Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy

Pharmacogenomics J. 2001;1(1):65-70. doi: 10.1038/sj.tpj.6500012.


Thymidylate synthase (TS) catalyses the conversion of deoxy-uridylate to deoxy-thymidylate and is essential for DNA synthesis. The human TS gene promoter is polymorphic, having either double or triple tandem repeats of a 28-bp sequence. Here we determined the significance of this polymorphism in humans and its prediction for clinical outcome of patients with metastatic colorectal cancer treated with 5-fluorouracil. The TS mRNA level was analyzed using RT-PCR. Individuals homozygous for the triple repeat variant (L/L) had 3.6 times higher TS mRNA levels compared to those homozygous for the double repeat variant (S/S) in tumor tissue (P = 0.004). We tested 50 patients with disseminated colorectal cancer who received 5-FU treatment to determine whether this TS polymorphism will predict clinical outcome. We found individuals with S/S genotype had a response rate of 50% (4/8) when compared to 9% (2/22) in those with L/L and 15% (3/20) in those with S/L genotype (P = 0.041). Patients with L/L had less severe side effects to 5-FU (P = 0.008). The data suggest that genotyping for the TS polymorphism may have the potential to identify patients more likely to respond to 5-FU based chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antimetabolites, Antineoplastic / adverse effects*
  • Female
  • Fluorouracil / adverse effects*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic*
  • RNA, Messenger / analysis
  • Thymidylate Synthase / genetics*


  • Antimetabolites, Antineoplastic
  • RNA, Messenger
  • Thymidylate Synthase
  • Fluorouracil