Histological and biochemical analysis of DNA damage after BNCT in rat model |
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| Affiliation: | 1. Division of Genome Stability Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan;2. Nazarbayev University, Kazakhstan;3. Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Japan;4. Department of Radiation Oncology, Juntendo University, Faculty of Medicine, Japan;5. Cancer Intelligence Care Systems, Inc., Life Sciences Center, Japan;6. Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan;7. Department of Radiation Oncology, National Cancer Center Hospital, Japan;1. Universidad Favaloro, FICEN, Av. Belgrano 1723 (1093), C.A.B.A., Buenos Aires, Argentina;2. CONICET, Av. Rivadavia 1917 (1033), C.A.B.A., Córdoba, Argentina;3. Comisión Nacional de Energía Atómica (CNEA), Av. Gral Paz 1499 (1650), Buenos Aires, Argentina;1. Nuclear Science and Technology Development Center, Hsinchu, Taiwan;2. Institute of Nuclear Engineering and Science, National Tsing Hua University, Hsinchu, Taiwan;1. School of Allied Health Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, Japan;2. Faculty of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan;3. Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki, Japan;4. Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan;1. Kyoto University Research Reactor Institute, Asashironishi 2-1010, Kumatori-cho, Sennan-gun, Osaka 590-0494, Japan;1. Department of Clinic-Surgical Sciences, Experimental Surgery Laboratory, University of Pavia, Italy;2. IGM-CNR and Department of Biology and Biotechnologies “L. Spallanzani”, University of Pavia, Italy;3. Department of Physics, University of Pavia, Italy;4. INFN (National Institute of Nuclear Physics) Section of Pavia, Italy;5. IRCCS S. Matteo Hospital, Pavia, Italy;6. Comisión Nacional de Energía Atómica (CNEA), Buenos Aires, Argentina;7. CONICET, Argentina |
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| Abstract: | To understand the mechanism of tumor cell death induced by boron neutron capture therapy (BNCT) and to optimize BNCT condition, we used rat tumor graft models and histological and biochemical analyses were carried out focusing on DNA damage response. Rat lymphosarcoma cells were grafted subcutaneously into male Wister rats. The rats with developed tumors were then treated with neutron beam irradiation 45 min after injection of 330 mg/kg bodyweight boronophenylalanine (10BPA) (+BPA) or saline control (–BPA). BNCT was carried out in the National Nuclear Center of the Republic of Kazakhstan (neutron flux: 1×109 nvt/s, fluence: 6×1011 nvt) with the presence of background γ-irradiation of 33 Gy. 6 and 20 h after BNCT treatment, tumors were resected, fixed and subjected to immunohistochemistry and biochemical analyses. Immunostaining of nuclei showed that double strand break (DSB) marker gamma H2AX staining was high in 20 h/+BPA sample but not in 20 h/–BPA samples. Poly(ADP-ribose), DSB and single strand break markers of DNA, also demonstrated this tendency. These two markers were observed at low levels in unirradiated tissues or 6 h after BNCT either under −BPA and +BPA conditions. HMGB1 level increased in 6 h/+BPA but not in 6 h/−BPA or 20 h/+BPA samples. The persistent staining of γH2AX and poly(ADP-ribose) in +BPA group suggests accumulated DSB damage after BNCT. The early HMGB1 upregulation and γH2AX and poly(ADP-ribose) observed later might be the markers for monitoring the DNA damage induced by BNCT. |
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| Keywords: | BNCT DNA damage response BPA γH2AX PAR HMGB1 |
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