Targeted radiosensitization by the Chk1 inhibitor SAR-020106.
Int J Radiat Oncol Biol Phys
; 85(4): 1110-8, 2013 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-22981708
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Quinases
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Pirazinas
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Radiossensibilizantes
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Tolerância a Radiação
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Fase G2
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Reparo do DNA
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Isoquinolinas
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article