Fluorouracil

Fluorouracil

Clinical data
Pregnancy category	AU: D D (intravenous), X (topical) (US)
Routes of administration	Intravenous (infusion or bolus) and topical
ATC code	L01BC02 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	28 to 100%
Protein binding	8 to 12%
Metabolism	Intracellular and hepatic (CYP-mediated)
Elimination half-life	10 to 20 minutes
Excretion	Renal
Identifiers
IUPAC name 5-fluoro-1H-pyrimidine-2,4-dione
CAS Number	51-21-8
PubChem CID	3385
DrugBank	APRD00516
CompTox Dashboard (EPA)	DTXSID2020634
ECHA InfoCard	100.000.078
Chemical and physical data
Formula	C4H3FN2O2
Molar mass	130.077 g/mol g·mol−1

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.

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 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 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.

It is a key component in Tegafur-uracil.

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 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.

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.

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
• Special Issue: 5-Fluorouracil