{"id":{"repo_id":"freiburg-diss","oai_identifier":"oai:freidok.uni-freiburg.de:2097"},"canonical_url":"https://search.dev.ndltd.org/etd/freiburg-diss/oai:freidok.uni-freiburg.de:2097","repository":{"repo_id":"freiburg-diss","name":"University of Freiburg","base_url":"https://freidok.uni-freiburg.de/oai/oai2.php"},"display":{"title":"Preclinical evaluation of a novel telomerase inhibitor in malignant cells of the hematopoietic system","abstract":"Telomerase represents an attractive target for a mechanism-based therapeutic approach because its activation has been associated with unlimited proliferation in most cancer cells. Recently, a non-nucleosidic small molecule inhibitor, BIBR1532, has been identified which is highly selective for the inhibition of telomerase resulting in telomere dysfunction and delayed growth arrest in tumor cells. Here we examined the effects of BIBR1532 in different leukemia cell lines as well as in primary cells from patients with AML and CLL in short term culture assays. We observed a dose dependent direct cytotoxicity in concentrations ranging from 30 to 80 µM. Importantly, there was no effect on the in vitro proliferative capacity of normal CD34+ cells from cord blood and leukapheresis samples. Q-FISH analysis revealed that high concentrations of BIBR1532 induced a time-dependent individual telomere decapping which was associated with loss of TRF2 and increased phosphorylation of p53. Ectopic expression of hTERT revealed the close correlation of the protective role of the catalytic activity, telomere length and cellular stability. We conclude that High Dose BIBR1532 exerts a direct cytotoxic effect on malignant cells of the hematopoietic system which appears to be induce rapid sequestration of individual telomeres, the rate of proliferation plays also a crucial role in cells with longer telomeres.","abstract_html":"Telomerase represents an attractive target for a mechanism-based therapeutic approach because its activation has been associated with unlimited proliferation in most cancer cells. Recently, a non-nucleosidic small molecule inhibitor, BIBR1532, has been identified which is highly selective for the inhibition of telomerase resulting in telomere dysfunction and delayed growth arrest in tumor cells. Here we examined the effects of BIBR1532 in different leukemia cell lines as well as in primary cells from patients with AML and CLL in short term culture assays. We observed a dose dependent direct cytotoxicity in concentrations ranging from 30 to 80 µM. Importantly, there was no effect on the in vitro proliferative capacity of normal CD34+ cells from cord blood and leukapheresis samples. Q-FISH analysis revealed that high concentrations of BIBR1532 induced a time-dependent individual telomere decapping which was associated with loss of TRF2 and increased phosphorylation of p53. Ectopic expression of hTERT revealed the close correlation of the protective role of the catalytic activity, telomere length and cellular stability. We conclude that High Dose BIBR1532 exerts a direct cytotoxic effect on malignant cells of the hematopoietic system which appears to be induce rapid sequestration of individual telomeres, the rate of proliferation plays also a crucial role in cells with longer telomeres.","abstract_has_math":false,"creators":["El Daly, Hesham"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Martens, Uwe M."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":null,"date_issued":"","date_published":null,"updated_at":"2026-07-24T02:22:33Z","subjects":["telomerase","telomere","TRF2","telomere dysfunction","leukemia"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://freidok.uni-freiburg.de/data/2097","outbound_label":"Repository record","outbound_source":"source_url"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Martens, Uwe M."]},{"key":"dc:creator","label":"Author","values":["El Daly, Hesham"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:type","label":"Dc Type","values":["DoctoralThesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["telomerase","telomere","TRF2","telomere dysfunction","leukemia"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Telomerase represents an attractive target for a mechanism-based therapeutic approach because its activation has been associated with unlimited proliferation in most cancer cells. Recently, a non-nucleosidic small molecule inhibitor, BIBR1532, has been identified which is highly selective for the inhibition of telomerase resulting in telomere dysfunction and delayed growth arrest in tumor cells. Here we examined the effects of BIBR1532 in different leukemia cell lines as well as in primary cells from patients with AML and CLL in short term culture assays. We observed a dose dependent direct cytotoxicity in concentrations ranging from 30 to 80 µM. Importantly, there was no effect on the in vitro proliferative capacity of normal CD34+ cells from cord blood and leukapheresis samples. Q-FISH analysis revealed that high concentrations of BIBR1532 induced a time-dependent individual telomere decapping which was associated with loss of TRF2 and increased phosphorylation of p53. Ectopic expression of hTERT revealed the close correlation of the protective role of the catalytic activity, telomere length and cellular stability. We conclude that High Dose BIBR1532 exerts a direct cytotoxic effect on malignant cells of the hematopoietic system which appears to be induce rapid sequestration of individual telomeres, the rate of proliferation plays also a crucial role in cells with longer telomeres.","Telomerase ist ein attraktives Ziel für eine Mechanismus-basierende Therapie, da die unbegrenzte Proliferation in den meisten Krebszellen mit ihrer Aktivierung in Zusammenhang steht. Kürzlich ist ein nicht-nukleosidischer small-molecule Inhibitor - BIBR1532 - identifiziert worden, der für die Hemmung von Telomerase hoch-spezifisch ist und das Wachstum von Tumorzellen einschränkt. In dieser Arbeit wurde die Wirkung von BIBR1532 sowohl in verschiedenen Leukämie-Zelllinien als auch in primären Zellen von Patienten mit AML und CLL in Kurzzeit-Kulturen untersucht. <br>Es konnte ein Dosis-abhängiger und direkt zytotoxischer Effekt für BIBR1532 beobachtet werden, wenn die Substanz über 20 µM eingesetzt wurde. Interessanterweise war der Zelltod von der katalytischen Tätigkeit der Telomerase unabhängig und wurde vielmehr in Zellen mit sehr langen Telomeren verzögert. Wir konnten eine Zeit-abhängige Erosion individueller Telomere beobachten, die im Zusammenhang mit dem Verlust von TRF2 und einer erhöhten Phosphorylierung von p53 steht. Es ist wichtig anzumerken, dass die proliferative Kapazität von normalen CD34+ Zellen aus Nabelschnurblut und Leukapheresis-Proben von der Behandlung mit BIBR1532 nicht betroffen war. <br>Daher muss postuliert werden, dass die Verwendung höherer Konzentrationen des Telomerase-Inhibitors dieser Klasse eine direkte zytotoxische Wirkung auf Tumorzellen des hämatopoietischen Systems hat, der auf einen direkten Schaden der Struktur individueller Telomere zurückgeführt werden kann, und der von einer Telomerase-abhängigen Telomerverkürzung getrennt betrachtet werden muss. Ein solcher Mechanismus könnte zum Ansatzpunkt neuer onkologischer Therapieformen führen."]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Preclinical evaluation of a novel telomerase inhibitor in malignant cells of the hematopoietic system","Präklinische Untersuchung eines neuen Telomerase Inhibitors in malignen Zellen des hämatopoietischen Systems"]}]}],"canonical_facts":{"dc:contributor":["Martens, Uwe M."],"dc:creator":["El Daly, Hesham"],"dc:description.abstract":["Telomerase represents an attractive target for a mechanism-based therapeutic approach because its activation has been associated with unlimited proliferation in most cancer cells. Recently, a non-nucleosidic small molecule inhibitor, BIBR1532, has been identified which is highly selective for the inhibition of telomerase resulting in telomere dysfunction and delayed growth arrest in tumor cells. Here we examined the effects of BIBR1532 in different leukemia cell lines as well as in primary cells from patients with AML and CLL in short term culture assays. We observed a dose dependent direct cytotoxicity in concentrations ranging from 30 to 80 µM. Importantly, there was no effect on the in vitro proliferative capacity of normal CD34+ cells from cord blood and leukapheresis samples. Q-FISH analysis revealed that high concentrations of BIBR1532 induced a time-dependent individual telomere decapping which was associated with loss of TRF2 and increased phosphorylation of p53. Ectopic expression of hTERT revealed the close correlation of the protective role of the catalytic activity, telomere length and cellular stability. We conclude that High Dose BIBR1532 exerts a direct cytotoxic effect on malignant cells of the hematopoietic system which appears to be induce rapid sequestration of individual telomeres, the rate of proliferation plays also a crucial role in cells with longer telomeres.","Telomerase ist ein attraktives Ziel für eine Mechanismus-basierende Therapie, da die unbegrenzte Proliferation in den meisten Krebszellen mit ihrer Aktivierung in Zusammenhang steht. Kürzlich ist ein nicht-nukleosidischer small-molecule Inhibitor - BIBR1532 - identifiziert worden, der für die Hemmung von Telomerase hoch-spezifisch ist und das Wachstum von Tumorzellen einschränkt. In dieser Arbeit wurde die Wirkung von BIBR1532 sowohl in verschiedenen Leukämie-Zelllinien als auch in primären Zellen von Patienten mit AML und CLL in Kurzzeit-Kulturen untersucht. <br>Es konnte ein Dosis-abhängiger und direkt zytotoxischer Effekt für BIBR1532 beobachtet werden, wenn die Substanz über 20 µM eingesetzt wurde. Interessanterweise war der Zelltod von der katalytischen Tätigkeit der Telomerase unabhängig und wurde vielmehr in Zellen mit sehr langen Telomeren verzögert. Wir konnten eine Zeit-abhängige Erosion individueller Telomere beobachten, die im Zusammenhang mit dem Verlust von TRF2 und einer erhöhten Phosphorylierung von p53 steht. Es ist wichtig anzumerken, dass die proliferative Kapazität von normalen CD34+ Zellen aus Nabelschnurblut und Leukapheresis-Proben von der Behandlung mit BIBR1532 nicht betroffen war. <br>Daher muss postuliert werden, dass die Verwendung höherer Konzentrationen des Telomerase-Inhibitors dieser Klasse eine direkte zytotoxische Wirkung auf Tumorzellen des hämatopoietischen Systems hat, der auf einen direkten Schaden der Struktur individueller Telomere zurückgeführt werden kann, und der von einer Telomerase-abhängigen Telomerverkürzung getrennt betrachtet werden muss. Ein solcher Mechanismus könnte zum Ansatzpunkt neuer onkologischer Therapieformen führen."],"dc:format.medium":["application/pdf"],"dc:subject":["telomerase","telomere","TRF2","telomere dysfunction","leukemia"],"dc:title":["Preclinical evaluation of a novel telomerase inhibitor in malignant cells of the hematopoietic system","Präklinische Untersuchung eines neuen Telomerase Inhibitors in malignen Zellen des hämatopoietischen Systems"],"dc:type":["DoctoralThesis"]},"updated_at":"2026-07-24T02:22:33Z"}