Radiosensitization by inhibition of homologous recombination repair combined with high LET heavy ion irradiation

Okayasu, Ryuichi*; Hirakawa, Hirokazu*; Noguchi, Miho; Yu, D.*; Takahashi, Momoko; Hirayama, Ryoichi*; Fujimori, Akira*

17AAG, an Hsp90 inhibitor was shown to radiosensitize certain human tumor cells exposed to X-rays, while this sensitization was not clearly observed in normal human cells. The mechanism of this was suggested to come from inhibition of DNA double strand break (DSB) repair, particularly impairment of homologous recombination repair (HRR) pathway by this drug (Noguchi et al 2006). Key proteins associated with HRR seem to be affected by this inhibitor. To our surprise, tumor radiosensitization with 17AAG was also observed in cells exposed to high LET carbon ions (70 kev/um). Independently we also found that knockdown of BRCA2, a key HRR protein significantly radiosensitized human tumor cells. These results indicate that there seem to be a radio-sensitization mechanism associated with the combination of HRR inhibition and high LET radiation, and this may occur particularly in S-phase cells. Furthermore, we also used mouse xenograft model to examine the combined effect of 17AAG and high LET carbon irradiation. For this purpose, SQ5 human lung tumor cells were implanted on the leg of nude mice and the tumor growth was observed in the combined treatment as compared with radiation or drug treatment alone. Our preliminary results indicate that tumor growth was more inhibited in the 17AAG and carbon irradiation than carbon or 17AAG treatment alone. These data suggest that an effective tumor control might be obtained by combining an HRR inhibitor with high LET carbon irradiation.