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.
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.
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005472:Fluorouracil / Q000633:toxicity*; D051379:Mice; D009154:Mutation; D012313:RNA / Q000096:biosynthesis*; D013936:Thymidine / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000172:deficiency
D012313:RNA; D013940:Thymidylate Synthase; D005472:Fluorouracil; D013936:Thymidine