Fluorouracil

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Fluorouracil
Fluorouracil2DACS.svg
Fluorouracil3DanZ.gif
Systematic (IUPAC) name
5-fluoro-1H,3H-pyrimidine-2,4-dione
Clinical data
Trade names Adrucil, Carac, Efudex
AHFS/Drugs.com monograph
MedlinePlus a682708
Licence data US FDA:link
Pregnancy cat. D (AU)
D (IV), X (topical) (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes IV (infusion or bolus) and topical
Pharmacokinetic data
Bioavailability 28 to 100%
Protein binding 8 to 12%
Metabolism Intracellular and hepatic (CYP-mediated)
Half-life 16 minutes
Excretion Renal
Identifiers
CAS number 51-21-8 YesY
ATC code L01BC02
PubChem CID 3385
DrugBank DB00544
ChemSpider 3268 YesY
UNII U3P01618RT YesY
KEGG D00584 YesY
ChEBI CHEBI:46345 YesY
ChEMBL CHEMBL185 YesY
Chemical data
Formula C4H3FN2O2 
Mol. mass 130.077 g/mol
Physical data
Melt. point 282 - 283 °C (-195 °F)
 YesY (what is this?)  (verify)

Fluorouracil /flʊrʊræsɪl/ 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 the antimetabolites.[1]

Medical uses[edit]

Fluorouracil has been given systemically for anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers).[2] It has also been given topically for actinic keratoses and Bowen's disease.[2]

Adverse effects[edit]

Adverse effects by frequency:[2][3][4][5][6][7]

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):

  • Lacrimation (the expulsion of tears without any emotional or physiologic reason)

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.[2] Neutropenia tends to peak about 9-14 days after beginning treatment.[2] Thrombocytopenia tends to peak about 7-17 days after the beginning of treatment and tends to recover about 10 days after its peak.[2] 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.[8] Life-threatening cardiotoxicity includes: arrhythmias, ventricular tachycardia and cardiac arrest, secondary to transmural ischaemia.[8]

During topical use:[2][6]

Common (>1% frequency):

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

Uncommon (0.1-1% frequency):

  • hyper- or hypopigmentation
  • Scarring

Contraindications[edit]

It is contraindicated in patients that are severely debilitated or in patients with myelosuppression due to either radiotherapy or chemotherapy.[5] It is likewise contraindicated in pregnant or breastfeeding women.[5] It should also be avoided in patients that do not have malignant illnesses.[5]

Interactions[edit]

Its use should be avoided in patients receiving drugs known to modulate dihydropyrimidine dehydrogenase (such as the antiviral drug, sorivudine).[5] It may also increase the INR and prothrombin times in patients on warfarin.[5]

Dosing concerns[edit]

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.[9][10][11] 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.[9] 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).[12][13][14][15] 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.[12][13]

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) 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.[16] Calcium folinate provides an exogenous source of reduced folinates and hence stabilise the 5-FU-TS complex hence enhancing 5-FU's cytotoxicity.[17]

Synthesis[edit]

5-FU was designed, synthesized and patented by Charles Heidelberger in 1957.[18][19]

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.[20] Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.[21] 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.[22]

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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FluoropyrimidineActivity_WP1601 go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to PubChem Compound go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to WikiPathways go to article go to article go to article go to article go to article go to article go to article go to article go 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. ^ Brayfield, A, ed. (13 December 2013). "Fluorouracil". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 16 April 2014. 
  2. ^ 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
  3. ^ "DBL™ FLUOROURACIL INJECTION BP" (PDF). TGA eBusiness Services. Hospira Australia Pty Ltd. 21 June 2012. Retrieved 24 January 2014. 
  4. ^ "ADRUCIL (fluorouracil) injection [Teva Parenteral Medicines, Inc.]". DailyMed. Teva Parenteral Medicines, Inc. August 2012. Retrieved 24 January 2014. 
  5. ^ 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. 
  6. ^ a b "Efudex, Carac (fluorouracil topical) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 24 January 2014. 
  7. ^ "Adrucil (fluorouracil) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 24 January 2014. 
  8. ^ Cite error: The named reference MD was invoked but never defined (see the help page).
  9. ^ a b Gamelin, E.; Boisdron-Celle, M (1999). Dose monitoring of 5-fluorouracil in patients with colorectal or head and neck cancer—status of the art 30 (1). Critical Reviews in Oncology/Hematology. pp. 71–79. 
  10. ^ Felici A.; J. Verweij; A. Sparreboom (2002). Dosing strategies for anticancer drugs: the good, the bad and body-surface area 38 (13). Eur J Cancer. pp. 1677–84. 
  11. ^ Baker SD; Verweij J; Rowinsky EK; Donehower RC; Schellens JH; Grochow LB; Sparreboom A (2002). Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001 94 (24). J Natl Cancer Inst. pp. 1883–8. 
  12. ^ a b Capitain O; Asevoaia A; Boisdron-Celle M; Poirier AL; Morel A; Gamelin E (2012). Individual Fluorouracil Dose Adjustment in FOLFOX Based on Pharmacokinetic Follow-Up Compared With Conventional Body-Area-Surface Dosing: A Phase II, Proof-of-Concept Study 11 (4). Clin Colorectal Cancer. pp. 263–267. 
  13. ^ a b Saam, J; Critchfield GC; Hamilton SA; Roa BB; Wenstrup RJ; Kaldate RR (2011). Body surface area-based dosing of 5-fluoruracil results in extensive interindividual variability in 5-fluorouracil exposure in colorectal cancer patients on FOLFOX regimens 10 (3). Clin Colorectal Cancer. pp. 203–6. 
  14. ^ Beumer JH; Boisdron-Celle M; Clarke W; Courtney JB; Egorin MJ; Gamelin E; Harney RL; Hammett-Stabler C; Lepp S; Li Y; Lundell GD; McMillin G; Milano G; Salamone SJ (2009). Multicenter evaluation of a novel nanoparticle immunoassay for 5-fluorouracil on the Olympus AU400 analyzer 31 (6). Ther Drug Monit. pp. 688–94. 
  15. ^ Goldberg RM; Rothenberg ML; Van Cutsem E; Benson AB 3rd; Blanke CD; Diasio RB; Grothey A; Lenz HJ; Meropol NJ; Ramanathan RK; Becerra CH; Wickham R; Armstrong D; Viele C (2007). The Continuum of Care: A Paradigm for the Management of Metastatic Colorectal Cancer 12. The Oncologist. pp. 38–50. 
  16. ^ 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. 
  17. ^ "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. 
  18. ^ Chu E (September 2007). "Ode to 5-Fluorouracil". Clinical Colorectal Cancer 6 (9): 609. doi:10.3816/CCC.2007.n.029. 
  19. ^ National Academy of Sciences, Biographical Memoirs,80:135
  20. ^ Sneader W. (2005). Drug Discovery, p. 255.
  21. ^ Cohen, Seymour (30 January 2008). "50 years ago in cell biology: A virologist recalls his work on cell growth inhibition". The Scientist. 
  22. ^ 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]