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Fluorouracil
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Fluorouracil

Systematic (IUPAC) name

5-fluoro-1H-pyrimidine-2,4-dione

Identifiers CAS number 51-21-8 ATC code PubChem DrugBank ChemSpider UNII L01BC02 CID 3385 APRD00516 3268 U3P01618RT

Chemical data Formula Mol. mass SMILES C4H3FN2O2 130.077 g/mol eMolecules & PubChem Physical data Melt. point 282 283 C (-195 F) Pharmacokinetic data Bioavailability 28 to 100% Protein binding 8 to 12% Metabolism Half-life Excretion Intracellular and hepatic (CYP-mediated) 10 to 20 minutes Renal Therapeutic considerations Pregnancy cat. Legal status Routes D(AU) D (intravenous), X (topical) (US) -only (US) Intravenous (infusion or bolus) and topical (what is this?) (verify)

Fluorouracil (5-FU or f5U) (sold under the brand names Adrucil, Carac, Efudex and Fluoroplex) is a drug that is a pyrimidine analog which is used in the treatment of cancer. It works through noncompetitive inhibition of thymidylate synthase. Due to its noncompetitive nature and effects on thymidine synthesis, 5-FU is frequently referred to as the "suicide inactivator". It belongs to the family of drugs called antimetabolites. It is typically administered with leucovorin.

Uses
The chemotherapy agent 5-FU (fluorouracil), which has been in use against cancer for about 40 years, acts in several ways, but principally as a thymidylate synthase inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleotide required for DNA replication. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) into thymidine monophosphate (dTMP). Facing a scarcity of dTMP, rapidly dividing cancerous cells undergo cell death via thymineless death[1]. Like many anti-cancer drugs, 5-FU's effects are felt system wide but fall most heavily upon rapidly dividing cells that make heavy use of their nucleotide synthesis machinery,

such as cancer cells (other parts of the body with rapidly dividing cells include the cells lining the digestive tract). Some of its principal uses are in colorectal cancer, and pancreatic cancer, in which it has been the established form of chemotherapy for decades (platinum-containing drugs approved for human use in the US since 1978 are also very well established). It is also sometimes used in the treatment of inflammatory breast cancer, an especially aggressive form of breast cancer. 5-FU is also used in ophthalmic surgery, specifically to augment trabeculectomy (an operation performed to lower the intraocular pressure in patients with glaucoma) in patients deemed to be at high risk for failure. 5-FU acts as an anti-scarring agent in this regard, since excessive scarring at the trabeculectomy site is the main cause for failure of the surgery. Fluorouracil can be used topically (as a cream) for treating actinic (solar) keratoses and some types of basal cell carcinomas of the skin. It is often referred to by its trade names Efudex, Carac or Fluoroplex. Due to Fluorouracil's toxicity and the fact that it can be manufactured using the same reaction as uracil, its precursor, 5-Fluoroorotic Acid, is commonly used in laboratories to screen against organisms capable of synthesizing uracil. It is a key component in Tegafur-uracil.

Synthesis
5-FU was designed, synthesized and patented by Charles Heidelberger in 1957. [2] [3][4] 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.

Mode of action
As a pyrimidine analogue, it is transformed inside the cell into different cytotoxic metabolites which are then incorporated into DNA and RNA, finally inducing cell cycle

arrest and apoptosis by inhibiting the cell's ability to synthesize DNA. It is an S-phase specific drug and only active during certain cell cycles. In addition to being incorporated in DNA and RNA, the drug has been shown to inhibit the activity of the exosome complex, an exoribonuclease complex of which the activity is essential for cell survival. Capecitabine is a prodrug that is converted into 5-FU in the tissues. It can be administered orally.

Adverse effects
Side effects include myelosuppression, mucositis, dermatitis, diarrhea and cardiac toxicity. 5-FU injection and topical even in small doses cause both acute 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.[5] When using a pyrimidine-based drug, users must be aware that some people have a genetic inability to metabolize them. Current theory points to nearly 8% of the population having what is termed DPD deficiency. There are laboratory tests to determine the relative activity of the DPD enzyme. Currently there are only three labs offering DPD testing: Myriad Genetic Laboratories in Salt Lake City, UT has the most comprehensive test. In addition to full sequence analysis of the DPYD gene, Myriad performs an analysis of the TYMS gene which accounts for moderate gastrointestinal toxicities. Coventry Diagnostics [1] in Troy, MI and DNAVision (Belgium) has a quantitative analysis. GenPath diagnostics in Elmwood Park, NJ is also offering this test as a part of their pharmacogenomics effort. Additionally, EntroGen now offers genotyping reagents to clinical laboratories interested in developing an in-house DPYD mutation screen. It is expected that with a potential 500,000 people in North America using the pyrimidinebased 5-FU, this form of testing will increase. The typical starting dose of capecitabine is 2,500 mg/m2 per day in Europe and 2,000 mg/m2 per day in the US. Probably the main action of 5-FU occurs when a 5-FU metabolite binds to thymidylate synthase. This binding is stable only in the presence of methylenetetrahydrofolate. It is speculated that this may explain why people in the US a country that mandates adding folic acid to some foodsapparently require a lower dose of capecitabine than people in Europecountries that do not mandate added folic acid.[6]
[7]

The body converts both folic acid and leucovorin to methylenetetrahydrofolate. Each of those precursors amplify the effect of 5-FU in one animal study.[8] However, another animal study seemed to indicate that, given the same 5-FU treatment, that a special diet containing no folic acid (0 ppm) worked better than the normal diet.[9]

Folic acid may amplify the desired action and the toxicity of 5-FU. The exact mechanism of interaction is unknown.[10] When 5-FU is given intravenously, it is typically mixed with leucovorin in order to increase 5-FU activity. Folic acid may work as well as leucovorin, but the one human study performed (with a high dose of folic acid, from 40 mg/m2 to 140 mg/m2) had disappointing results and concluded that further studies were needed.[11] There is some confusion about whether the amount of folic acid in a normal diet and multivitamins is enough to interact badly with 5-FU.[12] One study showed that 79 percent of the patients who switched from 5-FU (with leucovorin) to Xeloda (capecitabine) had serious side effects. None of the patients who switched from Xeloda to 5-FU (with leucovorin) had serious side effects. The researchers don't know why.[13]

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. [14]Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice. [15] 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. [16]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective Wikipedia articles.
[17]

[[File: [[ ]] [[ ]] [[

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

References
1. ^ Longley D.B. et al, Nature Reviews Cancer 3, 330-338 (May 2003) 2. ^ JNCI Journal of the National Cancer Institute 1999 91(15):1278-1280 3. ^ Clinical Colorectal Cancer: "Ode to 5-Fluorouracil", Clinical Colorectal Cancer 2007(Sept)6(9):609 4. ^ National Academy of Sciences, Biographical Memoirs,80:135 5. ^ "Chemotherapy-induced Damage to the CNS as a Precursor Cell Disease" by Dr. Mark D. Noble, University of Rochester 6. ^ "Capecitabine: have we got the dose right?" by Rachel Midgley and David J Kerr 2008 7. ^ "Regional Variation in Capecitabine Metabolism and Toxicity" by Rachel Midgley 8. ^ "Modulation of fluorouracil antitumor activity by folic acid in a murine model system" by Raghunathan and Priest 1999. 9. ^ "Response to 5-fluorouracil chemotherapy is modified by dietary folic acid deficiency in Apc(Min/+) mice." by Tucker JM, Davis C, Kitchens ME, Bunni MA, Priest DG, Spencer HT, Berger FG. 2003 10. ^ "folic-acid and Xeloda Interactions" 11. ^ "Handbook of drug-nutrient interactions" by Joseph I. Boullata, Vincent T. Armenti, 2007, p.207, 208 12. ^ "Xeloda and Folic acid" 13. ^ "Switching from 5FU to Xeloda Can Cause Significant Side Effects" 14. ^ Sneader W. (2005). Drug Discovery, p. 255. 15. ^ Seymour Cohen, 50 years ago in cell biology: A virologist recalls his work on cell growth inhibition, The Scientist, 30th January 2008, http://www.thescientist.com/news/display/54259/ 16. ^ CHARLES HEIDELBERGER, N. K. CHAUDHURI, PETER DANNEBERG, DOROTHY MOOREN, LOIS GRIESBACH, ROBERT DUSCHINSKY, R. J. SCHNITZER, E. PLEVEN & J. SCHEINER, Fluorinated Pyrimidines, A New Class of Tumour-Inhibitory Compounds, Nature 179, 663 - 666 (30 March 1957) 17. ^ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601". http://www.wikipathways.org/index.php/Pathway:WP1601.

[edit] External links

Cancerbackup.org.uk Fluorouracil's use in cancer

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Intracellular chemotherapeutic agents/antineoplastic agents (L01)

Block Vinca alkaloids (Vinblastine, Vincristine, Vinflunine, Vindesine, microtubule Vinorelbine) assembly Block Taxanes (Cabazitaxel, Docetaxel, Larotaxel, Ortataxel, Paclitaxel, microtubule Tesetaxel) Epothilones (Ixabepilone) disassembly dihydrofolate reductase inhibitor (Aminopterin, Methotrexate, Pemetrexed, Pralatrexate) thymidylate synthase inhibitor (Raltitrexed, Pemetrexed) adenosine deaminase inhibitor (Pentostatin) Purine DNA precursors/ antimetabolites (S phase) Pyrimidine halogenated/ribonucleotide reductase inhibitors (Cladribine, Clofarabine, Fludarabine) thiopurine (Thioguanine, Mercaptopurine) thymidylate synthase inhibitor (Fluorouracil, Capecitabine, Tegafur, Carmofur, Floxuridine) DNA polymerase inhibitor (Cytarabine) ribonucleotide reductase inhibitor (Gemcitabine) hypomethylating agent (Azacitidine, Decitabine) Deoxyribonucleotide ribonucleotide reductase inhibitor (Hydroxycarbamide)

Folic acid

I TopoisomeraseII inhibitors (S phase)

Camptotheca (Camptothecin, Topotecan, Irinotecan, Rubitecan, Belotecan) Podophyllum (Etoposide, Teniposide)

Anthracyclines (Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Amrubicin, Pirarubicin, II+Intercalation Valrubicin, Zorubicin) Anthracenediones (Mitoxantrone, Pixantrone)

Nitrogen mustards: Mechlorethamine Cyclophosphamide (Ifosfamide, Trofosfamide) Chlorambucil (Melphalan, Prednimustine) Bendamustine Uramustine Estramustine Nitrosoureas: Carmustine Lomustine (Semustine) Alkylating Fotemustine Nimustine Ranimustine Streptozocin Alkyl sulfonates: Busulfan (Mannosulfan, Treosulfan) Crosslinking of DNA (CCNS) Aziridines: Carboquone ThioTEPA Triaziquone Triethylenemelamine Alkylating- Platinum (Carboplatin, Cisplatin, Nedaplatin, Oxaliplatin, like Triplatin tetranitrate, Satraplatin) Nonclassical Intercalation Hydrazines (Procarbazine) Triazenes (Dacarbazine, Temozolomide) Altretamine Mitobronitol Streptomyces (Actinomycin, Bleomycin, Mitomycin, Plicamycin)

Enzyme inhibitors Receptor antagonists

FI (Tipifarnib) CDK inhibitors (Alvocidib, Seliciclib) PrI (Bortezomib) PhI (Anagrelide) IMPDI (Tiazofurine) LI (Masoprocol) PARP inhibitor (Olaparib) HDAC (Vorinostat, Romidepsin) ERA (Atrasentan) retinoid X receptor (Bexarotene) sex steroid (Testolactone)

Amsacrine Trabectedin retinoids (Alitretinoin, Tretinoin) Arsenic trioxide asparagine depleters (Asparaginase/Pegaspargase) Other/ungroupedCelecoxib Demecolcine Elesclomol Elsamitrucin Etoglucid Lonidamine Lucanthone Mitoguazone Mitotane Oblimersen mTOR inhibitors (Everolimus, Temsirolimus)

M: NEO tsoc, mrkr tumr, epon, para drug (L1i/1e/V03) Retrieved from "http://en.wikipedia.org/wiki/Fluorouracil" Categories: Organofluorides | Antineoplastic drugs | Pyrimidinediones
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