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.]
Side effects of use by injection are common.[ They may include inflammation of the mouth, loss of appetite, cytopenia, hair loss, and inflammation of the skin.][ When used as a cream, irritation at the site of application usually occurs.][ Use of either form in pregnancy may harm the fetus.][ Fluorouracil is in the antimetabolite and pyrimidine analog families of medications.][
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Fluorouracil was patented in 1956 and came into medical use in 1962.
Medical uses
Fluorouracil has been given systemically for anal cancer, breast cancer, colorectal, oesophageal, stomach cancer, pancreatic and (especially head and neck cancers).[ (a type of cutaneous squamous-cell carcinoma), and as eye drops for treatment of ocular surface squamous neoplasia.]
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.][
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Non-topical use, i.e. administration by injection, should be avoided in patients who do not have malignant illnesses.
in 2020, the EU and UK license was updated to state that fluorouracil was contra-indicated in patients that "have a known complete absence of dihydropyrimidine dehydrogenase (DPD) activity".
No fluorouracil dose has been proven safe in patients with absent DPD activity."
Within the UK, DPYD testing to check for this contraindication is now routine practice;
Adverse effects
Adverse effects by frequency include:
During systemic use
Common (> 1% frequency):
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Nausea
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Vomiting
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Diarrhea (see below for details)
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Mucositis
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Headache
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Hand-foot syndrome
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Myelosuppression (see below for details)
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Alopecia (hair loss)
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Photosensitivity
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Maculopapular eruption
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Itch
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Cardiotoxicity (see below for details)
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Persistent hiccups
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Mood disorders (irritability, anxiety, depression)
Uncommon (0.1–1% frequency):
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Oesophagitis
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GI ulceration and bleeding
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Proctitis
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Nail disorders
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Vein pigmentation
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Confusion
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Cerebellar syndrome
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Encephalopathy
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Visual changes
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Photophobia
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Lacrimation (the expulsion of tears without any emotional or physiologic reason)
Rare (< 0.1% frequency):
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Anaphylaxis
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Allergic reactions
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Fever without signs of infection
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Mania, reversible dementia
[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.]
Diarrhea is severe and may be dose-limiting and is exacerbated by co-treatment with calcium folinate.[ Neutropenia tends to peak about 9–14 days after beginning treatment.][ Thrombocytopenia tends to peak about 7–17 days after the beginning of treatment and tends to recover about 10 days after its peak.][ 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.]
During topical use
Common (> 1% frequency):
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Local pain
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Itchiness
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Burning
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Stinging
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Crusting
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Weeping
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Dermatitis
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Photosensitivity
Uncommon (0.1–1% frequency):
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Hyper- or hypopigmentation
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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.
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.
Numerous studies have found significant relationships between concentrations of 5-FU in blood plasma and both desirable or undesirable effects on patients.
Uridine Triacetate is a potential antidote for cases of suspected overdose.
Dangers to pets
The US Food and Drug Administration has highlighted the dangers of inadvertent administration to pets.
The FDA reports that it has received 20 reports of fatal outcomes in dogs following accidental ingestion of topical fluorouracil.
Interactions
It may increase the INR and prothrombin times in people on warfarin.[ Fluorouracil's efficacy is decreased when used alongside allopurinol, which can be used to decrease fluorouracil induced stomatitis through use of allopurinol mouthwash.]
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.
Mechanism of action
5-FU acts in several ways and is classically described 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.
5-FU is also converted inside cells into 5-fluorouridine triphosphate (5FUTP), which can be incorporated into RNA (especially ribosomal RNA, tRNA, snRNA, and mRNA) in place of uridine.
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.
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.
Interactive pathway map
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
