Fluorouracil

Fluorouracil(5-FU,5-fluorouracil), sold under the brand nameAdrucilamong others, is acytotoxicchemotherapymedication used to treatcancer.Byintravenous injectionit is used for treatment ofcolorectal cancer,oesophageal cancer,stomach cancer,pancreatic cancer,breast cancer, andcervical cancer.As a cream it is used foractinic keratosis,basal cell carcinoma, and skinwarts.
Side effects of use by injection are common.They may include inflammation of the mouth, loss of appetite,low blood cell counts, hair loss, and inflammation of the skin.When used as a cream, irritation at the site of application usually occurs.Use of either form inpregnancymay harm the fetus.Fluorouracil is in theantimetaboliteandpyrimidine analogfamilies of medications.How it works is not entirely clear, but it is believed to involve blocking the action ofthymidylate synthaseand thus stopping the production ofDNA.
Fluorouracil was patented in 1956 and came into medical use in 1962.It is on theWorld Health Organization's List of Essential Medicines.In 2022, it was the 270th most commonly prescribed medication in the United States, with more than 900,000 prescriptions.
Fluorouracil has been given systemically foranal,breast,colorectal,oesophageal,stomach,pancreaticandskin cancers(especiallyhead and neck cancers).It has also been given topically (on the skin) foractinic keratoses, skin cancers andBowen's disease(a type ofcutaneous squamous-cell carcinoma), and as eye drops for treatment ofocular surface squamous neoplasia.Other uses include ocular injections into a previously createdtrabeculectomyblebto inhibit healing and cause scarring of tissue, thus allowing adequateaqueous humorflow to reduce intraocular pressure.
Fluorouracil is contraindicated in patients who are severely debilitated and in patients withbone marrow suppressiondue 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.
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".In US, as of 2024, there is no specific contraindication on the package inserts however, there is a cautionary warning: "Increased risk of serious or fatal adverse reactions in patients with low or absent Dipyrimidine Dehydrogenase activity: withhold or permanently discontinue fluorouracil in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of dipyrimidine 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,this is not the case in the US.
Adverse effects by frequency include:
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 withcalcium folinate.Neutropeniatends to peak about 9–14 days after beginning treatment.Thrombocytopeniatends to peak about 7–17 days after the beginning of treatment and tends to recover about 10 days after its peak.Cardiotoxicityis a fairly common side effect, usually manifesting asanginaor symptoms associated withcoronary artery spasm, but about 0.55% of those receiving the drug will develop life-threatening cardiotoxicity.Life-threatening cardiotoxicity includes:arrhythmias,ventricular tachycardiaandcardiac arrest, secondary to transmural ischaemia.
Common (> 1% frequency):
Uncommon (0.1–1% frequency):
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 includeataxia,nystagmus, anddysmetria.
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.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.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).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.
Numerous studies have found significant relationships between concentrations of 5-FU in blood plasma and both desirable or undesirable effects on patients.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.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.
Uridine Triacetateis a potential antidote for cases of suspected overdose.
TheUS Food and Drug Administrationhas highlighted the dangers of inadvertent administration to pets.While fluorouracil is sometimes used off label to treat horses, its administration to dogs in particular can be fatal.
The FDA reports that it has received 20 reports of fatal outcomes in dogs following accidental ingestion of topical  fluorouracil.
It may increase the INR and prothrombin times in people onwarfarin.Fluorouracil's efficacy is decreased when used alongsideallopurinol, which can be used to decrease fluorouracil induced stomatitis through use of allopurinol mouthwash.
Thedihydropyrimidine dehydrogenase(DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil,capecitabine, andtegafur.Genetic variationswithin the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who areheterozygousorhomozygousfor these variations may have partial or completeDPD deficiency; an estimated 0.2% of individuals have completeDPD deficiency.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 includemyelosuppression,neurotoxicityandhand-foot syndrome.
5-FU acts in several ways, but principally as athymidylate synthase (TS) inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidinethymidylate (dTMP), which is anucleotiderequired forDNA replication.Thymidylate synthasemethylates deoxyuridine monophosphate (dUMP) to formthymidine monophosphate(dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death viathymineless death.Calcium folinate provides an exogenous source of reduced folinates and hence stabilises the 5-FU-TS complex, hence enhancing 5-FU's cytotoxicity.
In 1954, Abraham Cantarow and Karl Paschkis found liver tumors absorbed radioactiveuracilmore readily than did normal liver cells.Charles Heidelberger, who had earlier found that fluorine influoroacetic acidinhibited a vital enzyme, asked Robert Duschinsky and Robert Schnitzer atHoffmann-La Rocheto synthesize fluorouracil.Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.The original 1957 reportIn 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.
In 2003, scientists isolated 5-fluorouracil derivatives, closely related compounds, from the marine sponge,Phakelliafusca, collected aroundYongxing Islandof theXisha Islandsin theSouth China Sea. This is significant because fluorine-containingnatural productsare extremely rare.
Click on genes, proteins and metabolites below to link to respective articles.
The name "fluorouracil" is theINN,USAN,USPname, andBAN. The form "5-fluorouracil" is often used; it shows that there is a fluorine atom on the 5th carbon of auracilring.