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 light of their anti-proliferative activity. However, their use as chemotherapeu...
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| Format: | Article |
| Language: | English |
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University of Sarajevo, Institute for Genetic Engineering and Biotechnology
2018-12-01
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| Series: | Genetics & Applications |
| Subjects: | |
| Online Access: | https://genapp.ba/editions/index.php/journal/article/view/108 |
| _version_ | 1828091200314277888 |
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| author | Mia Stanić Iart Luca Shytaj Marina Lusic |
| author_facet | Mia Stanić Iart Luca Shytaj Marina Lusic |
| author_sort | Mia Stanić |
| collection | DOAJ |
| description |
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.
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| first_indexed | 2024-04-11T06:09:17Z |
| format | Article |
| id | doaj.art-05cb2663dd92420383e16ff55a6f0af1 |
| institution | Directory Open Access Journal |
| issn | 2566-2937 2566-431X |
| language | English |
| last_indexed | 2024-04-11T06:09:17Z |
| publishDate | 2018-12-01 |
| publisher | University of Sarajevo, Institute for Genetic Engineering and Biotechnology |
| record_format | Article |
| series | Genetics & Applications |
| spelling | doaj.art-05cb2663dd92420383e16ff55a6f0af12022-12-22T04:41:20ZengUniversity of Sarajevo, Institute for Genetic Engineering and BiotechnologyGenetics & Applications2566-29372566-431X2018-12-0122PHARMACOLOGIC TOPOISOMERASE-I INHIBITION CAUSES DNA DAMAGE AND MORTALITY IN ACTIVATED CD4+ T CELLSMia Stanić0Iart Luca Shytaj1Marina Lusic2Department of Infectious Diseases, Integrative Virology, University Hospital and German Center for Infection Research (DZIF), Heidelberg, GermanyDepartment of Infectious Diseases, Integrative Virology, University Hospital and German Center for Infection Research (DZIF), Heidelberg, GermanyDepartment of Infectious Diseases, Integrative Virology, University Hospital and German Center for Infection Research (DZIF), Heidelberg, Germany 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. https://genapp.ba/editions/index.php/journal/article/view/108Topoisomerase-ItopotecanH2AXCD4 T cells |
| spellingShingle | Mia Stanić Iart Luca Shytaj Marina Lusic PHARMACOLOGIC TOPOISOMERASE-I INHIBITION CAUSES DNA DAMAGE AND MORTALITY IN ACTIVATED CD4+ T CELLS Genetics & Applications Topoisomerase-I topotecan H2AX CD4 T cells |
| title | PHARMACOLOGIC TOPOISOMERASE-I INHIBITION CAUSES DNA DAMAGE AND MORTALITY IN ACTIVATED CD4+ T CELLS |
| title_full | PHARMACOLOGIC TOPOISOMERASE-I INHIBITION CAUSES DNA DAMAGE AND MORTALITY IN ACTIVATED CD4+ T CELLS |
| title_fullStr | PHARMACOLOGIC TOPOISOMERASE-I INHIBITION CAUSES DNA DAMAGE AND MORTALITY IN ACTIVATED CD4+ T CELLS |
| title_full_unstemmed | PHARMACOLOGIC TOPOISOMERASE-I INHIBITION CAUSES DNA DAMAGE AND MORTALITY IN ACTIVATED CD4+ T CELLS |
| title_short | PHARMACOLOGIC TOPOISOMERASE-I INHIBITION CAUSES DNA DAMAGE AND MORTALITY IN ACTIVATED CD4+ T CELLS |
| title_sort | pharmacologic topoisomerase i inhibition causes dna damage and mortality in activated cd4 t cells |
| topic | Topoisomerase-I topotecan H2AX CD4 T cells |
| url | https://genapp.ba/editions/index.php/journal/article/view/108 |
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