Pyrimidine Antagonists:Flurouracil (5-FU)

• Flurouracil (5-FU), normally given by IV administration (oral absorption erratic)
  • Biotransformed to ribosyl- and deoxyribosyl- derivatives.
    • Mechanism of Action:
      • One derivative, 5-fluoro-2'-deoxyuridine 5'-phosphate (FdUMP), inhibits thymidylate synthase and its cofactor,a tetrahydrofolate derivative, resulting in inhibition of thiamine nucleotide synthesis.
      • Another derivative, 5-fluorouridine triphosphate is incorporated into RNA, interfering with RNA function.
      • Cytotoxicity:effects on both RNA and DNA
  • Clinical Use: Systemically -- adenocarcinomas; Topically: skin cancer
  •  Major Toxicity: myelosuppression, mucositis.