Mechanism of Action
Structurally, the drug is a pyrimidine analogue in which the hydrogen atom at the 5th position is replaced by fluorine. Fluorouracilum is inactive on its own and acts as a prodrug. Inside the cell, it undergoes enzymatic conversion, acting via two main pathways:
- DNA Synthesis Blockade. 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 a halt in DNA synthesis and so-called "thymineless death" of the cell.
- RNA Function Disruption. 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 ultimate cytotoxic effect is due to this combined blow to the functions of both DNA and RNA.
Pharmacokinetics and Resistance
Routes of administration: The drug is administered intravenously or applied topically. Oral administration is not used due to extremely high toxicity to the gastrointestinal mucosa.
Metabolism: The rate of drug degradation in the body depends directly 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 (such as methotrexate or mercaptopurine). The primary targets for administration are solid tumors of the gastrointestinal tract and glandular organs.
Main indications in oncology:
- Colorectal cancer. Often used as part of combination therapy, for example, together with angiogenesis inhibitors (bevacizumab).
- Gastric, esophageal, and pancreatic cancer.
- Primary liver cancer.
- Breast cancer.
Side Effects and Toxicity
Like most cytotoxic agents, the drug exhibits pronounced toxicity toward rapidly dividing healthy cells.
- Gastrointestinal tract: Severe ulcerative lesions of the mucous membranes, manifesting as stomatitis and enteritis.
- Skin: Prolonged use can lead to a specific "hand-foot" syndrome (palmar-plantar erythrodysesthesia). It is characterized by purplish discoloration, marked swelling, and pain in the palms and soles.
- Embryotoxicity: The drug is strictly contraindicated in pregnant women. The critical period is the first 12 weeks (first trimester). In early stages (weeks 1–3), it affects the zygote and blastocyst within the fallopian tubes and uterine cavity, causing gross developmental defects in the embryo and fetal demise.
Administration Details and Prescription
The drug is available as a 5% solution in 5 mL ampoules. The standard dosage regimen is calculated based on body surface area (e.g., 600 mg/m² intravenously once daily).
Sample Prescription: 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 called flucytosine. Inside fungi, it is converted into 5-fluorouracil by the enzyme cytosine deaminase. Human cells lack this enzyme. However, the human intestinal microflora is capable of carrying out this conversion. The 5-fluorouracil formed in the intestine is absorbed into the bloodstream and can cause systemic side effects typical of cytotoxic drugs, even when treating a fungal infection.