The cytotoxicity of 5-fluorouracil is due to its incorporation into RNA not its inhibition of thymidylate synthase as evidenced by the use of a mouse cell mutant deficient in thymidylate synthase

Jpn J Cancer Res. 1986 Jul;77(7):620-4.


The biochemical basis for the cytotoxicity of 5-fluorouracil is still controversial; it is not clear whether the mechanism involves interference with DNA metabolism or incorporation of the drug into RNA. To distinguish between these two possibilities, we took advantage of a mutant strain of the mouse mammary tumor cell line FM3A that is deficient in thymidylate synthase, which is widely believed to be the target of 5-fluorouracil. We demonstrated that the target of the cytotoxicity of 5-fluorouracil was not thymidylate synthase; instead, the cytotoxicity was positively correlated with drug incorporation into RNA under conditions where thymidine increased the incorporation of 5-fluorouracil into RNA concentration-dependently.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Fluorouracil / toxicity*
  • Mice
  • Mutation
  • RNA / biosynthesis*
  • Thymidine / metabolism
  • Thymidylate Synthase / antagonists & inhibitors*
  • Thymidylate Synthase / deficiency


  • RNA
  • Thymidylate Synthase
  • Fluorouracil
  • Thymidine