Journal
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
Volume 85, Issue 4, Pages 1110-1118Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ijrobp.2012.08.006
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Funding
- EACR fellowship
- EMBO fellowship
- Cancer Research UK Programme Grant
- Rosetrees Trust
- Oracle Cancer Trust
- Cancer Research UK [13407, 11566] Funding Source: researchfish
- National Institute for Health Research [ACF-2008-22-002] Funding Source: researchfish
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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 G(2)/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 G(1) 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-gamma 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. (C) 2013 Elsevier Inc.
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