Lihat sumber Fluorourasil

{{Drugbox
| verifiedrevid = 443823794
| IUPAC_name = 5-fluoro-1''H''-pirimidina-2,4-dion
| image = Fluorouracil.svg
| width = 120
| image2 = Fluorouracil-3D-vdW.png

<!--Clinical data-->
| tradename = Carac
| Drugs.com = {{drugs.com|monograph|fluorouracil}}
| MedlinePlus = a682708
| pregnancy_AU = D
| pregnancy_category = <br>D (intravena), X (topikal) <small>([[United States|US]])</small>
| legal_US = hanya Rx
| routes_of_administration = [[Terapi intravena|Intravena]] (infus atau [[wikt:bolus|bolus]]) dan topikal

<!--Pharmacokinetic data-->
| bioavailability = 28 hingga 100%
| protein_bound = 8 hingga 12%
| metabolism = Intraselular dan [[hati|hepatik]] ([[sitokrom P450|CYP]]-mediasi)
| elimination_half-life = 10 hingga 20 menit
| excretion = [[Ginjal|Renal]]

<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number = 51-21-8
| ATC_prefix = L01
| ATC_suffix = BC02
| PubChem = 3385
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = APRD00516
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3268
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = U3P01618RT
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00584
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 46345
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 185

<!--Chemical data-->
| C=4 | H=3 | F=1 | N=2 | O=2 
| molecular_weight = 130.077 g/mol
| smiles = c1c(c(=O)[nH]c(=O)[nH]1)F
| InChI = 1/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9)
| InChIKey = GHASVSINZRGABV-UHFFFAOYAG
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GHASVSINZRGABV-UHFFFAOYSA-N
| melting_point = 282 - 283
}}
'''Fluorourasil''' ('''5-FU''' atau '''f5U''') (dijual dengan merek '''Adrucil, Carac, Efudix, Efudex''' and '''Fluoroplex''') adalah [[obat farmasi|obat]] dari analog pirimidina yang digunakan untuk perawatan [[kanker]]. Adalah "penghambat bunuh diri" (''suicide inhibition'') yang bekerja melalaui penghambatan dari [[timidilat sintase]]. Masuk dalam kelompok obat-obatan yang disebut [[antimetabolit]]. Umumnya digunakan bersama [[leukovorin]].
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== 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). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via [[Thymineless Death|thymineless death]].<ref>{{cite journal |author=Longley DB, Harkin DP, Johnston PG |title=5-fluorouracil: mechanisms of action and clinical strategies |journal=Nat. Rev. Cancer |volume=3 |issue=5 |pages=330–8 |year=2003 |month=May |pmid=12724731 |doi=10.1038/nrc1074 |url=http://www.nature.com/nrc/journal/v3/n5/full/nrc1074.html}}</ref>

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 keratosis|actinic (solar) keratoses]] and some types of [[basal cell carcinoma]]s 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.<ref>{{cite journal |title=Awards, Appointments, Announcements |journal=J Natl Cancer Inst |volume=91 |issue=15 |pages=1278–80 |year=1999 |doi=10.1093/jnci/91.15.1278  |url=http://jnci.oxfordjournals.org/content/91/15/1278.full}}</ref><ref>{{cite journal |author=Chu E |title=Ode to 5-Fluorouracil |journal=Clinical Colorectal Cancer |volume=6 |issue=9 |pages=609 |date=September 2007 |doi=10.3816/CCC.2007.n.029 |url=http://cigjournals.metapress.com/content/b464v2u31594jj28/}}</ref><ref>National Academy of Sciences, Biographical Memoirs,80:135</ref>

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|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 ==
[[Adverse drug reaction|Side effect]]s include [[myelosuppression]], [[mucositis]], [[dermatitis]], [[diarrhea]] and [[cardiac toxicity]].

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.<ref>[http://www.urmc.rochester.edu/biomedical-genetics/faculty/chemotherapy-induced-damage-to-cns.cfm "Chemotherapy-induced Damage to the CNS as a Precursor Cell Disease"] by Dr. Mark D. Noble, University of Rochester</ref>

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.  Many labs offer DPD testing: Laboratory Corporation of America was one of the first to make the test available commercially on a large scale (Test Number 511176).  [[MYGN|Myriad Genetic Laboratories]] in [[Salt Lake City, UT]] also offers a 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 in [[Troy, Michigan|Troy, MI]] and DNAVision ([[Belgium]]) have quantitative analyses. 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 pyrimidine-based 5-FU, this form of testing will increase.

The typical starting dose of capecitabine is 2,500&nbsp;mg/m2 per day in Europe and 2,000&nbsp;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 foods—apparently require a lower dose of capecitabine than people in Europe—countries that do not mandate added folic acid.<ref>{{cite journal |author=Midgley R, Kerr DJ |title=Capecitabine: have we got the dose right? |journal=Nat Clin Pract Oncol |volume=6 |issue=1 |pages=17–24 |year=2009 |month=January |pmid=18936793 |doi=10.1038/ncponc1240 |url=http://www.nature.com/nrclinonc/journal/v6/n1/full/ncponc1240.html}}
</ref><ref>{{cite web |author=Midgley, Rachel |title=Regional Variation in Capecitabine Metabolism and Toxicity |publisher=Medscape.com |url=http://www.medscape.com/viewarticle/583704_3}}
</ref>

The body converts both folic acid and [[leucovorin]] to methylenetetrahydrofolate.
Each of those precursors amplify the effect of 5-FU in one animal study.<ref>
{{cite journal |author=Raghunathan K, Priest DG |title=Modulation of fluorouracil antitumor activity by folic acid in a murine model system |journal=Biochem. Pharmacol. |volume=58 |issue=5 |pages=835–9 |year=1999 |month=September |pmid=10449194 |url=http://linkinghub.elsevier.com/retrieve/pii/S0006-2952(99)00157-4 |doi=10.1016/S0006-2952(99)00157-4}}
</ref> 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.<ref>
{{cite journal |author=Tucker JM, Davis C, Kitchens ME, ''et al.'' |title=Response to 5-fluorouracil chemotherapy is modified by dietary folic acid deficiency in Apc(Min/+) mice |journal=Cancer Lett. |volume=187 |issue=1–2 |pages=153–62 |year=2002 |month=December |pmid=12359363 |url=http://linkinghub.elsevier.com/retrieve/pii/S0304383502004020 |doi=10.1016/S0304-3835(02)00402-0}}</ref>

Folic acid may amplify the desired action and the toxicity of 5-FU.
The exact mechanism of interaction is unknown.<ref>[http://www.drugs.com/drug-interactions/folic-acid_d00241_xeloda_d04311.html "Folic-acid and Xeloda Interactions"]</ref>

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&nbsp;mg/m<sup>2</sup> to 140&nbsp;mg/m<sup>2</sup>) had disappointing results and concluded that further studies were needed.<ref>[http://books.google.com/books?id=mst5gVH6WUcC&pg=PA207&lpg=PA207&dq=Fluorouracil++folic+acid&source=bl&ots=UyQaJKJbKg&sig=yRWu9ms-4MWv4EQokYmjwi_HPeM&hl=en&ei=CmPTScejMZrslQfhzpz7Cw&sa=X&oi=book_result&resnum=10&ct=result "Handbook of drug-nutrient interactions"] by Joseph I. Boullata, Vincent T. Armenti, 2007, p.207, 208</ref> 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.<ref>[http://www.medkb.com/Uwe/Forum.aspx/cancer-forum/16/Xeloda-and-Folic-acid "Xeloda and Folic acid"]</ref>

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 were unsure of why.<ref>
[http://fightcolorectalcancer.org/research_news/2008/07/switching_from_5fu_to_xeloda_can_cause_significant_side_effects "Switching from 5FU to Xeloda Can Cause Significant Side Effects"]</ref>

Trissel and colleagues have shown that 5-FU and leucovorin are physically incompatible when mixed in portable-pump reservoirs.<ref>{{cite journal |author=Trissel LA, Martinez JF, Xu QA |title=Incompatibility of fluorouracil with leucovorin calcium or levoleucovorin calcium |journal=Am J Health Syst Pharm |volume=52 |issue=7 |pages=710–5 |year=1995 |month=April |pmid=7627739 }}</ref>  Similarly, infusion of 5-FU and leucovorin via permanent indwelling catheters is complicated by catheter blockage due to calcium carbonate formation (Ardalan and Flores, 1995).<ref>{{cite journal |author=Ardalan B, Flores MR |title=A new complication of chemotherapy administered via permanent indwelling central venous catheter |journal=Cancer |volume=75 |issue=8 |pages=2165–8 |year=1995 |month=April |pmid=7697607 |doi=10.1002/1097-0142(19950415)75:8<2165::AID-CNCR2820750821>3.0.CO;2-W }}</ref>

== 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.<ref>Sneader W. (2005). ''Drug Discovery'', p. 255.</ref> Some credit Heidelberger and Duschinsky  with the discovery that 5-fluorouracil markedly inhibited tumors in mice.<ref>{{cite journal |author=Cohen, Seymour |title=50 years ago in cell biology: A virologist recalls his work on cell growth inhibition |journal=The Scientist |date=30 January 2008 |url=http://www.the-scientist.com/news/display/54259/}}</ref> 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.<ref>{{cite journal |author=Heidelberger C, Chaudhuri NK, Danneberg P, ''et al.'' |title=Fluorinated pyrimidines, a new class of tumour-inhibitory compounds |journal=Nature |volume=179 |issue=4561 |pages=663–6 |year=1957 |month=March |pmid=13418758 |doi=10.1038/179663a0 }}</ref>

== Interactive pathway map ==
{{FluoropyrimidineActivity WP1601}}
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== Referensi ==
{{reflist}}

== Pranala luar ==
* {{en}} [http://www.cancerbackup.org.uk/Treatments/Chemotherapy/Individualdrugs/Fluorouracil Cancerbackup.org.uk – Fluorouracil's use in cancer] {{Webarchive|url=https://web.archive.org/web/20081216011012/http://www.cancerbackup.org.uk/Treatments/Chemotherapy/Individualdrugs/Fluorouracil |date=2008-12-16 }}
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{{Chemotherapeutic agents}}

[[Kategori:Organofluorides]]
[[Kategori:Antineoplastic antimetabolites]]
[[Kategori:Pyrimidinediones]]
[[Kategori:Thymidylate synthase inhibitors]]
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[[Kategori:Fluoropirimidina]]
[[Kategori:Antagonis pirimidina]]
[[Kategori:Pirimidinadiona]]
[[Kategori:Penghambat sintase timidilat]]
[[Kategori:Turunan urasil]]
[[Kategori:Obat Esensial Organisasi Kesehatan Dunia]]
[[Kategori:Basa nukleotida]]