n.
An antineoplastic agent, C4H3FN2O2, used especially in the treatment of cancers of the skin, breast, and digestive system.
fluorouracil
Dictionary:
fluor·o·u·ra·cil (flʊr'ō-yʊr'ə-sĭl, flôr'-, flōr'-)  |
| 5min Related Video: fluorouracil |
| Oncology Encyclopedia: Fluorouracil |
Key Terms: Cytotoxic drug, DNA, Infusion therapy.
Definition
Fluorouracil is a medication that kills cancer cells. It is also known as 5-FU or 5-fluourouracil, and as the brand name Adrucil.
Purpose 5-FU may be used in combination with other chemotherapy agents to treat cancers of the breast, stomach, colon, rectum, and pancreas.
Description 5-FU is a cytotoxic drug. This means that it kills cancer cells. 5-FU kills cells by interfering with the activities of DNA and RNA, which are molecules in the cells important in expressing genetic material.
Recommended Dosage
Most frequently, 5-FU is given as an injection into the vein (intravaneous injection or IV). Many different doses and regimens are used depending on the cancer diagnosis, and patients should discuss with their physician the dose based on the individual protocol used. A sample dose is 500 to 1,000 mg per square meter of body surface area given as a 24-hour infusion for four to five days every three weeks. A dose of 425 mg per square meter of body surface area per day for five days given along with the drug leucovorin is also common.
Precautions
Patients with allergic reaction to 5-FU should not be administered this drug. It is also inadvisable for pregnant women. 5-FU should be administered with caution to patients with impaired liver or kidney function, or in patients with a history of heart problems.
Side Effects
The amount of drug given and the duration of which it is given during a single session greatly influences the side effects seen. For example, when given as a 24-hour continuous infusion, the most common side effects are diarrhea and mouth ulcers. If 5-FU is given as a bolus infusion (a high quantity of the drug all at once), the most common side effect is bone marrow suppression; this results in a decrease of the white blood cells responsible for fighting infections, the platelets responsible for blood clotting, and the red blood cells responsible for providing oxygen to the cells of the body.
The severity of the side effects is increased when 5-FU is given with the drug leucovorin. Vomiting, diarrhea, nausea, and loss of appetite (anorexia) may occur regardless of how 5-FU is administered. The diarrhea side effect may be severe in some patients, and it is important for them to alert their doctor immediately so that appropriate medications for the diarrhea can be prescribed.
5-FU may cause rashes, increased sensitivity to sunlight, changes in skin color, changes to the fingernails, and redness and swelling in the palms of the hands and soles of the feet. Patients who have had heart disease before starting therapy with 5-FU may have problems with blood flow to the heart. Rarely, 5-FU may cause an allergic reaction, dry eyes, sleepiness, confusion, headache, changes in walking gait, involuntary rapid movement of the eyes, and difficulty speaking. When 5-FU is applied directly on the skin, there are usually no side effects except for those to the skin itself. These may include burning sensations, pain, and darkening of the skin color.
Some authorities recommend discontinuation of 5-FU therapy as soon as mild side effects are observed as a way of reducing the extent of injury to the digestive tract. Administration may then be restarted at a lower dose after the side effects have stopped.
Interactions
People taking fluorouracil should consult their doctor before taking any other prescription drug, over-thecounter drug, or herbal remedy.
—Bob Kirsch
| Dental Dictionary: fluorouracil (topical) |
n
trade names: Efudex, Fluoroplex; drug class: topical antineoplastic; action: inhibits synthesis of DNA and RNA in susceptible cells; uses: keratosis, basal cell carcinoma.
| Drug Info: Fluorouracil, 5-FU |
Brand names: Adrucil®, Carac™, Efudex®, Fluoroplex®
Chemical formula:
- Drug Forms:
- Fluorouracil Topical solution (below)
- Fluorouracil, 5-FU injection
- Fluorouracil Solution for injection
- Fluorouracil Topical cream
- Español:
- Fluorouracilo, Solución tópica
- Inyección de fluorouracilo, 5-FU
- Fluorouracilo, Solución para inyección
- Fluorouracilo, Crema tópica
Fluorouracil Topical solution
What is this medicine?
FLUOROURACIL, 5-FU is a chemotherapy agent. It is used on the skin to treat skin cancer and skin conditions that could become cancer.
This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.
What should I tell my health care provider before I take this medicine?
They need to know if you have any of these conditions:
• DPD enzyme deficiency
• recent or current radiation therapy
• swelling or open sores at the treatment site
• an unusual or allergic reaction to fluorouracil, other chemotherapy, other medicines, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding
How should I use this medicine?
This medicine is only for use on the skin. Follow the directions on the prescription label. Wash hands before and after use. Wash affected area and gently pat dry. To apply this medicine use a cotton-tipped applicator, or use gloves if applying with fingertips. If applied with unprotected fingertips, it is very important to wash your hands well after you apply this medicine. Avoid applying to the eyes, nose, or mouth. Apply enough medicine to cover the affected area. You can cover the area with a light gauze dressing, but do not use tight or air-tight dressings. Finish the full course prescribed by your doctor or health care professional, even if you think your condition is better. Do not stop taking except on the advice of your doctor or health care professional.
Talk to your pediatrician regarding the use of this medicine in children. Special care may be needed.
Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.
What may interact with this medicine?
Interactions are not expected. Do not use any other skin products without telling your doctor or health care professional.
This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.
What should I watch for while using this medicine?
Visit your doctor or health care professional for checks on your progress. You will need to use this medicine for 2 to 6 weeks. This may be longer depending on the condition being treated. You may not see full healing for another 1 to 2 months after you stop using the medicine.
Treated areas of skin can look unsightly during and for several weeks after treatment with this medicine.
This medicine can make you more sensitive to the sun. Keep out of the sun. If you cannot avoid being in the sun, wear protective clothing and use sunscreen. Do not use sun lamps or tanning beds/booths.
What side effects may I notice from receiving this medicine?
Side effects that you should report to your doctor or health care professional as soon as possible:
• severe redness and swelling of normal skin
Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
• dark colored skin
• eye irritation including burning, itching, sensitivity, stinging, or watering
• increased sensitivity of the skin to sun and ultraviolet light
• pain and burning of the affected area
• scaling or swelling of the affected area
• skin rash, itching of the affected area
• tenderness
This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Where should I keep my medicine?
Keep out of the reach of children.
Store at room temperature between 15 and 30 degrees C (59 and 86 degrees F). Do not freeze. Keep container tightly closed. Throw away any unused medicine after the expiration date.
Last updated: 7/1/2002
Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.
| Wikipedia: Fluorouracil |
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| Systematic (IUPAC) name | |
|---|---|
| 5-fluoro-1H-pyrimidine-2,4-dione | |
| Identifiers | |
| CAS number | 51-21-8 |
| ATC code | L01BC02 |
| PubChem | 3385 |
| DrugBank | APRD00516 |
| 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 |
 (what is this?) (verify) |
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Fluorouracil (5-FU or f5U) (Adrucil, Efudex, Fluoroplex) 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.
Contents |
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 monophosphate (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 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.
It is a key component in Tegafur-uracil.
Synthesis
5-FU was synthesized by Robert Duschinsky in the late 1950s. 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 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, 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. Currently there are only three labs offering DPD testing: Myriad Genetic Laboratories in Salt Lake City, UT has the most comprehensive 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 and DNAVision (Belgium) has a quatitative analysis. 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.[2][3]
The body converts both folic acid and leucovorin to methylenetetrahydrofolate. Each of those precursors amplify the effect of 5-FU in one animal study.[4] 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.[5]
Folic acid may amplify the desired action and the toxicity of 5-FU. The exact mechanism of interaction is unknown.[6]
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.[7] 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.[8]
One study showed that 79 percent of the patients who switched from 5-FU (with leucovorin) to Xeloda had serious side effects. None of the patients who switched from Xeloda to 5-FU (with leucovorin) had serious side effects. The researchers don't know why.[9]
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, and in 1957 they reported its efficacy against transplanted tumors in rats and mice.[10]
References
- ^ "Chemotherapy-induced Damage to the CNS as a Precursor Cell Disease" by Dr. Mark D. Noble, University of Rochester
- ^ "Capecitabine: have we got the dose right?" by Rachel Midgley and David J Kerr 2008
- ^ "Regional Variation in Capecitabine Metabolism and Toxicity" by Rachel Midgley
- ^ "Modulation of fluorouracil antitumor activity by folic acid in a murine model system" by Raghunathan and Priest 1999.
- ^ "Response to 5-fluorouracil chemotherapy is modified by dietary folic acid deficiency in Apc(Min/+) mice." by Tucker JM, Davis C, Kitchens ME, Bunni MA, Priest DG, Spencer HT, Berger FG. 2003
- ^ "folic-acid and Xeloda Interactions"
- ^ "Handbook of drug-nutrient interactions" by Joseph I. Boullata, Vincent T. Armenti, 2007, p.207, 208
- ^ "Xeloda and Folic acid"
- ^ "Switching from 5FU to Xeloda Can Cause Significant Side Effects"
- ^ Sneader W. (2005). Drug Discovery, p. 255.
External links
- Cancerbackup.org.uk – Fluorouracil's use in cancer
- DermnetNZ – Fluorouracil cream
- 5-Fluorouracil - ASR reagents for DPYD mutation analysis - EntroGen, Inc
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