Fluorouracil

Fluorouracil

Systematic (IUPAC) name
5-fluoro-1H-pyrimidine-2,4-dione
Clinical data
Trade names	Carac
AHFS/Drugs.com	monograph
MedlinePlus	a682708
Pregnancy cat.	D(AU) D (intravenous), X (topical) (US)
Legal status	℞-only (US)
Routes	Intravenous (infusion or bolus) and topical
Pharmacokinetic data
Bioavailability	28 to 100%
Protein binding	8 to 12%
Metabolism	Intracellular and hepatic (CYP-mediated)
Half-life	10 to 20 minutes
Excretion	Renal
Identifiers
CAS number	51-21-8 Y
ATC code	L01BC02
PubChem	CID 3385
DrugBank	APRD00516
ChemSpider	3268 Y
UNII	U3P01618RT Y
KEGG	D00584 Y
ChEBI	CHEBI:46345 Y
ChEMBL	CHEMBL185 Y
Chemical data
Formula	C4H3FN2O2
Mol. mass	130.077 g/mol
SMILES	eMolecules & PubChem
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
Melt. point	282 - 283 °C (-195 °F)
N(what is this?)  (verify)

Fluorouracil (5-FU or f5U) (sold under the brand names Adrucil, Carac, Efudix, Efudex and Fluoroplex) 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. 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 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.^[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. 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). 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, 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 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 foods—apparently require a lower dose of capecitabine than people in Europe—countries 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 were unsure of why.^[13]

Trissel and colleagues have shown that 5-FU and leucovorin are physically incompatible when mixed in portable-pump reservoirs. ^[14] 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). ^[15]

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.^[16] Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.^[17] 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.^[18]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective Wikipedia articles. ^[19]

[[File:

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

[[ ]]

|{{{bSize}}}px]]

Fluorouracil (5-FU) Activity edit

References

1. ^ 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. http://www.nature.com/nrc/journal/v3/n5/full/nrc1074.html. 
2. ^ "Awards, Appointments, Announcements". J Natl Cancer Inst 91 (15): 1278–80. 1999. doi:10.1093/jnci/91.15.1278. http://jnci.oxfordjournals.org/content/91/15/1278.full. 
3. ^ Chu E (September 2007). "Ode to 5-Fluorouracil". Clinical Colorectal Cancer 6 (9): 609. doi:10.3816/CCC.2007.n.029. http://cigjournals.metapress.com/content/b464v2u31594jj28/. 
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. ^ Midgley R, Kerr DJ (January 2009). "Capecitabine: have we got the dose right?". Nat Clin Pract Oncol 6 (1): 17–24. doi:10.1038/ncponc1240. PMID 18936793. http://www.nature.com/nrclinonc/journal/v6/n1/full/ncponc1240.html. 
7. ^ Midgley, Rachel. "Regional Variation in Capecitabine Metabolism and Toxicity". Medscape.com. http://www.medscape.com/viewarticle/583704_3. 
8. ^ Raghunathan K, Priest DG (September 1999). "Modulation of fluorouracil antitumor activity by folic acid in a murine model system". Biochem. Pharmacol. 58 (5): 835–9. doi:10.1016/S0006-2952(99)00157-4. PMID 10449194. http://linkinghub.elsevier.com/retrieve/pii/S0006-2952(99)00157-4. 
9. ^ Tucker JM, Davis C, Kitchens ME, et al. (December 2002). "Response to 5-fluorouracil chemotherapy is modified by dietary folic acid deficiency in Apc(Min/+) mice". Cancer Lett. 187 (1–2): 153–62. doi:10.1016/S0304-3835(02)00402-0. PMID 12359363. http://linkinghub.elsevier.com/retrieve/pii/S0304383502004020. 
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. ^ Trissel LA, Martinez JF, Xu QA (April 1995). "Incompatibility of fluorouracil with leucovorin calcium or levoleucovorin calcium". Am J Health Syst Pharm 52 (7): 710–5. PMID 7627739. 
15. ^ Ardalan B, Flores MR (April 1995). "A new complication of chemotherapy administered via permanent indwelling central venous catheter". Cancer 75 (8): 2165–8. doi:10.1002/1097-0142(19950415)75:8<2165::AID-CNCR2820750821>3.0.CO;2-W. PMID 7697607. 
16. ^ Sneader W. (2005). Drug Discovery, p. 255.
17. ^ Cohen, Seymour (30 January 2008). "50 years ago in cell biology: A virologist recalls his work on cell growth inhibition". The Scientist. http://www.the-scientist.com/news/display/54259/. 
18. ^ 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. 
19. ^ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601". http://www.wikipathways.org/index.php/Pathway:WP1601. 

External links

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