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Lookup NU author(s): Michael Batey, Dr Yan Zhao, Suzanne Kyle, Professor Herbie Newell, Professor Nicola CurtinORCiD
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Ataxia telangiectasia mutated (ATM) kinase signals DNA double-strand breaks (DSB) to cell-cycle arrest via p53 and DNA repair. ATM-defective cells are sensitive to DSB-inducing agents, making ATM an attractive target for anticancer chemo-and radiosensitization. KU59403 is an ATM inhibitor with the potency, selectivity, and solubility for advanced preclinical evaluation. KU59403 was not cytotoxic to human cancer cell lines (SW620, LoVo, HCT116, and MDA-MB-231) per se but significantly increased the cytotoxicity of topoisomerase I and II poisons: camptothecin, etoposide, and doxorubicin. Chemo-and radiosensitization by ATM inhibition was not p53-dependent. Following administration to mice, KU59403 distributed to tissues and concentrations exceeding those required for in vitro activity were maintained for at least 4 hours in tumor xenografts. KU59403 significantly enhanced the antitumor activity of topoisomerase poisons in mice bearing human colon cancer xenografts (SW620 and HCT116) at doses that were nontoxic alone and well-tolerated in combination. Chemosensitization was both dose-and schedule-dependent. KU59403 represents a major advance in ATM inhibitor development, being the first compound to show good tissue distribution and significant chemosensitization in in vivo models of human cancer, without major toxicity. KU59403 provides the first proof-of-principle preclinical data to support the future clinical development of ATM inhibitors. (C) 2013 AACR.
Author(s): Batey MA, Zhao Y, Kyle S, Richardson C, Slade A, Martin NMB, Lau A, Newell DR, Curtin NJ
Publication type: Article
Publication status: Published
Journal: Molecular Cancer Therapeutics
Year: 2013
Volume: 12
Issue: 6
Pages: 959-967
Print publication date: 01/06/2013
Online publication date: 19/03/2013
Acceptance date: 22/02/2013
ISSN (print): 1535-7163
ISSN (electronic): 1538-8514
Publisher: American Association for Cancer Research
URL: http://dx.doi.org/10.1158/1535-7163.MCT-12-0707
DOI: 10.1158/1535-7163.MCT-12-0707
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