Pharmacologic topoisomerase-I inhibition causes DNA damage and mortality in activated CD4+ T cells
Journal Title: Genetics & Applications - Year 2018, Vol 2, Issue 2
Abstract
Topoisomerase-I is required for DNA replication. It acts by preventing torsional stress caused by DNA winding during replication fork progression. Topoisomerase-I inhibitors are widely used in many cancer therapies, in light of their anti-proliferative activity. However, their use as chemotherapeutics is associated with significant toxicity due to the off-target effects on healthy cells. We analyzed the dose-time-toxicity profile of a clinically employed topoisomerase-I inhibitor, i.e. topotecan, on primary CD4+T cells. This cell type was chosen to model a typical in-vivo interaction, due to the wide use of topotecan in the treatment of T-cell lymphomas. Our results show that a clinically achievable concentration of topotecan can induce toxic effects in healthy CD4+ T cells as early as 7 hours of the in vitro treatment. Toxicity of the drug was markedly increased by prolonging the post-treatment follow-up, but not by increasing concentrations, suggesting that clinical doses of topotecan can induce cell death and DNA damage in non-cancerous activated CD4+ T lymphocytes.
Authors and Affiliations
Mia Stanic, Iart Luca Shytaj, Marina Lusic
Keywords
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- EP ID EP520749
- DOI 10.31383/ga.vol2iss2pp51-56
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Pharmacologic topoisomerase-I inhibition causes DNA damage and mortality in activated CD4+ T cells
Topoisomerase-I is required for DNA replication. It acts by preventing torsional stress caused by DNA winding during replication fork progression. Topoisomerase-I inhibitors are widely used in many cancer therapies, in l...
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