Fluoropyrimidines

What Are Fluoropyrimidines?

• Class: Antimetabolite chemotherapy (pyrimidine analogs).
• Prototype: 5-fluorouracil (5-FU).
• Other agents: Capecitabine (oral prodrug of 5-FU), Tegafur (part of S-1), and other investigational derivatives.
• Mechanism: They mimic pyrimidine bases (uracil/thymine) and interfere with DNA and RNA synthesis.

Mechanism of Action

1. DNA synthesis inhibition
   • 5-FU → converted intracellularly to FdUMP
   • FdUMP binds thymidylate synthase (TS) → inhibits conversion of dUMP → dTMP
   • This causes “thymineless death” → impaired DNA replication.
2. RNA incorporation
   • 5-FU → FUTP → incorporates into RNA → disrupts RNA processing and function.
3. Prodrugs
   • Capecitabine: absorbed orally → converted in liver/tumor tissue to 5-FU.
   • Designed to generate higher 5-FU concentration in tumor cells (via thymidine phosphorylase, higher in tumors).

Clinical Uses

• GI cancers: Colorectal, gastric, pancreatic, esophageal.
• Breast cancer: Often in metastatic setting.
• Head & neck cancers.
• Topical 5-FU: Actinic keratosis, superficial basal cell carcinoma.

Administration

• 5-FU IV bolus → more incorporation into RNA (↑ mucositis, myelosuppression).
• 5-FU continuous infusion → more TS inhibition (↑ hand–foot syndrome, diarrhea).
• Capecitabine (oral) → similar to continuous infusion 5-FU.

Adverse Effects

• GI: Diarrhea, mucositis, nausea, vomiting.
• Dermatologic: Hand–foot syndrome (palmar-plantar erythrodysesthesia).
• Myelosuppression (more with bolus 5-FU).
• Cardiotoxicity: Coronary vasospasm, angina, arrhythmias, rarely MI.
• Neurotoxicity (rare, cerebellar syndrome with high-dose 5-FU).

Pharmacogenomics

• DPD (dihydropyrimidine dehydrogenase) deficiency:
  • DPD is the main enzyme that metabolizes 5-FU.
  • Deficiency → severe, potentially fatal toxicity (myelosuppression, mucositis, neurotoxicity).
  • Genetic testing sometimes recommended.

Monitoring

• CBC (myelosuppression).
• GI toxicity, hand–foot syndrome.
• Cardiac symptoms during infusion.
• Consider DPD testing in patients with unexpected severe toxicity.

Key Clinical Pearls for Oncology Pharmacist

• Capecitabine ≈ continuous 5-FU (do NOT give both together).
• Leucovorin (folinic acid) is given with 5-FU → stabilizes FdUMP–TS complex, ↑ efficacy.
• DPD deficiency → life-threatening toxicity.
• 5-FU infusion vs bolus have different toxicity profiles (important in regimen design).
• Important backbone drug in regimens like FOLFOX, CAPOX, FOLFIRI, ECF, FLOT.