Small-molecule drugs mimicking DNA damage: a new strategy for sensitizing tumors to radiotherapy.
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.
Quanz
Maria
M
Institut Curie, Centre de Recherche, Orsay, France.
Berthault
Nathalie
N
Roulin
Christophe
C
Roy
Maryline
M
Herbette
Aurélie
A
Agrario
Céline
C
Alberti
Christophe
C
Josserand
Véronique
V
Coll
Jean-Luc
JL
Sastre-Garau
Xavier
X
Cosset
Jean-Marc
JM
Larue
Lionel
L
Sun
Jian-Sheng
JS
Dutreix
Marie
M
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
D016207:Cytokines; C468783:H2AX protein, human; D006657:Histones; D011838:Radiation-Sensitizing Agents