title: Targeted radiosensitization by the Chk1 inhibitor SAR-020106.
abstract: OBJECTIVE
  To explore the activity of a potent Chk1 inhibitor (SAR-020106) in combination with radiation.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  The Chk1 inhibitor SAR-020106 is a potent radiosensitizer in tumor cell lines defective in p53 signaling.
authors.affiliation: The Institute of Cancer Research, London, United Kingdom. g.borst@nki.nl
authors.forename: Gerben R
authors.initials: GR
authors.lastname: Borst
authors.forename: Martin
authors.initials: M
authors.lastname: McLaughlin
authors.forename: Joan N
authors.initials: JN
authors.lastname: Kyula
authors.forename: Sari
authors.initials: S
authors.lastname: Neijenhuis
authors.forename: Aadil
authors.initials: A
authors.lastname: Khan
authors.forename: James
authors.initials: J
authors.lastname: Good
authors.forename: Shane
authors.initials: S
authors.lastname: Zaidi
authors.forename: Ned G
authors.initials: NG
authors.lastname: Powell
authors.forename: Pascal
authors.initials: P
authors.lastname: Meier
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Garrett
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects*; D016195:G2 Phase / Q000187:drug effects* / Q000235:genetics; D006367:HeLa Cells; D006657:Histones / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008853:Microscopy / Q000379:methods; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D027383:Papillomaviridae / Q000145:classification; D011494:Protein Kinases / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D059008:Time-Lapse Imaging / Q000379:methods; D014410:Tumor Stem Cell Assay / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; D006657:Histones; D007546:Isoquinolines; D011719:Pyrazines; D011838:Radiation-Sensitizing Agents; C547874:SAR 020106; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse