Fluorouracil

"F5U" redirects here. For the Flying Flapjack, see Vought XF5U.

Fluorouracil

Systematic (IUPAC) name
5-Fluoro-1H,3H-pyrimidine-2,4-dione
Clinical data
Pronunciation	/ˌflʊroʊˈjʊrəˌsɪl/
Trade names	Adrucil, Carac, Efudex, Efudix
AHFS/Drugs.com	monograph
MedlinePlus	a682708
Licence data	US FDA:link
Pregnancy category	AU: D D (IV), X (topical) (US)
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Routes of administration	IV (infusion or bolus) and topical
Pharmacokinetic data
Bioavailability	28 to 100%
Protein binding	8 to 12%
Metabolism	Intracellular and hepatic (CYP-mediated)
Biological half-life	16 minutes
Excretion	Renal
Identifiers
CAS Number	51-21-8 Y
ATC code	L01BC02 (WHO)
PubChem	CID: 3385
IUPHAR/BPS	4789
DrugBank	DB00544 Y
ChemSpider	3268 Y
UNII	U3P01618RT Y
KEGG	D00584 Y
ChEBI	CHEBI:46345 Y
ChEMBL	CHEMBL185 Y
Chemical data
Formula	C4H3FN2O2
Molecular mass	130.077 g/mol
SMILES c1c(c(=O)[nH]c(=O)[nH]1)F
InChI InChI=1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9) Y Key:GHASVSINZRGABV-UHFFFAOYSA-N Y
Physical data
Melting point	282–283 °C (540–541 °F)
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Fluorouracil (5-FU) sold as Adrucil among others, is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called the antimetabolites.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.

Medical uses

Fluorouracil has been given systemically for anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers). It has also been given topically for actinic keratoses, skin cancers and Bowen's disease.

Adverse effects

Adverse effects by frequency include:

During systemic use

Common (> 1% frequency):

• Nausea
• Vomiting
• Diarrhea (see below for details)
• Mucositis
• Headache
• Myelosuppression (see below for details)
• Alopecia (hair loss)
• Photosensitivity
• Hand-foot syndrome
• Maculopapular eruption
• Itch
• Cardiotoxicity (see below for details)
• Persistent hiccups
• 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

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, but usually this cardiotoxicity is just angina or symptoms associated with coronary artery spasm, but in about 0.55% of those receiving the drug will develop life-threatening cardiotoxicity. Life-threatening cardiotoxicity includes: arrhythmias, ventricular tachycardia and cardiac arrest, secondary to transmural ischaemia.

During topical use

Common (> 1% frequency):

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

Uncommon (0.1–1% frequency):

• hyper- or hypopigmentation
• Scarring

Neurological damage

5-FU injection and topical even in small doses cause both acute central nervous system (CNS) damage and progressively worsening delayed degeneration of the CNS in mice. This latter effect is caused by 5-FU-induced damage to the oligodendrocytes that produce the insulating myelin sheaths.

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.

Contraindications

It is contraindicated in patients that are severely debilitated or in patients with myelosuppression due to either radiotherapy or chemotherapy. It is likewise contraindicated in pregnant or breastfeeding women. It should also be avoided in patients that do not have malignant illnesses.

Interactions

Its use should be avoided in patients receiving drugs known to modulate dihydropyrimidine dehydrogenase (such as the antiviral drug sorivudine). It may also increase the INR and prothrombin times in patients on warfarin.Fluoruracil's efficacy is decreased when used alongside allopurinol which can be used to decrease fluoruracil induced stomatitis through use of allopurinol mouthwash.

Dosing concerns

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.

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. 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. 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.

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 thymidine, which is a nucleoside 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. Calcium folinate provides an exogenous source of reduced folinates and hence stabilises the 5-FU-TS complex, hence enhancing 5-FU's cytotoxicity.

History

In 1954 Abraham Cantarow and Karl Paschkis found liver tumors absorbed radioactive uracil more readily than 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 Hoffman-La Roche to synthesize fluorouracil. Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice. The original 1957 report in Nature has Heidelberger as lead author, along with N. K. Chaudhuri, Peter Danneberg, Dorothy Mooren, Louis Griesbach, Robert Duschinsky, R. J. Schnitzer, E. Pleven, and J. Scheiner.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

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|{{{bSize}}}px|alt=Fluorouracil (5-FU) Activity edit]]

File:FluoropyrimidineActivity_WP1601.png

Fluorouracil (5-FU) Activity edit

External links

• Cancerbackup.org.uk – Fluorouracil's use in cancer
• [1]