Thymidylate synthase is a target of 5-fluoruracil, a
pyrimidine analog used to treat gastrointestinal and other
cancers. The
5-fluorouracil metabolite, fluoro-
deoxyuridine monophosphate, forms a ternary complex with
thymidylate synthase and 5,10-methylene
tetrahydrofolate. The purpose of this study was to evaluate the time-honored connection between
thymidylate synthase and
5-fluorouracil. From our literature search spanning reports from 1995 to 2007 published in journals having an impact factor greater than 2, we stratified the
tumors within each article, according to low versus high
thymidylate synthase expression. These groups were subdivided into responders, stable disease or
disease progression. The relationship between
thymidylate synthase expression and
5-fluorouracil response was analyzed for the overall group, as well as for subsets. Overall, the literature supported an approximately 2-fold inverse relationship between
thymidylate synthase expression and response to 5-fluoruracil. We found no change in the trend for a relationship between
thymidylate synthase and
5-fluorouracil when the literature was stratified by date of publication, impact factor of the journal in which the report was published, or substrate (
mRNA versus
protein) for measuring
thymidylate synthase expression. Of note, there is no significant change in the trend when comparing
5-fluorouracil treatment alone or in combination with
leucovorin. We found a decline of this trend when certain chemotherapeutics were used in combination with
5-fluorouracil. In sum, the connection between
thymidylate synthase expression and patient response to
5-fluorouracil does not satisfy expectations for an effective drug-target relationship; and thus, studies of the
thymidylate synthase tandem repeat status might only be clinically valuable in regards to patient toxicity. Thus, we question the reliability of
thymidylate synthase expression as a clinical predictor of
5-fluorouracil response. Future research could perhaps be directed towards alternate targets and metabolites of
5-fluorouracil, in an effort to find a clinically relevant
biomarker panel for response and to optimize fluoropyrimidine-based
therapy.