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Targeted Radiosensitization by the Chk1 Inhibitor SAR-020106

Borst, Gerben R., McLaughlin, Martin, Kyula, Joan N., Neijenhuis, Sari, Khan, Aadil, Good, James, Zaidi, Shane, Powell, Ned G., Meier, Pascal, Collins, Ian, and others. (2012) Targeted Radiosensitization by the Chk1 Inhibitor SAR-020106. International Journal of Radiation Oncology Biology Physics, 85 (4). pp. 1110-1118. ISSN 0360-3016. (doi:10.1016/j.ijrobp.2012.08.006) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:58562)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)
Official URL
http://doi.org/10.1016/j.ijrobp.2012.08.006

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-?H2AX-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
DOI/Identification number: 10.1016/j.ijrobp.2012.08.006
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Michelle Garrett
Date Deposited: 11 Nov 2016 10:33 UTC
Last Modified: 13 Mar 2020 04:08 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/58562 (The current URI for this page, for reference purposes)
Garrett, Michelle D.: https://orcid.org/0000-0002-3939-1673
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