title: Small-molecule drugs mimicking DNA damage: a new strategy for sensitizing tumors to radiotherapy.
abstract: OBJECTIVE
  Enhanced DNA repair activity is often associated with tumor resistance to radiotherapy. We hypothesized that inhibiting DNA damage repair would sensitize tumors to radiation-induced DNA damage.
  
  
  METHODS
  A novel strategy for inhibiting DNA repair was tested. We designed small DNA molecules that mimic DNA double-strand breaks (called Dbait) and act by disorganizing damage signaling and DNA repair. We analyzed the effects of Dbait in cultured cells and on xenografted tumors growth and performed preliminary studies of their mechanism(s) of action.
  
  
  RESULTS
  The selected Dbait molecules activate H2AX phosphorylation in cell culture and in xenografted tumors. In vitro, this activation correlates with the reduction of Nijmegen breakage syndrome 1 and p53-binding protein 1 repair foci formation after irradiation. Cells are sensitized to irradiation and do not efficiently repair DNA damage. In vivo, Dbait induces regression of radioresistant head and neck squamous cell carcinoma (Hep2) and melanoma (SK28 and LU1205) tumors. The combination of Dbait32Hc treatment and fractionated radiotherapy significantly enhanced the therapeutic effect. Tumor growth control by Dbait molecules depended directly on the dose and was observed with various irradiation protocols. The induction of H2AX phosphorylation in tumors treated with Dbait suggests that it acts in vivo through the induction of "false" DNA damage signaling and repair inhibition.
  
  
  CONCLUSIONS
  These data validate the concept of introducing small DNA molecules, which mimic DNA damage, to trigger "false" signaling of DNA damage and impair DNA repair of damaged chromosomes. This new strategy could provide a new method for enhancing radiotherapy efficiency in radioresistant tumors.
authors.affiliation: Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Quanz
authors.forename: Nathalie
authors.initials: N
authors.lastname: Berthault
authors.forename: Christophe
authors.initials: C
authors.lastname: Roulin
authors.forename: Maryline
authors.initials: M
authors.lastname: Roy
authors.forename: Aurélie
authors.initials: A
authors.lastname: Herbette
authors.forename: Céline
authors.initials: C
authors.lastname: Agrario
authors.forename: Christophe
authors.initials: C
authors.lastname: Alberti
authors.forename: Véronique
authors.initials: V
authors.lastname: Josserand
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Coll
authors.forename: Xavier
authors.initials: X
authors.lastname: Sastre-Garau
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Cosset
authors.forename: Lionel
authors.initials: L
authors.lastname: Larue
authors.forename: Jian-Sheng
authors.initials: JS
authors.lastname: Sun
authors.forename: Marie
authors.initials: M
authors.lastname: Dutreix
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000532:radiotherapy*; D010766:Phosphorylation; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; C468783:H2AX protein, human; D006657:Histones; D011838:Radiation-Sensitizing Agents