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Targeted radiosensitization by the Chk1 inhibitor SAR-020106

Borst, G., McLaughlin, M., Kyula, J., Neijenhuis, S., Khan, A., Good, J., Zaidi, S., Powell, Ned George, Meier, P., Collins, I., Garrett, M., Verheji, M. and Harrington, K. 2013. Targeted radiosensitization by the Chk1 inhibitor SAR-020106. International Journal of Radiation Oncology - Biology - Physics 85 (4) , pp. 1110-1118. 10.1016/j.ijrobp.2012.08.006

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Abstract

Purpose: To explore the activity of a potent Chk1 inhibitor (SAR-020106) in combination with radiation. Methods and Materials: Colony and mechanistic in vitro assays and a xenograft in vivo model. Results: SAR-020106 suppressed-radiation-induced G2/M arrest and reduced clonogenic survival only in p53-deficient tumor cells. SAR-020106 promoted mitotic entry following irradiation in all cell lines, but p53-deficient cells were likely to undergo apoptosis or become aneuploid, while p53 wild-type cells underwent a postmitotic G1 arrest followed by subsequent normal cell cycle re-entry. Following combined treatment with SAR-020106 and radiation, homologous-recombination-mediated DNA damage repair was inhibited in all cell lines. A significant increase in the number of pan-γH2AX-staining apoptotic cells was observed only in p53-deficient cell lines. Efficacy was confirmed in vivo in a clinically relevant human head-and-neck cell carcinoma xenograft model. Conclusion: The Chk1 inhibitor SAR-020106 is a potent radiosensitizer in tumor cell lines defective in p53 signaling.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RZ Other systems of medicine
Publisher: Elsevier
ISSN: 0360-3016
Last Modified: 04 Jun 2017 08:15
URI: http://orca.cf.ac.uk/id/eprint/74949

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