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 inpregnancy may harm the fetus.[3] Fluorouracil is in theantimetabolite andpyrimidine analog families of medications.[6][7] How it works is not entirely clear, but it is believed to involve blocking the action ofthymidylate synthase and thus stopping the production ofDNA.[3]
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)
Healed skin three+ years after treatment, showing some pigmentation loss
Fluorouracil is contraindicated in patients who are severely debilitated and in patients withbone 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]
in 2020, the EU and UK license was updated to state that fluorouracil was contra-indicated in patients that "have a known complete absence ofdihydropyrimidine dehydrogenase (DPD) activity".[15] 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."[16]
Within the UK, DPYD testing to check for this contraindication is now routine practice;[17] this is not the case in the US.[18]
Diarrhea is severe and may be dose-limiting and is exacerbated by co-treatment withcalcium 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 asangina or symptoms associated withcoronary artery spasm, but about 0.55% of those receiving the drug will develop life-threatening cardiotoxicity.[25] Life-threatening cardiotoxicity includes:arrhythmias,ventricular tachycardia andcardiac arrest, secondary to transmural ischaemia.[25]
The United States package insert warns thatacute cerebellar syndrome has been observed following injection of fluorouracil and may persist after cessation of treatment. Symptoms includeataxia,nystagmus, anddysmetria.[27]
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.[28][29][30] 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.[28] 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).[31][32][33][34] 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.[31][32]
Numerous studies have found significant relationships between concentrations of 5-FU in blood plasma and both desirable or undesirable effects on patients.[35][36] 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.[31][37] 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.[33][38][39]
TheUS Food and Drug Administration has highlighted the dangers of inadvertent administration to pets.[41] 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.[42]
It may increase the INR and prothrombin times in people onwarfarin.[14] Fluorouracil's efficacy is decreased when used alongsideallopurinol, which can be used to decrease fluorouracil induced stomatitis through use of allopurinol mouthwash.[43]
5-FU acts in several ways and is classically described as athymidylate synthase (TS) inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidinethymidylate (dTMP), which is anucleotide required forDNA replication.Thymidylate synthase methylates 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.[46] Calcium folinate provides an exogenous source of reduced folinates and hence stabilises the 5-FU-TS complex, hence enhancing 5-FU's cytotoxicity.[47]
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.[48] 5-FU incorporation into precursor rRNA impairs rRNA processing and maturation.[49] Incorporation into small nuclear RNA (snRNA), particularly U2snRNA, inhibits pseudouridylation, and results in faulty pre-mRNAsplicing.[48]
In 1954, Abraham Cantarow and Karl Paschkis found liver tumors absorbed radioactiveuracil more readily than did normal liver cells.Charles Heidelberger, who had earlier found that fluorine influoroacetic acid inhibited a vital enzyme, asked Robert Duschinsky and Robert Schnitzer atHoffmann-La Roche to synthesize fluorouracil.[50] Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.[51] The original 1957 report[52][53]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.[54]
In 2003, scientists isolated 5-fluorouracil derivatives, closely related compounds, from the marine sponge,Phakellia fusca, collected aroundWoody Island of theParacel Islands in theSouth China Sea. This is significant because fluorine-containingnatural products are extremely rare.[55]
The name "fluorouracil" is theINN,USAN,USP name, andBAN. The form "5-fluorouracil" is often used; it shows that there is a fluorine atom on the 5th carbon of auracil ring.
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^Felici A, Verweij J, Sparreboom A (September 2002). "Dosing strategies for anticancer drugs: the good, the bad and body-surface area".European Journal of Cancer.38 (13):1677–1684.doi:10.1016/s0959-8049(02)00151-x.PMID12175683.
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