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Deoxyuridine suppression test on isolated rat bone marrow cells and the in vitro effect of bidisomide
A Rogister1, Y Vandenberghe, J Roba
1Product Safety Europe, Department of Toxicology, Searle European Development Centre, 11 rue Granbonpré, 1348 Mont-Saint-Guilbert, Belgium.
Abstract:
The deoxyuridine suppression test was performed on isolated rat bone marrow cells in order to study the effect of bidisomide, a new Class I antiarrhythmic agent, on folate-dependent DNA synthesis. Methotrexate and 5-fluorouracil, two known inhibitors of DNA synthesis, were included in the study to validate the test system. Methotrexate and 5-fluorouracil, at a concentration of 5.5 mum, decreased thymidine incorporation into DNA by way of the de novo pathway (thymidylate synthase activity). The salvage pathway of DNA synthesis (thymidine kinase activity), however, was not affected by these anticancer drugs. Bidisomide up to 1 mm did not affect the folate-dependent thymidylate synthase activity, nor the thymidine kinase activity of isolated rat bone marrow cells.
Insights
The new antiarrhythmic drug bidisomide does not affect DNA synthesis in rat bone marrow cells. This study found no impact on folate-dependent DNA synthesis or related enzyme activity with bidisomide treatment.
Area of Science:
- Pharmacology
- Molecular Biology
- Hematology
Background:
- Folate-dependent DNA synthesis is crucial for cell proliferation.
- Antiarrhythmic agents require thorough investigation for potential effects on cellular processes.
- The deoxyuridine suppression test is a validated method for assessing DNA synthesis pathways.
Purpose of the Study:
- To investigate the effect of bidisomide, a novel Class I antiarrhythmic agent, on folate-dependent DNA synthesis.
- To evaluate the impact of bidisomide on thymidylate synthase and thymidine kinase activities in rat bone marrow cells.
- To validate the deoxyuridine suppression test system using known DNA synthesis inhibitors.
Main Methods:
- The deoxyuridine suppression test was conducted on isolated rat bone marrow cells.
- Cells were treated with bidisomide, methotrexate, and 5-fluorouracil.
- Thymidine incorporation into DNA was measured to assess de novo and salvage pathways of DNA synthesis.
Main Results:
- Methotrexate and 5-fluorouracil (5.5 µM) inhibited thymidylate synthase activity, validating the test system.
- These inhibitors did not affect thymidine kinase activity (salvage pathway).
- Bidisomide, up to 1 mM, showed no inhibitory effect on either thymidylate synthase or thymidine kinase activity.
Conclusions:
- Bidisomide does not interfere with folate-dependent DNA synthesis in rat bone marrow cells.
- The drug does not inhibit key enzymes involved in DNA synthesis, namely thymidylate synthase and thymidine kinase.
- These findings suggest bidisomide has a favorable safety profile regarding DNA synthesis in hematopoietic cells.
