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Thymidylate synthase expression and activity: relation to S-phase parameters and 5-fluorouracil sensitivity
J F Mirjolet1, M Barberi-Heyob, J L Merlin
1Centre Alexis Vautrin, Laboratoire de Recherche en Oncologie, Vandoeuvre-les-Nancy, France.
British Journal of Cancer
|July 14, 1998
Summary
Cell cycle parameters like S-phase duration (SPD) and labelling index (LI) better predict 5-fluorouracil (5-FU) sensitivity than thymidylate synthase (TS) expression or activity. These findings aid in optimizing chemotherapy and radiotherapy planning.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- 5-fluorouracil (5-FU) is a key chemotherapy agent.
- Predicting 5-FU sensitivity is crucial for effective cancer treatment.
- Thymidylate synthase (TS) is a primary target of 5-FU, but its predictive value is debated.
Purpose of the Study:
- To evaluate the correlation between various biomarkers and 5-FU sensitivity in human cancer cell lines.
- To compare the predictive power of cell cycle parameters versus TS-related markers for 5-FU response.
Main Methods:
- Assessed TS and p53 gene expression, TS and dihydropyrimidine dehydrogenase (DPD) activity.
- Measured cell cycle parameters: S-phase fraction (SPF), bromodeoxyuridine labelling index (LI), and S-phase duration (SPD).
- Compared these parameters with 5-FU sensitivity across six human cancer cell lines over 7 days.
Main Results:
- No significant correlation was found between TS gene expression/activity and 5-FU sensitivity.
- TS activity was higher in proliferating cells but not significantly correlated with rapid growth or short S-phase duration (SPD).
- A strong significant correlation (P < 0.0001) was observed between LI, SPD, and 5-FU sensitivity.
Conclusions:
- Cell cycle parameters, specifically SPD and LI, may serve as superior predictors of 5-FU sensitivity compared to TS expression or activity.
- These findings have implications for personalized chemotherapy and concurrent radio-chemotherapy planning, particularly for hyperfractionated radiotherapy.