Fluorouracil
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Fluorouracil
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| Systematic (IUPAC) name | |
| 5-fluoro-1H-pyrimidine-2,4-dione | |
| Identifiers | |
| CAS number | |
| ATC code | L01 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C4H3FN2O2 |
| Mol. mass | 130.077 g/mol |
| 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 |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status | |
| Routes | Intravenous (infusion or bolus) and topical |
Fluorouracil (5-FU or f5U) is a pyrimidine analog, which is used as a drug in the treatment of cancer. It belongs to the family of drugs called antimetabolites. It is typically administered with Leucovorin.
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[edit] 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 monophoshate (dUMP) into thymidine monophosphate (dTMP).
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 use is in colorectal cancer and pancreatic cancer, in which it has been the established form of chemotherapy for decades (platinum-containing drugs have been approved for human use in the US since 1978 are are also very well established).
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 scaring 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.
[edit] 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.
[edit] Adverse effects
Side effects include myelosuppression, mucositis, dermatitis, diarrhea and cardiac toxicity.
5-FU also causes 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.[1]
When using a pyrimidine-based drug, all users must be aware that there is 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, but these tests are not commercially available. Thousands of patients eagerly await the increased availability of clinical DPD testing. Work in this sector has been carried out in both the U.S. and Europe. Currently there are only two labs offering DPD testing: Coventry Diagnostics and DNAVision (Belgium). GenPath diagnostics in Elmwood Park, NJ is also offering this test as a part of their pharmacogenomics effort. 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.
[edit] References
- ^ “Chemotherapy Causes Delayed Severe Neural Damage, Study Shows.”, BioMed Central/Journal of Biology (ScienceDaily), 2008-4-22, <http://www.sciencedaily.com/releases/2008/04/080421191425.htm>. Retrieved on 30 April 2008
[edit] External links
- Cancerbackup.org.uk – Fluorouracil's use in cancer
- DermnetNZ – Fluorouracil cream
- 5-Fluorouracile - DPYD genetic test - DNAVision
- 5-Fluorouracile - DPD Enzyme Deficiency test
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