Fluorouracil

Mechanism of action

By chemical structure, the drug is a pyrimidine analogue in which the hydrogen atom at the 5-position is replaced by fluorine. Fluorouracilum is inactive on its own and acts as a prodrug. Inside the cell, it undergoes enzymatic transformations, acting through two main pathways:

1. Blockade of DNA synthesis. The drug is converted into the active metabolite — fluorodeoxyuridine monophosphate. This substance potently inhibits the enzyme thymidylate synthase, making the synthesis of thymidine monophosphate impossible. An acute deficiency of thymine ensues, leading to the cessation of DNA synthesis and so-called "thymineless death" of the cell.
2. Disruption of RNA functions. Another metabolite, fluorouridine triphosphate, is incorporated directly into the RNA structure instead of uracil. This disrupts translation processes and leads to the synthesis of defective proteins.

The net cytotoxic effect is due to a combined hit on the functions of both DNA and RNA.

Pharmacokinetics and resistance

Routes of administration: The drug is administered intravenously or applied topically. Oral administration (by mouth) is not used due to extremely high toxicity to the mucous membrane of the gastrointestinal tract.

Metabolism: The rate of drug degradation in the body directly depends on the activity of the hepatic enzyme — dihydropyrimidine dehydrogenase (DPD).

Resistance: Tumor cells can acquire resistance to the drug. This occurs either by reducing their ability to convert the prodrug into active metabolites or by a compensatory increase in the production of the target enzyme — thymidylate synthase.

Indications for use

The spectrum of activity of the drug differs from other antimetabolites (e.g., methotrexate or mercaptopurine). The main targets for prescription are solid tumors of the gastrointestinal tract and glandular organs.

Main indications in oncology:

• Cancer of the large intestine (colorectal cancer). Often used as part of combination therapy, for example, together with angiogenesis inhibitors (bevacizumab).
• Cancer of the stomach, esophagus, and pancreas.
• Primary liver cancer.
• Breast cancer.

Side effects and toxicity

Like most cytotoxic drugs, it exhibits marked toxicity toward rapidly dividing healthy cells.

• Gastrointestinal tract: Severe ulcerative lesions of the mucous membranes, manifesting as stomatitis and enteritis.
• Skin: Prolonged use leads to a specific "hand-foot" syndrome (palmar-plantar erythrodysesthesia). It is characterized by purplish discoloration, severe edema, and pain in the palms and soles.
• Embryotoxicity: The drug is strictly contraindicated in pregnant women. The critical period is the first 12 weeks (1st trimester). In early stages (1–3 weeks), it affects the zygote and blastocyst within the lumen of the fallopian tubes and uterine cavity, causing gross developmental defects of the embryo and its death.

Administration guidelines and prescription

The drug is available as a 5% solution in 5 ml ampoules. The standard dosing regimen is calculated based on body surface area (e.g., 600 mg/m² intravenously once daily).

Prescription example: Rp.: Sol. Fluorouracili 5% - 5 ml D.t.d. N. 10 in ampull. S. Intravenously once daily at a dose of 600 mg/m² of body surface area.

Interesting pharmacological fact: There is a synthetic antifungal agent, flucytosine. Inside fungi, it is converted into 5-fluorouracil by the enzyme cytosine deaminase. Human cells lack this enzyme. However, human intestinal microflora is capable of performing this conversion. The 5-fluorouracil formed in the intestine is absorbed into the blood and can cause systemic side effects typical of cytostatics even during fungal infection treatment.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Antimetabolites: classification and differences between purine and pyrimidine analogues.
• The role of the enzyme dihydropyrimidine dehydrogenase (DPD) in the metabolism of cytostatics.
• Mechanisms of tumor resistance to chemotherapy.
• Targeted therapy: angiogenesis inhibitors (bevacizumab) in combination with cytostatics.
• Embryotoxic, teratogenic, and fetotoxic effects of medicinal products.

Other topics in the «Drugs and Prescriptions» section

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