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Volume 45 (2004)
- Issue 4 Pages 473-
- Issue 3 Pages 351-
- Issue 2 Pages 169-
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Volume 45, Issue 4
Displaying 1-13 of 13 articles from this issue
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Special Award Review Article
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Junya KOBAYASHI2004 Volume 45 Issue 4 Pages 473-478
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSDNA double-strand breaks represent the most potentially serious damage to a genome, and hence, many repair proteins are recruited to DNA damage sites by as yet poorly characterized sensor mechanisms. We clarified that NBS1 physically interacts with γ-H2AX to form nuclear foci at DNA damage sites. The fork-head associated (FHA) and the BRCA1 C-terminal domains (BRCT) of NBS1 are essential for this physical interaction and focus formation of NBS1 in response to DNA damage. The inhibition of this interaction by introduction of anti-γ-H2AX antibody into cells abolishes NBS1 foci formation in response to DNA damage. Consequently, the FHA/BRCT domain is likely to have a crucial role for both binding to histone and for re-localization of the NBS1/hMRE11/hRAD50 complex to the vicinity of DNA damage. Moreover, the foci formation of DNA repair-related proteins containing BRCT domain, such as BRCA1, requires the interaction with γ-H2AX in response to DNA damage. These findings indicate that the physical interaction between γ-H2AX and DNA repair-related proteins is indispensable for the recruitment of these proteins. Further, it was recently reported that the NBS1/hMRE11/hRAD50 complex has a crucial role for both the recruitment of ATM to DNA damage sites and the subsequent activation of ATM. Therefore, both γ-H2AX and the NBS1/hMRE11/hRAD50 complex might function for the initial recognition of DNA damage.
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Review Article
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Loreto B. FERIL, Jr., Takashi KONDO2004 Volume 45 Issue 4 Pages 479-489
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSThe biological effects of low intensity ultrasound (US) in vitro; the mechanisms involved; and the factors that can enhance or inhibit these effects are reviewed. The lowest possible US intensities required to induce cell killing or to produce free radicals were determined. Following sonication in the region of these intensities, the effects of US in combination with either hyperthermia, hypotonia, echo-contrast agents (ECA), CO2, incubation time, high cell density or various agents were examined. The results showed that hyperthermia, hypotonia and microbubbles are good enhancers of the bioeffects, while CO2, incubation time and high cell density are good inhibitors. Cellular membrane damage is pivotal in the events leading to cell death, with the cellular damage-and-repair mechanism as an important determinant of the fate of the damaged cells. The optimal level of apoptosis (with minimal lysis) and optimal gene transfection efficiency were attained using a pulsed low intensity US. In summary, the findings suggest that low intensity US is potentially useful in therapy, while on the other hand, they also call for further investigation of such clinical scenarios as high-grade fever, edema or use of ECA which may lead to the lowering of the threshold for bioeffects with diagnostic US.
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Short Communication
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Anirban KUMAR MITRA, Malini KRISHNA2004 Volume 45 Issue 4 Pages 491-495
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSIn vivo expression of cell survival factors protein kinase C (PKC), nuclear factor κB (NFκB), and extracellular signal-regulated kinase (Erk), which may contribute to the development of radioresistance following radiotherapy, was looked for. Their modulation with natural compounds (curcumin, rutin or nicotinamide) was attempted in mice bearing a serially transplanted fibrosarcoma. Expression of protein kinase C was isoform specific. No translocation of any of the isozymes was noticed following γ-irradiation as has been reported elsewhere. None of the isoforms could be significantly inhibited by the modulators. However, significant inhibition of radiation-induced ERK and NFκB was observed with both curcumin and nicotinamide. Therefore we conclude that use of inhibitors of MAP kinases or NFκB may be a more promising strategy to enhance tumour cell killing or to prevent the development of radioresistance during radiotherapy.
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Regular Papers
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Hiroshi SASAKI2004 Volume 45 Issue 4 Pages 497-508
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSLethal sectoring (LS) is the process for survival in which lethal damage remaining in irradiated cells is eliminated as lethal sector (offspring without reproductive integrity). This process occurs through the postirradiation 1st to 4th divisions with the accompanying appearance of a clonogenic progenitor (clonogen) (clonogenic sectoring: CS). The features of LS or CS and genomic instability (GI) were explored by analyzing the pedigrees of HeLa cells surviving α- (0.45 Gy) or X-irradiation (3 Gy) (20% survival dose). Most (~70%) of the lethal latent damage was eliminated from α-particle survivors through the 1st to 2nd divisions, but it persisted in X-ray survivors until the 2nd generation. Although the frequency of CS was similar to that of LS for α-irradiation, CS was higher than LS for X-irradiation. Nonlethal damage remaining in the clonogens led to an elevated incidence of delayed cell death in their progeny. The mean incidence was higher for α-particle (16.3%) than X-ray survivors (8.3%), indicating the greater potentiality for GI by α-particles. Evidence is available to suggest the intrinsic difference in the mechanisms of GI induction by these two radiations: the association of misrepaired clustered DNA damage (CD) with α-particles and unrepaired PLD with X-rays. A novel phenomenon, "delayed division delay (DDD)" was noticed, though occasionally (~10% per cell), with the progeny during the postirradiation 1st-3rd generations. DDD was much longer in α- (mean: ~11 h) than X-irradiated cells (~4 h). Supposedly DDD was triggered by delayed chromosome breakage. However, a significant shortening of cell-cycle time at the postirradiation 1st generation was recognized with X-ray survivors.
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Kunio SHINOHARA, Hisako NAKANO, Noriyuki MIYAZAKI, Masao TAGO, Ryosuke ...2004 Volume 45 Issue 4 Pages 509-514
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSThe effects of low linear energy transfer (LET) radiation on mammalian cells have been studied at dose-rates as high as 109 Gy/sec delivered as a single 3-nanosecond pulse, and no increase in cytotoxicity was shown compared with delivery at a conventional dose-rate. There have been no observations on the effects of radiation delivered at even higher dose-rates on the picosecond time-scale. Here we examined, for the first time, the effects on cultured mouse L5178Y cells and its radiosensitive XRCC4-deficient mutant M10 cells of sub-picosecond X-rays emitted from laser-produced plasmas at the ultrahigh dose-rate of 1012-10 13 Gy/sec. No increase in the sensitivity to the X-rays was observed compared with γ-rays at a conventional dose-rate. The increase in the sensitivity of L5178Y cells by labeling with 5-iododeoxyuridine was smaller than those irradiated with γ-rays at a conventional dose-rate, while the difference was apparently the reverse in M10 cells. The D10 ratio between L5178Y cells and M10 cells produced by the X-rays at temporally dense ionization was the same as that produced by X(γ)-rays at the conventional dose-rate, while the ratio is greatly reduced in the case of particle radiation. These results suggest that there is no increase in the cytotoxic effects of X-rays at dose-rates as high as 1013 Gy/sec, and that the increased cytotoxicity of particle radiation is not attributable to temporally dense ionization. It is discussed that the mechanism for the induction of radiation damage responsible for cytotoxicity may be slightly modified at ultrahigh dose-rates.
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Toshie OHTA, Mayumi IWAKAWA, Chisa OOHIRA, Shuhei NODA, Yang MINFU, Mi ...2004 Volume 45 Issue 4 Pages 515-519
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSThe multifraction regimens commonly used in conventional clinical radiotherapy are largely based on radiobiological experiments. However, no experimental reports on skin reactions focusing on inter-strain differences have displayed clinical relevance to the fractionated dose schedule. In this study, mice of inbred strains A/J, C57BL/6J, and C3H/HeMs were used to reveal inter-strain difference after multifractionated irradiation. Irradiation was performed daily at graded doses of 30-60 Gy total doses, with 10 fractions of 3-6 Gy. Acute skin reactions following irradiation were scored for 50 days after irradiation. Dividing a dose into a number of fractions obviously spared skin damage in the three strains of mice. No mouse exhibited a skin damage score more than 1.5, while single dose irradiation resulted in skin damage scores up to 3. The three different strains, however, showed varying susceptibility to fractionated irradiation within the range under 1.5. C3H/HeMs did not display any skin reaction after irradiation with 40 Gy total dose, while C57BL/6J and A/J demonstrated various skin reactions. Different latent periods of damage were also observed among the strains after irradiation at each dose.
Our data suggest that genetic factors cause obvious variations in severity of damage and latent period after fractionated irradiation.
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Kanji ISHIZAKI, Yuko HAYASHI, Hideaki NAKAMURA, Yoshihiro YASUI, Kensh ...2004 Volume 45 Issue 4 Pages 521-525
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSHuman fibroblast cells obtained from a normal individual and immortalized by introduction of the hTERT gene were irradiated with 0 to 5 Gy of acute high-dose-rate radiation (1.8 Gy/min) or chronic low-dose-rate radiation (0.3 mGy/min) in the G0 phase, and p53 activation was studied. After high-dose-rate irradiation, a dose-dependent induction of Ser15 phosphorylation was observed, whereas after low-dose-rate irradiation almost none was observed. Then we analyzed the focus formation of phosphorylated histone H2AX protein, which is closely correlated with the induction of double-strand breaks. High-dose-rate radiation induced a significant number of foci in a dose-dependent manner, whereas, low-dose-rate radiation could induce only a few foci even at the highest dose. These results strongly suggest that DNA damage induced by low-dose-rate radiation such as a double-strand break is efficiently repaired during chronic irradiation.
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Vipen BATRA, Vellappan KESAVAN, Kaushal P. MISHRA2004 Volume 45 Issue 4 Pages 527-533
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSThe role of various enzymes in folate dependent one-carbon metabolism, which are involved in mobilizing the folate pool for DNA synthesis and the DNA methylation reaction, was investigated. Male Swiss mice (6 weeks old) were subjected to 2, 5 and 7 Gy total body γ-irradiation. The animals were killed at intervals of 24, 48, 72, 96, 120 and 192 h and the livers were removed. Using a 12000 × g supernatant of 10% tissue homogenate, the activities of dihydrofolate reductase, thymidylate synthase and methylenetetrahydrofolate reductase were determined. The profiles of these folate enzymes were correlated to DNA damage by monitoring p53 protein profile and by comet tail moment analysis. A significant increase in activity of dihydrofolate reductase and thymidylate synthase was observed up to 96 h post-irradiation and the activity subsided thereafter, reaching control value after 192 h. A sharp decline in methylenetetrahydrofolate reductase activity was observed until 192 h after irradiation. Total folates declined by 54% after 96 h following irradiation, and p53 protein concentration in nuclei increased after irradiation, proportionate to radiation dose, and subsided slowly. Thus results indicate a significant drop in total folate levels and rise in p53 protein concentration in the liver after total body γ-irradiation. It may appear that, under radiation stress conditions, levels of enzymes involved in one-carbon metabolism for DNA repair, are modulated up to a certain time interval, in a dose specific manner. It may also appear that the requirements of folate for nucleotide base synthesis seem to be met at the expense of other one-carbon transfer reactions.
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Sadayuki BAN, Chika KONOMI, Mayumi IWAKAWA, Shigeru YAMADA, Tatsuya OH ...2004 Volume 45 Issue 4 Pages 535-541
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSThe in vitro radiation sensitivities of peripheral blood lymphocytes obtained from 48 normal females and 168 female cancer patients were measured with the cytokinesis-blocking micronucleus assay. Cancer patients group had significantly higher mean baseline micronucleus frequency than normal healthy controls. Breast cancer patients were more radiosensitive than normal individuals. Cervical cancer cases were less radiation sensitive than normal subjects. The relative lack of radiation sensitivity in cervical-cancer cases could be due to modification of the radiosensitivity of patients' immune-responsible cells by human papillomaviruses infection. Normal individuals and cancer patients were classified according to their radiation sensitivity which was evaluated with the radiation-induced micronucleus frequencies. Such a classification will be an important initial step to characterize the radiosensitive, radioresistant, or cancer-prone individuals using specific SNP typing.
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Mustafa Vecdi ERTEKIN, Salim Basol TEKIN, Fazli ERDOGAN, Ihsan KARSLiO ...2004 Volume 45 Issue 4 Pages 543-548
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSThere is currently substantial clinical interest in zinc (Zn) as a protective agent against radiation-related normal tissue injury. To further assess this drug's potential, the effect of Zn was studied in rats using a radiation-induced skin injury model. Sprague-Dawley rats were divided into four groups. Group 1 received neither Zn nor irradiation (control group). Group 2 received 30 Gy of gamma irradiation as a single dose to the right hind legs of the rats (RT Group). Groups 3 and 4 received the same irradiation plus 5 mg/kg/day Zn (RT+5 Zn group) or 10 mg/kg/day Zn orally (RT+10 Zn group), respectively. The rats were irradiated using a cobalt-60 teletherapy unit. Acute skin reactions were assessed every three days by two independent radiation oncology experts. At the endpoint of the study, light-microscopic findings were assessed by two independent expert pathology physicians. Clinically and histopathologically, irradiation increased dermatitis when compared with the control group (p < 0.05). The severity of radiodermatitis of the rats in the RT+5 Zn and RT+10 Zn groups was significantly lower than in the RT group (p < 0.05); radiodermatitis was seen earlier in the RT group than in the other groups (p < 0.05). Zn was found to be efficacious in preventing epidermal atrophy, dermal degeneration such as edema and collagen fiber loss, and hair follicle atrophy. The most protection for radiation dermatitis was observed in the RT+10 Zn group. It would be worthwhile studying the effects of zinc sulphate supplements in radiation-treated cancer patients, in the hope of reducing radiation-induced toxicity.
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K. B Hari KUMAR, M. C Sabu, P. S LIMA, Ramadasan KUTTAN2004 Volume 45 Issue 4 Pages 549-555
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSThe radio protective effect of the fruit pulp of Emblica officinalis Gaertn (Emblica) was studied in adult Swiss albino mice. Mice were treated with 2.5g/kg b.wt of Emblica for 10 consecutive days before irradiation and exposed to a single dose of 700 rads (7Gy) of radiation after the last dose. One group was given Emblica continuously for another 15 days after irradiation. Changes in the total leukocyte count, bone marrow viability and hemoglobin were studied after whole body irradiation. Administration of Emblica significantly increased these levels, which were lowered by irradiation. Animals were sacrificed at various time points after irradiation and the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX), and glutathione-S-transferase (GST), and levels of glutathione were assayed in the blood. The damage to the cell membrane after whole body irradiation was studied by measuring the tissue lipid peroxides levels. Administration of Emblica significantly enhanced the activity of the various antioxidant enzymes and GST as well as glutathione system in the blood. Treatment with Emblica also lowered the elevated levels of lipid peroxides in the serum. The data clearly indicated that the extract significantly reduced the bioeffects of radiation. Emblica extract may be useful in reducing the side effects produced during therapeutic radiation.
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Seyed JALAL HOSSEINIMEHR, Osamu INANAMI, Taku HAMASU, Momoko TAKAHASHI ...2004 Volume 45 Issue 4 Pages 557-561
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSWe investigated the effect of SCF, a c-kit ligand, on the radiosensitivity of HL60 cells. X-ray-induced apoptosis in HL60 cells was significantly lower in the presence of SCF than in the absence of SCF. This attenuation of X-ray-induced apoptosis by SCF was abolished by PD98059 (an ERK inhibitor), but not by wortmannin (a PI3-K inhibitor) or GF109203X (a PKC inhibitor). The expression of phospho-ERK1/2 (active form) and the ERK1/2-regulated expression of survivin were found to increase in cells treated with X irradiation and SCF. However, X irradiation alone induced down-regulation of the expression of phospho-ERK1/2. Our findings suggest that activation of c-kit by SCF confers radioresistance through up-regulation of ERK-dependent survivin expression in HL60 cells.
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Nobuhiko TAKAI, Xue-Zhi SUN, Koichi ANDO, Kenichi MISHIMA, Sentaro TAK ...2004 Volume 45 Issue 4 Pages 563-569
Published: 2004
Released on J-STAGE: December 28, 2004
JOURNAL FREE ACCESSThe relationship between an impairment of spatial navigation and an incidence of ectopic neurons in the dorsal hippocampus was investigated in adult rats that were prenatally exposed to X-ray irradiation. Adult rats which had received 1.5 Gy X-rays at embryonic day 15 (E15) showed significant learning disability in the water-maze task. According to the mean value of the swimming time, we categorized the irradiated adult rats into the following three groups: slightly damaged group, mildly damaged group and severely damaged group. No significant difference in the brain weight was found between the three categorized groups. Ectopic neurons appearing at abnormal places were prominently observed in the dorsal hippocampus of the severely damaged group with a remarkable learning disturbance, while no ectopia in the hippocampus was observed in the slightly damaged group. This may suggest that the cognitive dysfunction induced by prenatal exposure to X-ray irradiation may be, at least in part, attributable to ectopic neurons of the hippocampus.
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