Fluorouracil

UNDER REVIEW (September 2016)

Mechanism of Action:

An example of the group of anticancer drugs known as antimetabolites. Others include other pyrimidine antagonists (capecitabine and gemcitabine which are both ‘prodrugs’ that are converted into 5-FU in the body, premetrexed), folate antagonists (methotrexate), and purine antagonists (mercaptopurine, cytarabine, fludarabine).

Lecture and CAL materials:

  • Lecture: Introduction to the Treatment of Cancer

Drug specifics

Alternative drug name 5-fluorouracil, 5-FU
Effects Pyrimidine antagonists such as fluorouracil act to block the synthesis of pyrimidine containing nucleotides (C and T in DNA; C and U in RNA). The drugs used to block the construction of these nucleotide have structures that are similar to the natural compound. By acting as 'decoys', these drugs can prevent the production of the finished nucleotides. They may exert their effects at different steps in that pathway and may directly inhibit crucial enzymes. The pyrimidine antagonist may also be incorporated into a growing DNA chain and lead to termination of the process. For a cell to reproduce, it must first faithfully replicate all of the DNA in its genome. During DNA synthesis, pyrimidine and purine molecules must be made available to allow for the synthesis of the nucleotide building blocks and ultimately the new DNA molecules. A reduction in the availability of the raw materials needed to build DNA, such as is caused by the pyrimidine antagonists, leads to stoppage of DNA synthesis and inhibition of cell division. Cancer cells are often quite rapidly dividing and therefore engaged in DNA synthesis. RNA synthesis is necessary for protein production. The pyrimidine antagonists inhibit the normal processes of DNA and/or RNA synthesis. Fluorouracil is used to treat a number of solid tumours, including gastro-intestinal tract cancers and breast cancer. It is commonly used with folinic acid in advanced colorectal cancer. It may also be used topically for certain malignant and pre-malignant skin lesions.
Adverse actions Serious toxicity is unusual, but may include myelosuppression, mucositis, and rarely a cerebellar syndrome. On prolonged infusion, a desquamative hand–foot syndrome may occur.
Dose Fluorouracil is usually given intravenously because absorption following oral administration is unpredictable. However, the newer pyrimidine antagonist capcitabine can be given orally before being conveted into fluorouracil in the body.
Interactions See BNF.
Contraindications not specified
Comments OTHER ANTIMETABOLITE DRUGS. Methotrexate inhibits the enzyme dihydrofolate reductase, essential for the synthesis of purines and pyrimidines. Methotrexate is used as maintenance therapy for childhood acute lymphoblastic leukaemia, choriocarcinoma, non-Hodgkin's lymphoma, and a number of solid tumours. Intrathecal methotrexate is used in the CNS prophylaxis of childhood acute lymphoblastic leukaemia, and as a therapy for established meningeal cancer or lymphoma. Capecitabine, which is metabolised to fluorouracil, is given by mouth. It is used as monotherapy for metastatic colorectal cancer; it has been shown to be of similar efficacy as a combination of fluorouracil and folinic acid. It is also licensed for second-line treatment of locally advanced or metastatic breast cancer. Gemcitabine is used intravenously; it is given alone for palliative treatment or with cisplatin as a first-line treatment for locally advanced or metastatic non-small cell lung cancer. It is also used in the treatment of locally advanced or metastatic pancreatic cancer. Combined with cisplatin, gemcitabine is also licensed for the treatment of advanced bladder cancer. It is generally well tolerated but may cause mild gastro-intestinal side-effects and rashes. Cytarabine acts by interfering with pyrimidine synthesis. It is given subcutaneously, intravenously, or intrathecally. Its predominant use is in the induction of remission of acute myeloblastic leukaemia. It is a potent myelosuppressant and requires careful haematological monitoring. Fludarabine is licensed for the initial treatment of advanced B-cell chronic lymphocytic leukaemia (CLL) or after first-line treatment in patients with sufficient bone-marrow reserves. Pemetrexed inhibits thymidylate transferase and other folate-dependent enzymes. It is licensed for use with cisplatin for the treatment of unresectable malignant pleural mesothelioma which has not previously been treated with chemotherapy; it is given by intravenous infusion. Mercaptopurine is used as maintenance therapy for the acute leukaemias and in the management of ulcerative colitis and Crohn's disease. Azathioprine, which is metabolised to mercaptopurine, is generally used as an immunosuppressant. The dose of both drugs should be reduced if the patient is receiving allopurinol since it interferes with their metabolism.
Contributors