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Thymidylate synthetase inhibitors and fragile site expression in lymphocytes
Abstract:
The ability of three thymidylate synthetase inhibitors, fluorodeoxyuridine, fluorodeoxycytidine, and trifluorothymidine, to induce the expression of eight different folate-sensitive fragile sites has been investigated in 22 patients and compared with the efficacy of simple folate deprivation for inducing fragile site expression. Fluorodeoxyuridine and fluorodeoxycytidine were equal in their ability to elicit fragile site expression but fluorodeoxycytidine proved less cytotoxic under comparable culture conditions. Both fluorodeoxyuridine and fluorodeoxycytidine were found to be more efficient than trifluorothymidine at comparable concentrations but less efficient than simple folate deprivation in eliciting fragile site expression in lymphocytes. Since the three inhibitors induced expression of eight different folate-sensitive fragile sites, it is likely that all folate-sensitive fragile sites have a common underlying mechanism of expression. The practical application of thymidylate synthetase inhibitors in the routine detection of heritable fragile sites is discussed.
Insights
Three thymidylate synthetase inhibitors were tested for their ability to induce folate-sensitive fragile sites. Fluorodeoxyuridine and fluorodeoxycytidine were effective, suggesting a common mechanism for fragile site expression.
Area of Science:
- Genetics
- Molecular Biology
- Pharmacology
Background:
- Fragile sites are chromosomal regions prone to breakage.
- Folate-sensitive fragile sites are induced by folate deprivation.
- Thymidylate synthetase inhibitors affect DNA synthesis.
Purpose of the Study:
- To investigate the efficacy of three thymidylate synthetase inhibitors in inducing folate-sensitive fragile site expression.
- To compare the efficiency of these inhibitors with folate deprivation.
- To explore the underlying mechanism of folate-sensitive fragile site expression.
Main Methods:
- Investigated three thymidylate synthetase inhibitors: fluorodeoxyuridine, fluorodeoxycytidine, and trifluorothymidine.
- Assessed the induction of eight different folate-sensitive fragile sites in 22 patients.
- Compared inhibitor efficacy with simple folate deprivation in lymphocyte cultures.
Main Results:
- Fluorodeoxyuridine and fluorodeoxycytidine showed equal efficacy in eliciting fragile site expression, with fluorodeoxycytidine being less cytotoxic.
- Both fluorodeoxyuridine and fluorodeoxycytidine were more efficient than trifluorothymidine but less efficient than folate deprivation.
- All three inhibitors induced expression of eight distinct folate-sensitive fragile sites.
Conclusions:
- Folate-sensitive fragile sites likely share a common mechanism of expression.
- Thymidylate synthetase inhibitors show potential for routine detection of heritable fragile sites.