 130.078 g·mol−1
3D model (JSmol)
Melting point 282–283 °C (540–541 °F)
  • O=C1NC(=O)NC=C1F
  • InChI=1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9) Yes check.svgY
  • Key:GHASVSINZRGABV-UHFFFAOYSA-N Yes check.svgY
   (verify)

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]

Contents

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] In 2021, it was the 281st most commonly prescribed medication in the United States, with more than 800,000 prescriptions. [10] [11]

Medical uses

Efudix immediately post-treatment.jpg
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)
Efudix effect three plus years post-treatment.jpg
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). [12] It has also been given topically (on the skin) for actinic keratoses, skin cancers and Bowen's disease [12] (a type of cutaneous squamous-cell carcinoma), and as eye drops for treatment of ocular surface squamous neoplasia. [13] 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. [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]

Adverse effects

Adverse effects by frequency include: [12] [14] [15] [16] [17]

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 [18]
  • 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):

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]

During topical use

Common (> 1% frequency): [12] [22]

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

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. [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]

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. [37] 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. [37] [38] 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. [37] [38]

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. [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]

[[File:
FluoropyrimidineActivity WP1601.png go to articlego to articlego to articlego to pathway articlego to pathway articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to PubChem Compoundgo to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to pathway articlego to pathway articlego to articlego to articlego to articlego to articlego to articlego to WikiPathwaysgo to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
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FluoropyrimidineActivity WP1601.png go to articlego to articlego to articlego to pathway articlego to pathway articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to PubChem Compoundgo to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to pathway articlego to pathway articlego to articlego to articlego to articlego to articlego to articlego to WikiPathwaysgo to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to article
|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.

Related Research Articles

<span class="mw-page-title-main">Chemotherapy</span> Treatment of cancer using drugs that inhibit cell division or kill cells

Chemotherapy is the type of cancer treatment that uses one or more anti-cancer drugs in a standard regimen. Chemotherapy may be given with a curative intent, or it may aim only to prolong life or to reduce symptoms. Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer, which is called medical oncology.

<span class="mw-page-title-main">Folinic acid</span> Derivative of folic acid used in cancer treatment

Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.

<span class="mw-page-title-main">Capecitabine</span> Chemical compound

Capecitabine, sold under the brand name Xeloda among others, is a anticancer medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth.

<span class="mw-page-title-main">Anthracycline</span> Class of antibiotics

Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from Streptomyces bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder cancer, and lung cancers. The first anthracycline discovered was daunorubicin, which is produced naturally by Streptomyces peucetius, a species of Actinomycetota. Clinically the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin.

<span class="mw-page-title-main">Epirubicin</span> Chemical compound

Epirubicin is an anthracycline drug used for chemotherapy. It can be used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. It is marketed by Pfizer under the trade name Ellence in the US and Pharmorubicin or Epirubicin Ebewe elsewhere.

FOLFOX is a chemotherapy regimen for treatment of colorectal cancer, made up of the drugs folinic acid, fluorouracil, and oxaliplatin.

<span class="mw-page-title-main">Irinotecan</span> Cancer medication

Irinotecan, sold under the brand name Camptosar among others, is an anti-cancer medication used to treat colon cancer and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is used with cisplatin. It is given intravenously.

<span class="mw-page-title-main">Dihydropyrimidine dehydrogenase deficiency</span> Medical condition

Dihydropyrimidine dehydrogenase deficiency is an autosomal recessive metabolic disorder in which there is absent or significantly decreased activity of dihydropyrimidine dehydrogenase, an enzyme involved in the metabolism of uracil and thymine.

Panitumumab, sold under the brand name Vectibix, is a fully human monoclonal antibody specific to the epidermal growth factor receptor.

<span class="mw-page-title-main">Thymidylate synthase</span> Enzyme

Thymidylate synthase (TS) is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleotides and increased levels of dUMP arise. Both cause DNA damage.

<span class="mw-page-title-main">Dihydropyrimidine dehydrogenase (NADP+)</span> Class of enzymes

In enzymology, a dihydropyrimidine dehydrogenase (NADP+) (EC 1.3.1.2) is an enzyme that catalyzes the chemical reaction

Tegafur/uracil is a chemotherapy drug combination used in the treatment of cancer, primarily bowel cancer.

<span class="mw-page-title-main">Tegafur</span> Chemical compound

Tegafur is a chemotherapeutic prodrug of 5-fluorouracil (5-FU) used in the treatment of cancers. It is a component of the combination drug tegafur/uracil. When metabolised, it becomes 5-FU.

Ramucirumab is a fully human monoclonal antibody (IgG1) developed for the treatment of solid tumors. This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax.

Thymidylate synthase inhibitors are chemical agents which inhibit the enzyme thymidylate synthase and have potential as an anticancer chemotherapy. This inhibition prevents the methylation of C5 of deoxyuridine monophosphate (dUMP) thereby inhibiting the synthesis of deoxythymidine monophosphate (dTMP). The downstream effect is promotion of cell death because cells would not be able to properly undergo DNA synthesis if they are lacking dTMP, a necessary precursor to dTTP. Five agents were in clinical trials in 2002: raltitrexed, pemetrexed, nolatrexed, Plevitrexed( ZD9331/BGC9331), and GS7904L.

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<span class="mw-page-title-main">Trifluridine/tipiracil</span> Combination medication

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References

  1. ↑ "Fluorouracil – Definition and More from the Free Merriam-Webster Dictionary". Archived 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. Archived (PDF) from the original on 10 June 2022. Retrieved 8 June 2022.
  3. 1 2 3 4 5 6 "Fluorouracil". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  4. 1 2 "Fluorouracil topical". The American Society of Health-System Pharmacists. Archived 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. Archived from the original on 5 November 2017.
  8. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 511. ISBN   9783527607495. Archived from the original on 11 September 2017.
  9. ↑ 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.
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  11. ↑ "Fluorouracil - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  12. 1 2 3 4 5 6 7 Rossi S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN   978-0-9805790-9-3.
  13. ↑ 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.
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  15. ↑ "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.
  16. ↑ "ADRUCIL (fluorouracil) injection [Teva Parenteral Medicines, Inc.]". DailyMed. Teva Parenteral Medicines, Inc. August 2012. Archived from the original on 1 February 2014. Retrieved 24 January 2014.
  17. ↑ "Adrucil (fluorouracil) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 2 February 2014. Retrieved 24 January 2014.
  18. ↑ MedsFacts meta-analysis covering adverse side effect reports of 5fu(fluorouracil) patients who developed hiccups Archived 5 September 2014 at the Wayback Machine at MedsFact, 2013
  19. ↑ 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.
  20. ↑ 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.
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  22. ↑ "Efudex, Carac (fluorouracil topical) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 2 February 2014. Retrieved 24 January 2014.
  23. ↑ "Adrucil (Fluorouracil) Injection [TEVA Parenteral Medicines, Inc.]". Archived from the original on 14 August 2014.
  24. 1 2 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.
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  26. ↑ 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.
  27. 1 2 3 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.
  28. 1 2 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.
  29. 1 2 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ "Customizing Chemotherapy for Better Cancer Care". MyCare Diagnostics. Archived from the original on 28 April 2014.
  35. ↑ "A Brief History of BSA Dosing". MyCare Diagnostics. Archived from the original on 28 April 2014.
  36. ↑ 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.
  37. 1 2 3 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.
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