Targeted Radiosensitization by the Chk1 Inhibitor SAR-020106

被引：44

作者：

Borst, Gerben R. ^{[1
,2
]}

McLaughlin, Martin ^{[1
]}

Kyula, Joan N. ^{[1
]}

Neijenhuis, Sari ^{[1
]}

Khan, Aadil ^{[1
]}

Good, James ^{[1
]}

Zaidi, Shane ^{[1
]}

Powell, Ned G. ^{[3
]}

Meier, Pascal ^{[1
]}

Collins, Ian ^{[1
]}

Garrett, Michelle D. ^{[1
]}

Verheij, Marcel ^{[2
]}

Harrington, Kevin J. ^{[1
]}

机构：

[1] Inst Canc Res, London SW3 6JB, England

[2] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands

[3] Cardiff Univ, Sch Med, HPV Res Grp, Cardiff CF10 3AX, S Glam, Wales

来源：

INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS | 2013年 / 85卷 / 04期

关键词：

CHECKPOINT; REPAIR; P53; TUMORIGENESIS; ABROGATION; PATHWAY; KINASE; CELLS;

D O I：

10.1016/j.ijrobp.2012.08.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1110 / 1118

页数：9

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