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Thymidylate synthase and drug resistance
G J Peters1, C L van der Wilt, B van Triest
1Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands.
European Journal of Cancer (Oxford, England : 1990)
|July 1, 1995
Summary
Leucovorin enhances the antitumor effects of 5-fluorouracil (5FU) by increasing thymidylate synthase inhibition. This combination therapy improves patient outcomes, especially when thymidylate synthase levels are high.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Thymidylate synthase is a key target for anticancer drugs like 5-fluorouracil (5FU).
- Resistance to 5FU can occur due to inadequate thymidylate synthase inhibition.
- Folates, with leucovorin as a precursor, can enhance 5FU's mechanism of action.
Purpose of the Study:
- To investigate the role of thymidylate synthase inhibition in 5FU resistance.
- To evaluate the impact of leucovorin on 5FU efficacy and thymidylate synthase activity.
- To correlate thymidylate synthase levels and drug inhibition with treatment outcomes.
Main Methods:
- Utilized a murine model system to assess 5FU treatment effects.
- Administered 5FU alone and in combination with leucovorin.
- Measured thymidylate synthase levels and inhibition in clinical settings.
- Analyzed the relationship between thymidylate synthase levels, inhibition, and patient response.
Main Results:
- 5FU treatment induced a 4-fold increase in thymidylate synthase levels in mice, suggesting a resistance mechanism.
- Leucovorin addition to 5FU prevented this induction and enhanced antitumor effects 2-3 fold in the murine model.
- In patients, 5FU achieved ~50% thymidylate synthase inhibition, while the 5FU-leucovorin combination reached ~70% inhibition.
- High thymidylate synthase levels with low inhibition correlated with no treatment response.
Conclusions:
- Leucovorin potentiates 5FU's antitumor activity by enhancing thymidylate synthase inhibition.
- Thymidylate synthase levels and drug inhibition are critical determinants of 5FU treatment efficacy.
- Low thymidylate synthase levels may serve as an independent prognostic factor for adjuvant therapy success.