5-Fluorouracil

• Class: Antimetabolite – pyrimidine analog.
• Brand names: 

Mechanism of Action (MOA)

• Prodrug → intracellularly converted to active metabolites.
• Two key mechanisms:
  1. FdUMP (fluorodeoxyuridine monophosphate) → forms covalent complex with thymidylate synthase (TS) and folate cofactor → irreversibly inhibits TS → ↓ thymidine synthesis → DNA synthesis inhibition.
  2. FUTP (fluorouridine triphosphate) → incorporates into RNA → interferes with RNA processing and function.
• Cell cycle–specific → active in S-phase.

Clinical Uses

• Solid tumors (often in combination regimens):
  • Colorectal cancer (standard backbone of therapy: FOLFOX, FOLFIRI).
  • Gastroesophageal cancers.
  • Breast cancer (older regimens).
  • Pancreatic cancer (with leucovorin, oxaliplatin).
  • Head & neck cancers.
• Topical formulations: Actinic keratosis, superficial basal cell carcinoma.

Dosing (Adults)

• IV bolus or continuous infusion (different efficacy/toxicity profiles):
  • Bolus → more myelosuppression.
  • Continuous infusion → more mucositis, hand–foot syndrome.
• Typical regimens:
  • Bolus: 400–600 mg/m² IV on days 1–5 every 28 days.
  • Continuous infusion: 1,000–1,200 mg/m²/day IV × 4–5 days every 28 days, or weekly regimens.
• Leucovorin (folinic acid) is often co-administered → stabilizes the FdUMP-TS complex → enhances efficacy.

Toxicities

• Common
  • Myelosuppression (esp. neutropenia with bolus).
  • Mucositis, stomatitis.
  • Diarrhea.
  • Nausea, vomiting.
  • Hand–foot syndrome (palmar-plantar erythrodysesthesia, esp. with continuous infusion).
• Serious
  • Cardiotoxicity (angina, ischemia, arrhythmias).
  • Rare: neurotoxicity (cerebellar syndrome).
• Pharmacogenomics:
  • DPD deficiency (dihydropyrimidine dehydrogenase) → reduced metabolism → severe, life-threatening toxicity (myelosuppression, diarrhea, mucositis, neurotoxicity).

Monitoring

• CBC with differential (before each cycle).
• Mucositis, GI toxicity, hand–foot syndrome.
• Cardiac monitoring in high-risk patients.
• Consider DPD testing (genetic or phenotypic) in high-risk settings or severe unexpected toxicity.

Pharmacist Pearls

• Leucovorin enhances 5-FU’s binding to thymidylate synthase (opposite of its role with methotrexate rescue).
• Route and schedule matter: bolus → hematologic toxicity, infusion → mucocutaneous toxicity.
• Capecitabine is the oral prodrug of 5-FU.
• Watch for drug interactions (e.g., warfarin potentiation → ↑ INR).

Summary

5-FU is a backbone pyrimidine analog in many solid tumor regimens. Its activity is enhanced with leucovorin, and its toxicity is highly influenced by administration schedule and DPD activity. Careful monitoring for myelosuppression, mucositis, diarrhea, and hand–foot syndrome is critical.