Fluorouracil

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Fluorouracil
Systematic (IUPAC) name
5-fluoro-1H,3H-pyrimidine-2,4-dione
Clinical data
Trade namesAdrucil, Carac, Efudex
AHFS/Drugs.commonograph
MedlinePlusa682708
Licence dataUS FDA:link
Pregnancy cat.D (AU)
D (IV), X (topical) (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
RoutesIV (infusin or bolus) and topical
Pharmacokinetic data
Bioavailability28 to 100%
Protein binding8 to 12%
MetabolismIntracellular and hepatic (CYP-mediated)
Half-life16 minutes
ExcretionRenal
Identifiers
CAS number51-21-8 YesY
ATC codeL01BC02
PubChemCID 3385
DrugBankDB00544
ChemSpider3268 YesY
UNIIU3P01618RT YesY
KEGGD00584 YesY
ChEBICHEBI:46345 YesY
ChEMBLCHEMBL185 YesY
Chemical data
FormulaC4H3FN2O2 
Mol. mass130.077 g/mol
Physical data
Melt. point282 - 283 °C (-195 °F)
 YesY (what is this?)  (verify)
 
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Fluorouracil
Systematic (IUPAC) name
5-fluoro-1H,3H-pyrimidine-2,4-dione
Clinical data
Trade namesAdrucil, Carac, Efudex
AHFS/Drugs.commonograph
MedlinePlusa682708
Licence dataUS FDA:link
Pregnancy cat.D (AU)
D (IV), X (topical) (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
RoutesIV (infusin or bolus) and topical
Pharmacokinetic data
Bioavailability28 to 100%
Protein binding8 to 12%
MetabolismIntracellular and hepatic (CYP-mediated)
Half-life16 minutes
ExcretionRenal
Identifiers
CAS number51-21-8 YesY
ATC codeL01BC02
PubChemCID 3385
DrugBankDB00544
ChemSpider3268 YesY
UNIIU3P01618RT YesY
KEGGD00584 YesY
ChEBICHEBI:46345 YesY
ChEMBLCHEMBL185 YesY
Chemical data
FormulaC4H3FN2O2 
Mol. mass130.077 g/mol
Physical data
Melt. point282 - 283 °C (-195 °F)
 YesY (what is this?)  (verify)

Fluorouracil or 5-FU (trademarked as Adrucil (IV), Carac (topical), Efudex (topical)) 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 antimetabolites.

Medical uses[edit]

Fluorouracil has been given systemically for anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers).[1] It has also been given topically for actinic keratoses and Bowen's disease.[1]

Adverse effects[edit]

Adverse effects by frequency:[1][2][3][4][5][6]

During systemic use:

Common (>1% frequency):

  • Nausea
  • Vomiting
  • Diarrhoea (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)

Uncommon (0.1-1% frequency):

  • Oesophagitis
  • GI ulceration and bleeding
  • Proctitis
  • Nail disorders
  • Vein pigmentation
  • Confusion
  • Cerebellar syndrome
  • Encephalopathy
  • Visual changes
  • Photophobia

Rare (<0.1% frequency):

  • Anaphylaxis
  • Allergic reactions
  • Fever without signs of infection

Diarrhoea is severe and may be dose-limiting and is exacerbated by co-treatment with calcium folinate.[1] Neutropenia tends to peak about 9-14 days after beginning treatment.[1] Thrombocytopenia tends to peak about 7-17 days after the beginning of treatment and tends to recover about 10 days after its peak.[1]

During topical use:[1][5]

Common (>1% frequency):

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

Uncommon (0.1-1% frequency):

Contraindications[edit]

It is contraindicated in patients that are severely debilitated or in patients with myelosuppression due to either radiotherapy or chemotherapy.[4] It is likewise contraindicated in pregnant or breastfeeding women.[4] It should also be avoided in patients that do not have malignant illnesses.[4]

Interactions[edit]

Its use should be avoided in patients receiving drugs known to modulate dihydropyrimidine dehydrogenase (such as the antiviral drug, sorivudine).[4] It may also increase the INR and prothrombin times in patients on warfarin.[4]

Overdose[edit]

Due to the mode of administration overdose is unlikely.[2] The symptoms of overdose include:[2]

  • Nausea
  • Vomiting
  • Diarrhoea
  • Gastrointestinal ulceration and bleeding
  • Myelosuppression

Treatment for overdose is purely supportive.[2]

Mechanism of action[edit]

The chemotherapy agent 5-FU, which has been used against cancer for about 40 years, 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) into thymidine monophosphate (dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via thymineless death.[7] Calcium folinate provides an exogenous source of reduced folinates and hence stabilise the 5-FU-TS complex hence enhancing 5-FU's cytotoxicity.[8]

Synthesis[edit]

5-FU was designed, synthesized and patented by Charles Heidelberger in 1957.[9][10]

Since uracil is a normal component of RNA, the rationale behind the development of the drug was that cancer cells, with their increased genetic instability, might be more sensitive to 'decoy' molecules that mimic the natural compound than normal cells. The scientific goal in this case was to synthesize a drug which demonstrated specific uracil antagonism. The drug proved to have anti-tumor capabilities.

When elemental fluorine is reacted with uracil, 5-fluorouracil is produced. 5-Fluorouracil masquerades as uracil during the nucleic acid replication process. Because 5-fluorouracil is similar in shape to but does not perform the same chemistry as uracil, the drug inhibits RNA replication enzymes, thereby eliminating RNA synthesis and stopping the growth of cancerous cells.

History[edit]

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.[11] Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.[12] 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.[13]

Interactive pathway map[edit]

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
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Fluorouracil (5-FU) Activity edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601". 

References[edit]

  1. ^ a b c d e f g Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.  edit
  2. ^ a b c d "DBL™ FLUOROURACIL INJECTION BP" (PDF). TGA eBusiness Services. Hospira Australia Pty Ltd. 21 June 2012. Retrieved 24 January 2014. 
  3. ^ "ADRUCIL (fluorouracil) injection [Teva Parenteral Medicines, Inc.]". DailyMed. Teva Parenteral Medicines, Inc. August 2012. Retrieved 24 January 2014. 
  4. ^ a b c d e f "Fluorouracil 50 mg/ml Injection - Summary of Product Characteristics". electronic Medicines Compendium. Hospira UK Ltd. 24 August 2011. Retrieved 24 January 2014. 
  5. ^ a b "Efudex, Carac (fluorouracil topical) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 24 January 2014. 
  6. ^ "Adrucil (fluorouracil) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 24 January 2014. 
  7. ^ Longley DB, Harkin DP, Johnston PG (May 2003). "5-fluorouracil: mechanisms of action and clinical strategies". Nat. Rev. Cancer 3 (5): 330–8. doi:10.1038/nrc1074 . PMID 12724731. 
  8. ^ "5-Fluorouracil derivatives: a patent review". Expert Opinion on Therapeutic Patents 22 (2): 107–123. February 2012. doi:10.1517/13543776.2012.661413 . PMID 22329541. 
  9. ^ Chu E (September 2007). "Ode to 5-Fluorouracil". Clinical Colorectal Cancer 6 (9): 609. doi:10.3816/CCC.2007.n.029 . 
  10. ^ National Academy of Sciences, Biographical Memoirs,80:135
  11. ^ Sneader W. (2005). Drug Discovery, p. 255.
  12. ^ Cohen, Seymour (30 January 2008). "50 years ago in cell biology: A virologist recalls his work on cell growth inhibition". The Scientist. 
  13. ^ Heidelberger C, Chaudhuri NK, Danneberg P, et al. (March 1957). "Fluorinated pyrimidines, a new class of tumour-inhibitory compounds". Nature 179 (4561): 663–6. doi:10.1038/179663a0 . PMID 13418758. 

External links[edit]