Mechanism of Action of 5-Fluorouracil

Introduction

5-Fluorouracil (5-FU) is an antimetabolite chemotherapeutic drug used in the treatment of various solid tumors, including colorectal, breast, head and neck, and gastrointestinal cancers. Mechanism of Action of 5-Fluorouracil centers on its ability to inhibit DNA and RNA synthesis, leading to impaired cell proliferation. As a pyrimidine analog, 5-FU interferes with rapidly dividing cancer cells, making it an essential drug in oncology practice.

5-FU pharmacology
Mechanism of action of 5-Fluorouracil
Mechanism of action of 5-Fluorouracil
5-Fluorouracil clinical pharmacology
Mechanism of action of 5-Fluorouracil
MOA of 5-Fluorouracil
MOA of 5-Fluorouracil
Pharmacology and clinical uses of 5-Fluorouracil

Mechanism of Action (Step-wise)

  1. Conversion to Active Metabolites
    • 5-FU is a prodrug that undergoes intracellular activation.
    • It is converted to fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP).
  2. Inhibition of Thymidylate Synthase
    • FdUMP binds irreversibly to thymidylate synthase.
    • This blocks the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP).
    • Result: depletion of thymidine triphosphate (dTTP), an essential DNA building block.
  3. DNA Synthesis Inhibition
    • Lack of dTTP prevents proper DNA replication and repair.
    • Leads to DNA strand breaks and apoptosis in rapidly dividing cells.
  4. RNA Incorporation
    • FUTP is incorporated into RNA in place of uridine triphosphate (UTP).
    • This disrupts RNA processing, stability, and protein synthesis.
  5. Overall Effect
    • Inhibition of both DNA and RNA synthesis.
    • Selectively affects rapidly proliferating cancer cells.
5-FU MOA Flowchart
Pharmacology and clinical uses of 5-Fluorouracil flowchart

Pharmacokinetics

  • Administration: Intravenous (most common) or topical (for skin cancers).
  • Absorption: Poor oral bioavailability due to rapid degradation.
  • Distribution: Widely distributed in body tissues.
  • Metabolism: Primarily metabolized in the liver by dihydropyrimidine dehydrogenase (DPD).
  • Excretion: Mainly renal.
  • Half-life: 10–20 minutes (very short, continuous infusion often used).

Clinical Uses

  • Colorectal cancer (first-line chemotherapy agent).
  • Breast cancer.
  • Gastric, pancreatic, and esophageal cancers.
  • Head and neck cancers.
  • Basal cell carcinoma and actinic keratosis (topical use).

Adverse Effects

  • Common: Myelosuppression, nausea, vomiting, diarrhea, mucositis, alopecia.
  • Less common: Hand-foot syndrome (palmar-plantar erythrodysesthesia).
  • Serious: Cardiotoxicity (angina, arrhythmias), neurotoxicity, severe toxicity in patients with DPD deficiency.

Comparative Analysis

Feature5-Fluorouracil (5-FU)MethotrexateCytarabine
Drug classPyrimidine analog (antimetabolite)Folate antagonist (antimetabolite)Pyrimidine analog (antimetabolite)
TargetThymidylate synthase, RNADihydrofolate reductaseDNA polymerase
Effect on DNA↓ dTMP → impaired DNA synthesis↓ purine and thymidylate synthesisInhibits DNA chain elongation
Effect on RNAIncorporated into RNANo direct RNA effectNo major RNA effect
Clinical usesGI cancers, breast, topical useLeukemia, lymphoma, solid tumorsLeukemia, lymphoma

MCQs

1. 5-Fluorouracil belongs to which drug class?
a) Alkylating agent
b) Antimetabolite
c) Topoisomerase inhibitor
d) Mitotic inhibitor

Answer: b) Antimetabolite


2. Which enzyme is inhibited by 5-FU?
a) Dihydrofolate reductase
b) Thymidylate synthase
c) DNA polymerase
d) RNA polymerase

Answer: b) Thymidylate synthase


3. What is the main effect of FdUMP?
a) Inhibition of dUMP → dTMP conversion
b) RNA chain elongation
c) DNA polymerase inhibition
d) ATP synthesis blockade

Answer: a) Inhibition of dUMP → dTMP conversion


4. Which active metabolite of 5-FU is incorporated into RNA?
a) FdUMP
b) FUTP
c) dUMP
d) dTMP

Answer: b) FUTP


5. What is the most serious toxicity associated with 5-FU in DPD deficiency?
a) Severe myelosuppression
b) Hypertension
c) Pulmonary fibrosis
d) Retinopathy

Answer: a) Severe myelosuppression


6. Which of the following cancers is NOT typically treated with 5-FU?
a) Colorectal cancer
b) Pancreatic cancer
c) Breast cancer
d) Small-cell lung cancer

Answer: d) Small-cell lung cancer


7. The topical form of 5-FU is used for:
a) Ovarian carcinoma
b) Basal cell carcinoma
c) Prostate cancer
d) Lymphoma

Answer: b) Basal cell carcinoma


8. Which enzyme metabolizes 5-FU?
a) CYP3A4
b) Dihydropyrimidine dehydrogenase (DPD)
c) Xanthine oxidase
d) Monoamine oxidase

Answer: b) Dihydropyrimidine dehydrogenase (DPD)


9. Hand-foot syndrome is an adverse effect of:
a) Vincristine
b) 5-Fluorouracil
c) Bleomycin
d) Cisplatin

Answer: b) 5-Fluorouracil


10. 5-FU primarily interferes with which cellular process?
a) Protein folding
b) DNA and RNA synthesis
c) Mitosis
d) Oxidative phosphorylation

Answer: b) DNA and RNA synthesis


FAQs

Q1. Is 5-FU a cell cycle–specific drug?
Yes, it is S-phase specific, affecting DNA synthesis.

Q2. Why is leucovorin sometimes given with 5-FU?
Leucovorin enhances binding of FdUMP to thymidylate synthase, increasing efficacy.

Q3. What is the main dose-limiting toxicity of 5-FU?
Myelosuppression.

Q4. Can 5-FU cause cardiotoxicity?
Yes, rare cases of angina, arrhythmias, and myocardial ischemia occur.

Q5. Why is DPD deficiency important in 5-FU therapy?
Patients with DPD deficiency cannot metabolize 5-FU efficiently, leading to severe toxicity.

Q6. How is 5-FU administered?
Mainly intravenously; topical formulations exist for dermatological use.


References

  • Goodman & Gilman’s The Pharmacological Basis of Therapeutics
  • Katzung Basic and Clinical Pharmacology
  • Harrison’s Principles of Internal Medicine
  • Cancer Chemotherapy Clinical Guidelines

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