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Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents

Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents

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Prüfsumme: MD5:ac4e58b870643b9149afed7acf406245

BIRK, Martina, Alexander BÜRKLE, Klaus PEKARI, Thomas MAIER, Mathias SCHMIDT, 2012. Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents. In: International Journal of Cancer. 130(4), pp. 798-807. ISSN 0020-7136. eISSN 1097-0215. Available under: doi: 10.1002/ijc.26036

@article{Birk2012-02-15cycle-21534, title={Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents}, year={2012}, doi={10.1002/ijc.26036}, number={4}, volume={130}, issn={0020-7136}, journal={International Journal of Cancer}, pages={798--807}, author={Birk, Martina and Bürkle, Alexander and Pekari, Klaus and Maier, Thomas and Schmidt, Mathias} }

Birk, Martina 2012-02-15 deposit-license Pekari, Klaus Maier, Thomas Birk, Martina Bürkle, Alexander Schmidt, Mathias Schmidt, Mathias eng 2013-02-07T08:37:32Z The mitotic spindle checkpoint (SPC) is a highly regulated mechanism in eukaryotic cells that ensures the even distribution of the duplicated genome between daughter cells. Malfunction of the SPC or deregulated expression of SPC regulatory proteins is frequently associated with a poor response to chemotherapeutic agents. We investigated various approved and investigational mitosis-specific agents, including spindle poisons, an Eg5 kinesin inhibitor, inhibitors of polo-like kinase 1 (Plk1) or Aurora-B kinase, a benzamide class HDAC inhibitor and compounds identified in a chemical genetics screen for their cell cycle-dependent cytotoxicities and for their activities toward SPC deficient (HT29, Caco-2, T47D) and SPC proficient human cell lines (A2780, HCT116, SW480). Using the RKOp27 cell system that allows inducible cell cycle arrest by the tunable expression of the cdk inhibitor p27Kip1, we found an exquisite proliferation-dependent cytotoxicity for all compounds except the aurora kinase inhibitor VX-680. Cytotoxicity of the antimitotic compounds was in general higher on SPC proficient than on deficient cells. We found two exceptions, a benzamide HDAC inhibitor which was effective on SPC proficient and deficient cells and an investigational compound, BYK72767, with a yet unknown mode of action. The degree of increased mitotic index was no predictor of cytotoxicity of the compounds nor was the phosphorylation of BubR1. However, SPC deficient cell lines were able to<br />tolerate mitotic arrest for far longer times than SPC proficient cells. We conclude that targeting of SPC deficient cancers with novel antimitotic principles remains a challenge but certain drug classes may be equally efficacious regardless of SPC status. International Journal of Cancer ; 130 (2012), 4. - S. 798-807 Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents 2013-02-07T08:37:32Z Bürkle, Alexander Pekari, Klaus Maier, Thomas

Dateiabrufe seit 01.10.2014 (Informationen über die Zugriffsstatistik)

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