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Evaluating the drug-target relationship between thymidylate synthase expression and tumor response to 5-fluorouracil.
Shayna L Showalter1, Timothy N Showalter, Agnes Witkiewicz
1Department of Surgery, Thomas Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University Philadelphia, Pennsylvania 19107, USA.
Abstract:
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.
Insights
Thymidylate synthase expression shows an inverse relationship with 5-fluorouracil response in cancer treatment. This study questions its reliability as a predictor, suggesting research into alternative biomarkers.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- 5-fluorouracil (5-FU) is a key chemotherapy agent targeting thymidylate synthase (TS).
- Fluoro-deoxyuridine monophosphate, a 5-FU metabolite, forms a complex with TS and 5,10-methylene tetrahydrofolate.
- The clinical utility of TS as a predictive biomarker for 5-FU efficacy is debated.
Purpose of the Study:
- To evaluate the long-standing association between thymidylate synthase expression and patient response to 5-fluorouracil.
- To determine if TS expression reliably predicts 5-FU treatment outcomes across various cancer types.
Main Methods:
- A comprehensive literature search was conducted for studies published between 1995 and 2007.
- Tumors were stratified by TS expression levels (low vs. high) and response (responders, stable disease, progression).
- Statistical analysis examined the relationship between TS expression and 5-FU response, considering publication date, journal impact factor, and measurement substrate.
Main Results:
- An approximate 2-fold inverse relationship was observed between TS expression and 5-FU response across the analyzed literature.
- This trend remained consistent regardless of publication date, journal impact factor, or whether mRNA or protein levels were measured.
- The relationship showed a decline when 5-FU was combined with certain chemotherapeutics, but remained stable when combined with leucovorin.
Conclusions:
- The correlation between thymidylate synthase expression and 5-fluorouracil response does not meet the criteria for an effective drug-target relationship.
- Thymidylate synthase expression may not be a reliable clinical predictor of 5-FU response, potentially being more relevant to patient toxicity.
- Future research should explore alternative targets and 5-FU metabolites to identify clinically relevant biomarkers for optimizing fluoropyrimidine-based therapies.
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