DNA damage induced by boron neutron capture therapy is partially repaired by DNA ligase IV

Boron neutron capture therapy (BNCT) is a particle radiation therapy that involves the use of a thermal or epithermal neutron beam in combination with a boron (B-10)-containing compound that specifically accumulates in tumor. B-10 captures neutrons and the resultant fission reaction produces an alpha (He-4) particle and a recoiled lithium nucleus (Li-7). These particles have the characteristics of high linear energy transfer (LET) radiation and therefore have marked biological effects. High-LET radiation is a potent inducer of DNA damage, specifically of DNA double-strand breaks (DSBs). The aim of the present study was to clarify the role of DNA ligase IV, a key player in the non-homologous end-joining repair pathway, in the repair of BNCT-induced DSBs. We analyzed the cellular sensitivity of the mouse embryonic fibroblast cell lines Lig4-/- p53-/- and Lig4+/+ p53-/- to irradiation using a thermal neutron beam in the presence or absence of B-10-para-boronophenylalanine (BPA). The Lig4-/- p53-/- cell line had a higher sensitivity than the Lig4+/+ p53-/-cell line to irradiation with the beam alone or the beam in combination with BPA. In BNCT (with BPA), both cell lines exhibited a reduction of the 50 % survival dose (D (50)) by a factor of 1.4 compared with gamma-ray and neutron mixed beam (without BPA). Although it was found that B-10 uptake was higher in the Lig4+/+ p53-/- than in the Lig4-/- p53-/- cell line, the latter showed higher sensitivity than the former, even when compared at an equivalent B-10 concentration. These results indicate that BNCT-induced DNA damage is partially repaired using DNA ligase IV.