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Volume 50, Issue 1
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Award Review Articles
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Nobuyuki HAMADA2009 Volume 50 Issue 1 Pages 1-9
Published: 2009
Released on J-STAGE: February 14, 2009
Advance online publication: October 07, 2008JOURNAL FREE ACCESSBiological effectiveness varies with the linear energy transfer (LET) of ionizing radiation. During cancer therapy or long-term interplanetary manned explorations, humans are exposed to high-LET energetic heavy ions that inactivate cells more effectively than low-LET photons like X-rays and γ-rays. Recent biological studies have illustrated that heavy ions overcome tumor radioresistance caused by Bcl-2 overexpression, p53 mutations and intratumor hypoxia, and possess antiangiogenic and antimetastatic potential. Compared with heavy ions alone, the combination with chemical agents (a Bcl-2 inhibitor HA14-1, an anticancer drug docetaxel, and a halogenated pyrimidine analogue 5-iodo-2'-deoxyuridine) or hyperthermia further enhances tumor cell killing. Beer, its certain constituents, or melatonin ameliorate heavy ion-induced damage to normal cells. In addition to effects in cells directly targeted with heavy ions, there is mounting evidence for nontargeted biological effects in cells that have not themselves been directly irradiated. The bystander effect of heavy ions manifests itself as the loss of clonogenic potential, a transient apoptotic response, delayed p53 phosphorylation, alterations in gene expression profiles, and the elevated frequency of gene mutations, micronuclei and chromosome aberrations, which arise in nonirradiated cells having received signals from irradiated cells. Proposed mediating mechanisms involve gap junctional intercellular communication, reactive oxygen species and nitric oxide. This paper reviews briefly the current knowledge of the biological effects of heavy-ion irradiation with a focus on recent findings regarding its potential benefits for therapeutic use as well as on the bystander effect.View full abstractDownload PDF (254K) -
Megumi TOYOSHIMA2009 Volume 50 Issue 1 Pages 11-17
Published: 2009
Released on J-STAGE: February 14, 2009
JOURNAL FREE ACCESSIonizing radiation activates a series of DNA damage response, cell cycle checkpoints to arrest cells at G1/S, S and G2/M, DNA repair, and apoptosis. The DNA damage response is thought to be the major determinant of cellular radiosensitivity and thought to operate in all higher eukaryotic cells. However, the radiosensitivity is known to differ considerably during ontogeny of mammals and early embryos of mouse for example are much more sensitive to radiation than adults. We have focused on the radiation-induced damage response during pre-implantation stage of mouse embryo. Our study demonstrates a hierarchy of damage responses to assure the genomic integrity in early embryonic development. In the sperm-irradiated zygotes, p53 dependent S-phase checkpoint functions to suppress erroneous replication of damaged DNA. The transcription-dependent function is not required and the DNA-binging domain of the protein is essential for this p53 dependent S-phase checkpoint. p21 mediated cleavage arrest comes next during early embryogenesis to prevent delayed chromosome damage at morula/ blastocyst stages. Apoptosis operates even later only in the cells of ICM at the blastocyst stage to eliminate deleterious cells. Thus, early development of sperm-irradiated embryos is protected at least by three mechanisms regulated by p53 and by p21.View full abstractDownload PDF (226K)
Reviews
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Shin-Ichiro YONEKURA, Nobuya NAKAMURA, Shuji YONEI, Qiu-Mei ZHANG-AKIY ...2009 Volume 50 Issue 1 Pages 19-26
Published: 2009
Released on J-STAGE: February 14, 2009
Advance online publication: November 06, 2008JOURNAL FREE ACCESSBase moieties in DNA are spontaneously threatened by naturally occurring chemical reactions such as deamination, hydrolysis and oxidation. These DNA modifications have been considered to be major causes of cell death, mutations and cancer induction in organisms. Organisms have developed the DNA base excision repair pathway as a defense mechanism to protect them from these threats. DNA glycosylases, the key enzyme in the base excision repair pathway, are highly conserved in evolution. Uracil constantly occurs in DNA. Uracil in DNA arises by spontaneous deamination of cytosine to generate pro-mutagenic U:G mispairs. Uracil in DNA is also produced by the incorporation of dUMP during DNA replication. Uracil-DNA glycosylase (UNG) acts as a major repair enzyme that protects DNA from the deleterious consequences of uracil. The first UNG activity was discovered in E. coli in 1974. This was also the first discovery of base excision repair. The sequence encoded by the ung gene demonstrates that the E. coli UNG is highly conserved in viruses, bacteria, archaea, yeast, mice and humans. In this review, we will focus on central and recent findings on the generation, biological consequences and repair mechanisms of uracil in DNA and on the biological significance of uracil-DNA glycosylase.View full abstractDownload PDF (365K) -
Naoya SHIKAZONO, Miho NOGUCHI, Kentaro FUJII, Ayumi URUSHIBARA, Akinar ...2009 Volume 50 Issue 1 Pages 27-36
Published: 2009
Released on J-STAGE: February 14, 2009
JOURNAL FREE ACCESSAfter living cells are exposed to ionizing radiation, a variety of chemical modifications of DNA are induced either directly by ionization of DNA or indirectly through interactions with water-derived radicals. The DNA lesions include single strand breaks (SSB), base lesions, sugar damage, and apurinic/apyrimidinic sites (AP sites). Clustered DNA damage, which is defined as two or more of such lesions within one to two helical turns of DNA induced by a single radiation track, is considered to be a unique feature of ionizing radiation. A double strand break (DSB) is a type of clustered DNA damage, in which single strand breaks are formed on opposite strands in close proximity. Formation and repair of DSBs have been studied in great detail over the years as they have been linked to important biological endpoints, such as cell death, loss of genetic material, chromosome aberration. Although non-DSB clustered DNA damage has received less attention, there is growing evidence of its biological significance. This review focuses on the current understanding of (1) the yield of non-DSB clustered damage induced by ionizing radiation (2) the processing, and (3) biological consequences of non-DSB clustered DNA damage.View full abstractDownload PDF (304K) -
Eiichiro MORI, Akihisa TAKAHASHI, Nobuhiro YAMAKAWA, Tadaaki KIRITA, T ...2009 Volume 50 Issue 1 Pages 37-42
Published: 2009
Released on J-STAGE: February 14, 2009
Advance online publication: October 29, 2008JOURNAL FREE ACCESSConventional clinical treatments with X-rays provide an effective modality for widely various human cancers, however, therapeutic results are sometimes poor. Many mutations have been reported to be in the p53 gene in advanced human cancers. The p53 plays a pivotal role in the pathway which controls apoptosis, cell growth and cell proliferation, and mutations or deletions in the p53 gene lead to resistance to cancer therapy. The involvement of the p53 gene in determining the sensitivity of many cell types toward low linear energy transfer (LET) radiation is now well established. In contrast to low LET radiation, high LET radiation has several potential advantages over X-rays, one of which is the fact that its effects may be independent of cellular p53 gene status. It is conceivable that effective future therapeutic strategies may be designed on the basis of genetic and biochemical events involved in cell death. Therefore, the accurate characterization and quantification of the mode of cell death, such as apoptosis and necrosis, has become increasingly important for the further understanding of the biological effectiveness of high LET radiation. This review discusses the mechanisms of p53-independent apoptosis by high LET radiation.View full abstractDownload PDF (308K)
Regular Papers
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Can DEMİREL, Sevil KILÇIKSIZ, Ozlem Izci AY, Serkan G&Uu ...2009 Volume 50 Issue 1 Pages 43-50
Published: 2009
Released on J-STAGE: February 14, 2009
JOURNAL FREE ACCESSThe aim of this study is to evaluate the potential radioprotective effects of N-acetylcysteine (NAC) against genotoxicity and cytotoxicity. The effect of WR-2721, as a representative of clinically used radioprotector, was compared with that of NAC, using the chromosomal aberration (CA) and micronucleus (MN) test systems in the irradiated rat's femoral bone marrow cells. We also investigated the mitotic index (MI), and the ratio of polychromatic erythrocytes (PCEs) to normochromatic erythrocytes (NCEs). The rats (n = 16) were divided randomly and equally into four groups: Control (C), Radiation (R), R+NAC (received irradiation and 1000 mg/kg NAC) and R+WR-2721 (received irradiation and 200 mg/kg WR-2721) rats. All the irradiated groups received whole-body gamma irradiation as a single dose of 6 Gy. Group R showed higher CA and MN formation when compared to C. Group R showed higher frequency of MN formation when compared to both R+NAC and R+WR-2721. The mean MI and PCE/NCE ratios were lower in Group R when compared to those of Group C. The mean MI and PCE/NCE ratios of both R+NAC and R+WR-2721 groups were lower when compared to those of Group C. The MI in Group R was lower when compared to that of both R+NAC and R+WR-2721 groups. In this study, the results give clues about the beneficial effects of NAC against radiation-induced genotoxicity and cytotoxicity in rat bone marrow and its effect may be comparable to that observed for WR-2721.View full abstractDownload PDF (431K) -
Shinji KAWABATA, Shin-Ichi MIYATAKE, Toshihiko KUROIWA, Kunio YOKOYAMA ...2009 Volume 50 Issue 1 Pages 51-60
Published: 2009
Released on J-STAGE: February 14, 2009
Advance online publication: October 29, 2008JOURNAL FREE ACCESSWe evaluate the clinical results of a form of tumor selective particle radiation known as boron neutron capture therapy (BNCT) for newly-diagnosed glioblastoma (NDGB) patients, especially in combination with X-ray treatment (XRT). Between 2002 and 2006, we treated 21 patients of NDGB with BNCT utilizing sodium borocaptate and boronophenylalanine simultaneously. The first 10 were treated with only BNCT (protocol 1), and the last 11 were treated with BNCT followed by XRT of 20 to 30 Gy (protocol 2) to reduce the possibility of local tumor recurrence. No chemotherapy was applied until tumor progression was observed. The patients treated with BNCT (protocol 1 plus 2) showed a significant survival prolongation compared with the institutional historical controls. BNCT also showed favorable results in correspondence with the RTOG- and EORTC-RPA subclasses. The median survival time (MST) was 15.6 months for protocols 1 and 2 together. For protocol 2, the MST was 23.5 months. The main causes of death were cerebrospinal fluid dissemination as well as local recurrence. Our modified BNCT protocol showed favorable results of patients with NDGB not only for those with good prognoses but also for those with poor prognoses.View full abstractDownload PDF (654K) -
Ana Lucia FACHIN, Stephano Spano MELLO, Paula SANDRIN-GARCIA, Cristina ...2009 Volume 50 Issue 1 Pages 61-71
Published: 2009
Released on J-STAGE: February 14, 2009
JOURNAL FREE ACCESSIonizing radiation (IR) imposes risks to human health and the environment. IR at low doses and low dose rates has the potency to initiate carcinogenesis. Genotoxic environmental agents such as IR trigger a cascade of signal transduction pathways for cellular protection. In this study, using cDNA microarray technique, we monitored the gene expression profiles in lymphocytes derived from radiation-exposed individuals (radiation workers). Physical dosimetry records on these patients indicated that the absorbed dose ranged from 0.696 to 39.088 mSv. Gene expression analysis revealed statistically significant transcriptional changes in a total of 78 genes (21 up-regulated and 57 down-regulated) involved in several biological processes such as ubiquitin cycle (UHRF2 and PIAS1), DNA repair (LIG3, XPA, ERCC5, RAD52, DCLRE1C), cell cycle regulation/proliferation (RHOA, CABLES2, TGFB2, IL16), and stress response (GSTP1, PPP2R5A, DUSP22). Some of the genes that showed altered expression profiles in this study can be used as biomarkers for monitoring the chronic low level exposure in humans. Additionally, alterations in gene expression patterns observed in chronically exposed radiation workers reinforces the need for defining the effective radiation dose that causes immediate genetic damage as well as the long-term effects on genomic instability, including cancer.View full abstractDownload PDF (656K) -
Masaki MIYAZAWA, Takamasa ISHII, Kayo YASUDA, Setsuko NODA, Hiromi ONO ...2009 Volume 50 Issue 1 Pages 73-83
Published: 2009
Released on J-STAGE: February 14, 2009
JOURNAL FREE ACCESSMuch attention has been focused on the mitochondrial superoxide anion (O2-), which is also a critical free radial produced by ionizing radiation. The specific role of the mitochondrial O2- on physiological aging in mammals is still unclear despite wide-spread evidence that oxidative stress is involved in aging and age-related diseases. The major endogenous source of O2- is generated as a byproduct of energy metabolism from mitochondria. In order to better understand how O2-relates to metazoan aging, we have comprehensively examined age-related changes in the levels of oxidative damage, mitochondrial O2- production, mitochondrial antioxidant enzyme activity and apoptosis induction in key organs of an inbred mouse strain (C57BL/6J). Oxidative damage accumulated and excess apoptosis occurred in the brain, oculus and kidney with aging, but comparatively little occurred in the heart and muscle. These rates are correlated with O2- levels. Mitochondrial O2- production levels increased with aging in the brain, oculus and kidney, and did not significantly increased in the heart and muscle. In contrast to O2- production, mitochondrial SOD activities increased in heart and muscle, and remained unchanged in the brain, oculus and kidney with aging. These results suggest that O2- production has high organ specificity, and oxidative damage by O2- from mitochondria mediated apoptosis can lead to organ atrophy and physiological dysfunction. In addition, O2- from mitochondria plays a core role in physiological aging.
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Short Communication
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Satoru ENDO, Kenichi TANAKA, Kazuo FUJIKAWA, Tetsuo HORIGUCHI, Tetsuo ...2009 Volume 50 Issue 1 Pages 83-87
Published: 2009
Released on J-STAGE: February 14, 2009
JOURNAL FREE ACCESSMicrodosimetry study has been carried out at the education and research mini-reactor of Kinki University (UTR-KINKI) using a tissue equivalent gas proportional counter (TEPC). The microdosimetric single event spectra for 0.5, 1, 2, 3 and 5 μm site sizes were obtained in the lineal energy range from 1 to 1000 keV/μm. Neutron and gamma-ray fractional doses were estimated from the single event spectra. The neutron dose fraction was varied from 35 to 55% for 0.5 to 5 μm site size. The averaged lineal energy, yD, for each site size was likewise estimated and found to be dependent on the site size. The averaged lineal energy for neutron was slightly larger than that of the fission neutrons from 252Cf, and the averaged lineal energy for gamma-ray had similar site-size-dependence of 25 keV gamma-rays and 250 kV X-rays. Relative biological effectiveness was found to be 4.1 ± 0.13 for UTR-KINKI using Tilikidis's 2 Gy-response function. The estimated RBE for UTR-KINKI neutrons is quite close to the previous biological experimental value of 4.3 ± 0.6 for micronucleated cells in gill cell of Medaka and 4.6 ± 0.5 for induction of lymphocyte apoptosis in the thymus of ICR mice.View full abstractDownload PDF (253K)
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