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Oral presentation

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*

no journal, , 

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.

Oral presentation

Direct action is the key to understand the high biological effects caused by particle beams

Hirayama, Ryoichi*; Matsumoto, Yoshitaka*; Uzawa, Akiko*; Takase, Nobuhiro*; Tsuruoka, Chizuru*; Wada, Mami*; Noguchi, Miho; Kase, Yuki*; Matsufuji, Naruhiro*; Ito, Atsushi*; et al.

no journal, , 

The contribution of indirect action mediated by OH radicals in cell killing can be estimated from the maximum degree of protection by dimethylsulfoxide (DMSO), which suppresses indirect action of radiation without affecting direct action. Exponentially growing Chinese hamster ovary cells under oxic and hypoxic conditions were exposed to X-rays and iron ions having a dose-averaged LET at 200 keV/micrometer in the presence or absence of DMSO, and the cell survival was determined using the colony formation assay. The contributions of indirect action of 76% and 50% were found for X-rays under oxic and hypoxic conditions, respectively. In contrast, the contributions of indirect action for iron ions were estimated to be 42% and 32%. The RBE values were 2.8 for oxic and 5.3 for hypoxic, and the OER values were 2.8 for X-rays and 1.5 for iron ions. When the RBE and OER were estimated separately for direct action (RBE(D) and OER(D)) and indirect action (RBE(I) and OER(I)); the RBE(D) was larger than RBE(I) under both normal and low oxygen concentrations. The OER(D) values for both X-rays and iron ions were lower than that for OER(I). Thus, direct action of radiation gives a remarkably higher RBE and lower OER for cell killing than indirect action. It is possible that particle beams may be highly effective in treating cancer if the particle therapy can only use the portion of direct action out of total radiation actions; this would be exemplified by the usage of radioactive 9C-ion beams and boron neutron capture.

Oral presentation

Hydrogen production in radiolysis of the mixture of mordenite and seawater

Kumagai, Yuta; Nagaishi, Ryuji; Kimura, Atsushi; Taguchi, Mitsumasa; Nishihara, Kenji; Yamagishi, Isao; Ogawa, Toru

no journal, , 

For decontamination of radioactive water, zeolite is a suitable adsorbent for radioactive Cs. The management of hydrogen produced by water radiolysis is an important issue of safety. Thus hydrogen production from the mixture of mordenite-type zeolite and water was studied. In particular, we focused on the influence of the incorporation of seawater into the mixture. The hydrogen yield from the mixture decreased monotonically as the weight fraction of seawater was decreased. However, the measured yield was higher than the yield expected from the direct radiolysis of water in the mixture. Moreover the hydrogen yield was not so effectively decreased by the dilution of seawater in the mixture as in seawater alone. Therefore the additional formation of hydrogen should be considered in the evaluation of hydrogen production from radiolysis of the mixture of mordnite and water.

Oral presentation

Near edge X-ray absorption spectroscopy of DNA damage induced by soft X-rays

Fujii, Kentaro; Yokoya, Akinari

no journal, , 

We have investigated the change of the spectra of the near edge X-ray absorption fine structure (NEXAFS) of DNA exposed to monochromatic soft X-rays. We used calf thymus DNA thin films as samples and observed N K-shell and O K-shell NEXAFS spectral changes. The typical monochromatic soft X-ray energies used for the irradiation (380, 435, 560, and 760eV) were obtained from SPring-8, BL23SU. The observed spectra show the initiation of the new products and the dissociation of molecular structure of the DNA by the irradiation. By comparing the spectral changes in NEXAFS with the yields of base lesions and strand breaks, we will discuss the molecular structure of DNA damage site and the site-selectivity of damage induction in DNA by soft X-rays.

Oral presentation

Significance of the repair synthesis in determining the biological consequences of clustered DNA damage

Shikazono, Naoya; Noguchi, Miho; Urushibara, Ayumi; O'Neill, P.*; Yokoya, Akinari

no journal, , 

no abstracts in English

Oral presentation

EPR study of unpaired electron species in DNA film induced by nitrogen and oxygen K-shell photoabsorption

Oka, Toshitaka; Yokoya, Akinari; Fujii, Kentaro

no journal, , 

no abstracts in English

Oral presentation

Order effect of base excision processes to repair clustered DNA damage

Yokoya, Akinari; Shiraishi, Iyo; Shikazono, Naoya

no journal, , 

In the present study, we investigate how the initial enzymatic repair affects the activity of the latter repair enzyme. Plasmid DNA (pUC18) irradiated with C$$^{6+}$$ ion is treated with two base excision repair enzymes, Nth and Fpg, which convert pyrimidine and purine lesions to a SSB. The enzymatic activities are quantified by measuring the conformational changes of the plasmid using agarose gel electrophoresis. Obtained results show that the amount of enzymatically induced SSB is slightly (about 5%) less in DNA sample treated with Nth first and then Fpg than that in the sample treated with Fpg first and then Nth, or with both enzymes simultaneously. The repairability of clustered damage induced by high-LET ions will be discussed.

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