Fluorouracil is an antimetabolite fluoropyrimidine analog of the nucleoside pyrimidine with antineoplastic activity. Fluorouracil and its metabolites possess a number of different mechanisms of action. In vivo, fluoruracil is converted to the active metabolite 5-fluorodeoxyuridine monophosphate (F-UMP); replacing uracil, F-UMP incorporates into RNA and inhibits RNA processing, thereby inhibiting cell growth. Another active metabolite, 5-5-fluoro-2′-deoxyuridine-5′-O-monophosphate (F-dUMP), inhibits thymidylate synthase, resulting in the depletion of thymidine triphosphate(TTP), one of the four nucleotide triphosphates used in the in vivo synthesis of DNA. Other fluorouracil metabolites incorporate into both RNA and DNA; incorporation into RNA results in major effects on both RNA processing and functions.
Mechanism of Action of Fluorouracil
The precise mechanism of action has not been fully determined, but the main mechanism of fluorouracil is thought to be the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor, N5–10-methylenetetrahydrofolate, to thymidylate synthase (TS) to form a covalently bound ternary complex. This results in the inhibition of the formation of thymidylate from uracil, which leads to the inhibition of DNA and RNA synthesis and cell death. Fluorouracil can also be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis.
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5-FU requires enzymatic conversion to the nucleotide (ribosylation and phosphorylation) in order to exert its cytotoxic activity. Several routes are available for the formation of the 5′-monophosphate nucleotide (F-UMP) in animal cells. 5-FU may be converted to fluorouridine by uridine phosphorylase and then to F-UMP by uridine kinase, or it may react directly with 5-phosphoribosyl-1-pyrophosphate (PRPP), in a reaction catalyzed by orotate phosphoribosyltransferase, to form F-UMP. Many metabolic pathways are available to F-UMP, including incorporation in to RNA. A reaction sequence crucial for antineoplastic activity involves reduction of the diphosphate nucleotide by the enzyme ribonucleoside diphosphate reductase to the deoxynucleotide level and the eventual formation of 5-fluoro-2′-deoxyuridine-5′-phosphate (F-dUMP). 5-FU also may be converted directly to the deoxyriboside 5-FUdR by the enzyme thymidine phosphorylase and further to F-dUMP, a potent inhibitor of thymidylate synthesis, by thymidine kinase. The interaction between F-dUMP and the enzyme thymidylate synthase leads to depletion of TTP, a necessary constituent of DNA … The folate cofactor, 5,10-methylenetetrahydrofolate, and F-dUMP form a covalently bound ternary complex with the enzyme. The inhibitory complex resembles the transition state formed during the normal enzymatic reaction when dUMP is converted to thymidylate. Although the physiological complex progresses to the synthesis of thymidylate by transfer of the methylene group and 2 hydrogen atoms from folate to dUMP, this reaction is blocked in the inhibitory complex by the stability of the fluorine-carbon bond on F-dUMP; sustained inhibition of the enzyme results
Indications of Fluorouracil
- For the topical treatment of multiple actinic or solar keratoses. In the 5% strength, it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Fluorouracil injection is indicated in the palliative management of some types of cancer, including colon, esophageal, gastric, rectum, breast, biliary tract, stomach, head and neck, cervical, pancreas, renal cell, and carcinoid.
- Colorectal Cancer
- Breast Cancer
- Stomach Cancer
- Pancreatic Cancer
- Malignant Neoplasm of Colon
- Malignant Neoplasm of Pancreas
- Malignant Neoplasm of Stomach
- Rectal Carcinoma
- Superficial Basal Cell Carcinoma
- Hyperkeratotic actinic keratosis
Therapeutic Uses
- Antimetabolites; Antimetabolites, Antineoplastic; Immunosuppressive Agents
- Fluorouracil is indicated for palliative treatment of carcinoma of the colon, rectum, breast, stomach, and pancreas in patients considered to be incurable by surgery or other means.
- Fluorouracil is also indicated for the treatment of bladder carcinoma, prostatic carcinoma, epithelial ovarian carcinoma, cervical carcinoma, endometrial carcinoma, anal carcinoma, esophageal carcinoma, metastatic tumors of skin carcinoma, and hepatoblastoma, and is used by intra-arterial injection for treatment of hepatic tumors and head and neck tumors.
- Fluorouracil, in combination therapy, is reasonable medical therapy at some point in the management of adrenocortical carcinoma, vulvar carcinoma, penile carcinoma and carcinoid tumors (gastrointestinal and neuroendocrine tumors).
- Although fluorouracil has been used for the treatment of malignant pleural effusions, the USP Division of Information Development Hematology-Oncology Advisory Panel believes there is insufficient evidence to support the effectiveness of fluorouracil in the treatment of malignant pleural effusions.
- Fluorouracil is used for the treatment of glaucoma during or following trabeculectomy surgery. Recommended for topical treatment of multiple actinic or solar keratoses.
Contraindications of Fluoruoracil
- Pregnancy
- A mother who is producing milk and breastfeeding
- Dihydropyrimidine dehydrogenase deficiency
- Allergies to Pyrimidine Analogues & Adhesive
Dosage of Fluorouracil
Strengths: 50 mg/mL
Colorectal Cancer
- In combination with leucovorin, or in combination with leucovorin and oxaliplatin or irinotecan: 400 mg/m2 by IV bolus on Day 1, followed by 2400 to 3000 mg/m2 as a continuous IV infusion over 46 hours every 2 weeks.
- When administered in a bolus dosing regimen in combination with leucovorin: 500 mg/m2 by IV bolus on Days 1, 8, 15, 22, 29, and 36 in 8-week cycles; if no toxicity is observed, 3 mg/kg may be administered on days 5, 7, and 9; no therapy is to be administered on days 4, 6, or 8; discontinue at the end of day 9, even with no apparent toxicity
Breast Cancer
- Administered as a component of a cyclophosphamide-based multidrug regimen: 500 or 600 mg/m2 IV on Days 1 and 8 every 28 days for 6 cycles
Stomach Cancer
- Administered as a component of a platinum-containing multidrug chemotherapy regimen: 200 to 1000 mg/m2 IV as a continuous infusion over 24 hours; the frequency of dosing in each cycle and the length of each cycle will depend on the dose of fluorouracil and the specific regimen administered
Pancreatic Cancer
- Administered in combination with leucovorin or as a component of a multidrug chemotherapy regimen that includes leucovorin: 400 mg/m2 by IV bolus on Day 1, followed by 2400 mg/m2 IV as a continuous infusion over 46 hours every 2 weeks
Side Effects of Fluorouracil
The Most Common
- confusion or disorientation
- diarrhea
- heartburn
- severe nausea or vomiting
- signs of anemia (low red blood cells; e.g., pale skin, unusual tiredness or weakness)
- signs of bleeding (e.g., unusual bruising or bleeding, pinpoint red spots on skin, black tarry stools, bloody nose, blood in urine, coughing blood, cuts that don’t stop bleeding)
- signs of liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
More Common
- Diarrhea
- heartburn
- sores in mouth and on lips
- Black, tarry stools
- cough or hoarseness, accompanied by fever or chills
- fever or chills
- lower back or side pain, accompanied by fever or chills
- nausea and vomiting (severe)
- painful or difficult urination, accompanied by fever or chills
- stomach cramps
Rare
- Blood in urine or stools
- pinpoint red spots on skin
- unusual bleeding or bruising
- Chest pain
- cough
- shortness of breath
- tingling of hands and feet, followed by pain, redness, and swelling
- trouble with balance
Drug Interactions of Fluorouracil
Fluorouracil may interact with following drugs, supplements & may change the efficacy of the drug
- celecoxib
- dapsone
- echinacea
- fluoxetine
- ganciclovir
- glipizide
- glyburide
- interferon
- ketamine
- leflunomide
- leucovorin
- levamisole
- live vaccines (e.g., BCG, yellow fever)
- losartan
- montelukast
- nateglinide
- other cancer medications (including but not limited to cytarabine, flucytosine, methotrexate)
- pimecrolimus
- phenytoin
- sulfamethoxazole
- tacrolimus
- tamoxifen
- tolbutamide
- trimethoprim
- voriconazole
- warfarin
- zafirlukast
Pregnancy Category of Fluorouracil
AU TGA Pregnancy Category: D
US FDA Pregnancy Category: D
Pregnancy:
There is a possibility of birth defects if fluorouracil is being used at the time of conception, or if it is taken during pregnancy. Use effective birth control while you are being treated with this medication. If you become pregnant while taking this medication, contact your doctor immediately.
Lactation
It is not known if fluorouracil passes into breast milk. Due to the potential for serious harm to the baby, women receiving fluorouracil should not breast-feed.
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