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DESCRIPTION
Fluorouracil (5-FU) (brand names: Adrucil, Carac, Efudix, Efudex and Fluoroplex) is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug used in the treatment of different types of cancer.
CLASSIFICATION
- AA
- BB
INDICATIONS
PHARMACOKINETICS
5-Fluorouracil (5-FU; see structure) is converted to three main active metabolites: fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP). The main mechanism of 5-FU activation is conversion to fluorouridine monophosphate (FUMP), either directly by orotate phosphoribosyltransferase (OPRT) with phosphoribosyl pyrophosphate (PRPP) as the cofactor, or indirectly via fluorouridine (FUR) through the sequential action of uridine phosphorylase (UP) and uridine kinase (UK). FUMP is then phosphorylated to fluorouridine diphosphate (FUDP), which can be either further phosphorylated to the active metabolite fluorouridine triphosphate (FUTP), or converted to fluorodeoxyuridine diphosphate (FdUDP) by ribonucleotide reductase (RR). In turn, FdUDP can either be phosphorylated or dephosphorylated to generate the active metabolites FdUTP and FdUMP, respectively. An alternative activation pathway involves the thymidine phosphorylase catalysed conversion of 5-FU to fluorodeoxyuridine (FUDR), which is then phosphorylated by thymidine kinase (TK) to FdUMP. Dihydropyrimidine dehydrogenase (DPD)-mediated conversion of 5-FU to dihydrofluorouracil (DHFU) is the rate-limiting step of 5-FU catabolism in normal and tumour cells. Up to 80% of administered 5-FU is broken down by DPD in the liver.
MOLECULAR MECHANISM
- As a pyrimidine analogue, it is transformed inside the cell into different cytotoxic metabolites incorporated into DNA and RNA: this lead to cell cycle arrest and apoptosis.
- In addition, 5-FU acts as a thymidylate synthase inhibitor: as a consequence it blocks the synthesis of the pyrimidine thymidine, required for DNA replication.
Summary of some of the strategies that have been investigated for increasing the anticancer activity of 5-fluorouracil (5-FU). Leucovorin (LV) increases the intracellular pool of 5,10-methylene tetrahydrofolate (CH2THF), thereby enhancing thymidylate synthase (TS) inhibition by fluorodeoxyuridine monophosphate (FdUMP). Eniluracil and uracil inhibit DPD-mediated degradation of 5-FU. Methotrexate (MTX) is thought to increase 5-FU activation by increasing phosphoribosyl pyrophosphate (PRPP) levels. Interferons (IFNs) have been reported to enhance thymidine phosphorylase (TP) activity, abrogate acute TS induction caused by 5-FU treatment and enhance 5-FU-mediated DNA damage. Capecitabine is a 5-FU pro-drug that is converted to 5'-deoxy-5-fluorouridine (5'DFUR) in the liver by the sequential action of carboxylesterase and cytidine deaminase. 5'DFUR is converted to 5-FU by TP.
FU and ROMO1
Antagonism between ROMO1 and mTOR ??
Coupled down-regulation of mTOR and telomerase activity during fluorouracil-induced apoptosis of hepatocarcinoma Cells 2007
Since inhibiting mTOR activity leads to cancer cell death while high levels of telomerase activity is associated with cancer cell proliferation, it is possible that mTOR may directly or indirectly regulate telomerase activity.
Drug resistance to 5-FU linked to reactive oxygen species modulator 1. 2007
To elucidate the relationship between 5-FU-induced ROS production and Romo1 expression, Romo1 siRNA was used to inhibit 5-FU-triggered Romo1 induction.
5-Fluorouracil: mechanisms of action and clinical strategies 2003
PHARMACOGENOMICS
SIDE EFFECTS
TOXICITY
RESISTANCE
DEPENDENCE AND WITHDRAW
DESCRIPTION
Fluorouracil (5-FU) (brand names: Adrucil, Carac, Efudix, Efudex and Fluoroplex) is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug used in the treatment of different types of cancer.
CLASSIFICATION
5-FU belongs to the family of drugs called antimetabolites: it is a pyrimidine analogue and works through irreversible inhibition of thymidylate synthase.
INDICATIONS
5-FU is indicated for colon and rectal cancers, breast cancers, gastrointestinal cancers (including anal, esophageal, pancreas and stomach cancers), head and neck cancers, hepatoma, ovarian cancers.
5-FU is usually administered intravenously, while Capecitabine, a prodrug that is converted into 5-FU in the tissues, can be administered orally.
MOLECULAR MECHANISM
SIDE EFFECTS
Side effects include nausea, vomiting, diarrhoea, mouth sores, poor appetite, anemia, pain and weakness, hand-foot syndrome (Palmar-plantar erythrodysesthesia or PPE), hair loss or thinning (may include face and body hair). Less common neurological side effects include confusion, difficulty with voluntary muscle movement, eye sensitivity to light, vision problems.
TOXICITY
Genetic and non-genetic factors are related to 5-FU toxicity. Non-genetic factors include sex, age and diet. Genetic factors include polymorphism in the genes for the enzymes thymidylate synthase (TS; TYMS gene), methylenetetrahydrofolate reductase (MTHFR gene) and dihydropyrimidine dehydrogenase (DPD; DPYD gene).
Dihydropyrimidine dehydrogenase (DPD) deactivates >80% of administered standard doses of 5-FU: impairment of this pyrimidine degradation pathway leads to toxic accumulation of the drug in 5-FU treated patients. A G>A mutation within the 5′-splicing site of intron 14 (IVS14+1 G>A) seems to be responsible of about 50% of 5-FU-related toxicity.
The MTHFR 677 C>T and 1298 A>C polymorphisms are common gene variants associated with low MTHFR activity. Patients with the variant MTHFR allele will have increased sensitivity to 5-FU based treatment and, possibly, an elevated risk of toxicity.
A 28-bp tandem repeat variant in the TYMS enhancer region (TYMSER 2R/2R, 2R/3R and 3R/3R), a single nucleotide polymorphism (SNP) at the 12th nucleotide of the second repeat in the 3R allele leading to a tri-allelic locus (2R, 3RC and 3RG) and a 6-bp deletion at bp 1494 in the 3′-untranslated region (UTR) have been found in TYMS gene. It has been proposed that high levels of TYMS expression protect cells from the cytotoxic effect of 5-FU and, as a result, lead to decreased toxicity.
