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Fluorouracil

Fluorouracil
Clinical data
Pronunciation/ˌflʊərˈjʊərəsɪl/[1]
Trade namesAdrucil, Carac, Efudex, others
AHFS/Drugs.comMonograph
MedlinePlusa682708
License data
Pregnancy
category
  • AU: D
Routes of
administration
Intravenous, topical
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability28 to 100%
Protein binding8 to 12%
MetabolismIntracellular and liver (CYP-mediated)
Elimination half-life16 minutes
ExcretionKidney
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 InfoCard100.000.078 Edit this at Wikidata
Chemical and physical data
FormulaC4H3FN2O2
Molar mass130.078 g·mol−1
3D model (JSmol)
Melting point282–283 °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) checkY
  • Key:GHASVSINZRGABV-UHFFFAOYSA-N checkY
  (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]

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

Male forearm showing oval scabbed skin patch with scales and reddening
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)
Male forearm showing healed skin with a creamy, shiny patch having pigmentation loss
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):

  • Anaphylaxis
  • Allergic reactions
  • Fever without signs of infection
  • Mania, reversible dementia[19][20]

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):

  • 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.[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 organic compounds are rare in nature, and also because manmade anticancer drugs are not frequently found to have analogues in nature.[46]

Interactive pathway map

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

[[File:
FluoropyrimidineActivity_WP1601go 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_WP1601go 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.

References

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  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.
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  4. ^ a b "Fluorouracil topical". The American Society of Health-System Pharmacists. Archived from the original on 26 December 2016. Retrieved 8 December 2016.
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Further reading

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Fluorouracil
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