Pharmacologic topoisomerase-I inhibition causes DNA damage and mortality in activated CD4+ T cells

  • Mia Stanić Department of Infectious Diseases, Integrative Virology, University Hospital and German Center for Infection Research (DZIF), Heidelberg, Germany
  • Iart Luca Shytaj Department of Infectious Diseases, Integrative Virology, University Hospital and German Center for Infection Research (DZIF), Heidelberg, Germany
  • Marina Lusic Department of Infectious Diseases, Integrative Virology, University Hospital and German Center for Infection Research (DZIF), Heidelberg, Germany

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.

Published
2018-12-25
How to Cite
STANIĆ, Mia; SHYTAJ, Iart Luca; LUSIC, Marina. Pharmacologic topoisomerase-I inhibition causes DNA damage and mortality in activated CD4+ T cells. Genetics & Applications, [S.l.], v. 2, n. 2, p. 51-56, dec. 2018. ISSN 2566-431X. Available at: <http://www.genapp.ba/index.php/genapp/article/view/69>. Date accessed: 18 june 2019. doi: https://doi.org/10.31383/ga.vol2iss2pp51-56.
Section
Research Articles