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Sample records for radiation-induced cell kill

  1. Potentiation of radiation-induced cell kill by synthetic metalloporphyrins

    International Nuclear Information System (INIS)

    O'Hara, J.A.; Douple, E.B.; Abrams, M.J.; Picker, D.J.; Giandomenico, C.M.; Vollano, J.F.

    1989-01-01

    The effects of the combination of several meso-substituted, water soluble metalloporphyrins with ionizing radiation on hypoxic and oxic monolayers of Chinese hamster fibroblast (V79N) cells were studied. The metalloporphyrins tested included a series of cationic metalloporphyrins complexed with Co(III), Zn(II), Fe(III), Cu(II), Pd(II) or Mn(III) and a series of anionic porphyrins chelated with Co(III), Fe(III), Cu(II), Rh(III), Mn(III) or Sn(IV). Both cationic and anionic free porphyrins were also tested. Cationic ligands were tetrakis(4N-methylpyridyl)porphine [TMPyP], tetrakis(4N-trimethylamino phenyl)porphine [TMAP], tetrakis(4N-butylpyridyl)porphine [TBPyP] and tetrakis(3N-methylpyridyl)porphine [3TMPyP]. Anionic ligands tested were tetrakis(4-sulfonato phenyl)porphine [TPPS], tetrakis(biphenyl)porphine sulfonate [TBPS] and tetrakis(4-carboxyphenyl)porphine [TCPP]. SER calculated from survival curves and SFR from one radiation dose were used to assess the relative effectiveness of this class as non-cytotoxic hypoxic and oxic cell-kill potentiators. Comparisons were made at 100 microM, which was essentially non-toxic (greater than 70% survival) for all porphyrins tested except for Co[TMPyP] (approximately 50% survival after 1 hour at 37 degrees C under oxic conditions). The greatest effects on radiation-induced cell kill were achieved with Co[TPPS] and Co[TMPyP] with SER values of 2.3 and 2.4 respectively. Porphyrin analogs with no coordinated metal were found to be less active than the same compound with metal. The overall charge on the molecule did not systematically relate to the biological activity of the compounds tested

  2. Reduction of radiation-induced cell cycle blocks by caffeine does not necessarily lead to increased cell killing

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    Musk, S.R. (Institute of Cancer Research, Sutton, Surrey (England))

    1991-03-01

    The effect of caffeine upon the radiosensitivities of three human tumor lines was examined and correlated with its action upon the radiation-induced S-phase and G2-phase blocks. Caffeine was found to reduce at least partially the S-phase and G2-phase blocks in all the cell lines examined but potentiated cytotoxicity in only one of the three tumor lines. That reductions have been demonstrated to occur in the absence of increased cell killing provides supporting evidence for the hypothesis that reductions may not be causal in those cases when potentiation of radiation-induced cytotoxicity is observed in the presence of caffeine.

  3. The probabilities of one- and multi-track events for modeling radiation-induced cell kill

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    Schneider, Uwe; Vasi, Fabiano; Besserer, Juergen [University of Zuerich, Department of Physics, Science Faculty, Zurich (Switzerland); Radiotherapy Hirslanden, Zurich (Switzerland)

    2017-08-15

    In view of the clinical importance of hypofractionated radiotherapy, track models which are based on multi-hit events are currently reinvestigated. These models are often criticized, because it is believed that the probability of multi-track hits is negligible. In this work, the probabilities for one- and multi-track events are determined for different biological targets. The obtained probabilities can be used with nano-dosimetric cluster size distributions to obtain the parameters of track models. We quantitatively determined the probabilities for one- and multi-track events for 100, 500 and 1000 keV electrons, respectively. It is assumed that the single tracks are statistically independent and follow a Poisson distribution. Three different biological targets were investigated: (1) a DNA strand (2 nm scale); (2) two adjacent chromatin fibers (60 nm); and (3) fiber loops (300 nm). It was shown that the probabilities for one- and multi-track events are increasing with energy, size of the sensitive target structure, and dose. For a 2 x 2 x 2 nm{sup 3} target, one-track events are around 10,000 times more frequent than multi-track events. If the size of the sensitive structure is increased to 100-300 nm, the probabilities for one- and multi-track events are of the same order of magnitude. It was shown that target theories can play a role for describing radiation-induced cell death if the targets are of the size of two adjacent chromatin fibers or fiber loops. The obtained probabilities can be used together with the nano-dosimetric cluster size distributions to determine model parameters for target theories. (orig.)

  4. Radiation related basic cancer research : research for radiation induced tumor cell killing

    International Nuclear Information System (INIS)

    Lee, Seung Hoon; Hong, Seok Il; Cho, Kyung Ja; Kim, Byung Gi; Lee, Kee Ho; Nam, Myung Jin

    1999-04-01

    The radioresistant clones was established from human U251 glioblastoma cell line through intermittently exposed to 3 Gy gamma-radiation for six months. Treatment of SNU-16 cells with various doses of radiation, TNF alpha and PMA resulted in a decrease in cell viability. The results prove that cell death of SNU16 is a apoptosis mediated by caspase-3. We have examined the expression of bcl-2 and c-myc in cervical cancer specimens and cervical intraepithelial neoplasia (CIN) to determine the role of coexpression of bcl-3 and c-myc during progression into cervical cancer. The frequent alterations in FHIT expression in many cervical carcinomas and their cell lines suggest that FHIT gene alterations are pla a role in cervical tumorigenesis. According to these correlation between the viability and apoptosis of RD cells, the proper range of the dosage for the investigation of differentiation potency in RD cells was assessed as 1 to 3Gy

  5. Radiation related basic cancer research : research for radiation induced tumor cell killing

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    Lee, Seung Hoon; Hong, Seok Il; Cho, Kyung Ja; Kim, Byung Gi; Lee, Kee Ho; Nam, Myung Jin

    1999-04-01

    The radioresistant clones was established from human U251 glioblastoma cell line through intermittently exposed to 3 Gy gamma-radiation for six months. Treatment of SNU-16 cells with various doses of radiation, TNF alpha and PMA resulted in a decrease in cell viability. The results prove that cell death of SNU16 is a apoptosis mediated by caspase-3. We have examined the expression of bcl-2 and c-myc in cervical cancer specimens and cervical intraepithelial neoplasia (CIN) to determine the role of coexpression of bcl-3 and c-myc during progression into cervical cancer. The frequent alterations in FHIT expression in many cervical carcinomas and their cell lines suggest that FHIT gene alterations are pla a role in cervical tumorigenesis. According to these correlation between the viability and apoptosis of RD cells, the proper range of the dosage for the investigation of differentiation potency in RD cells was assessed as 1 to 3Gy.

  6. Radiation-induced chromosome aberrations and cell killing in normal human fibroblasts and ataxia telangiectasia fibroblasts

    International Nuclear Information System (INIS)

    Kawata, T.; Saito, M.; Uno, T.; Ito, H.; Shigematsu, N.

    2003-01-01

    Full text: When cells are held in a non-dividing state (G0) after irradiation, an enhanced survival can be observed compared to that of immediate plating. A change of survival depending on post irradiation condition is known to be repair of potentially lethal damage (RPLD). The effects of confluent holding recovery (24-h incubation following irradiation) on chromosome aberrations in normal human fibroblasts (AG1522) and ataxia telangiectasia fibroblasts (GM02052C) were examined. A chemical-induced premature chromosome condensation (PCC) technique with fluorescent in situ hybridization (FISH) was applied to study chromosome aberrations in G2 and M-phase. Results from cell survival showed that the capacity for potentially lethal damage repair was normal in AG1522 cells but very little in GM02052C cells. The frequency of chromosome aberrations in AG1522 cells decreased when cells were allowed to repair for 24-h. Especially complex type exchanges were found to decrease markedly at high doses (4Gy and 6Gy). However, the frequency of chromosome aberrations including complex type exchanges showed little decrease in GM02052C cells. Confluent holding can effectively reduce chromosome aberrations, especially complex type exchanges in normal cells

  7. A novel multitarget model of radiation-induced cell killing based on the Gaussian distribution.

    Science.gov (United States)

    Zhao, Lei; Mi, Dong; Sun, Yeqing

    2017-05-07

    The multitarget version of the traditional target theory based on the Poisson distribution is still used to describe the dose-survival curves of cells after ionizing radiation in radiobiology and radiotherapy. However, noting that the usual ionizing radiation damage is the result of two sequential stochastic processes, the probability distribution of the damage number per cell should follow a compound Poisson distribution, like e.g. Neyman's distribution of type A (N. A.). In consideration of that the Gaussian distribution can be considered as the approximation of the N. A. in the case of high flux, a multitarget model based on the Gaussian distribution is proposed to describe the cell inactivation effects in low linear energy transfer (LET) radiation with high dose-rate. Theoretical analysis and experimental data fitting indicate that the present theory is superior to the traditional multitarget model and similar to the Linear - Quadratic (LQ) model in describing the biological effects of low-LET radiation with high dose-rate, and the parameter ratio in the present model can be used as an alternative indicator to reflect the radiation damage and radiosensitivity of the cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Membrane phospholipids and radiation-induced death of mammalian cells

    International Nuclear Information System (INIS)

    Wolters, H.

    1987-01-01

    Radiation-induced cell killing is generally believed to be a consequence of residual DNA damage or damage that is mis-repaired. However, besides this DNA damage, damage to other molecules or structures of the cell may be involved in the killing. Especially membranes have been suggested as a determinant in cellular radiosensitivity. In this thesis experiments are described, dealing with the possible involvement of membranes in radiation-induced killing of mammalian cells. A general treatise of membrane structure is followed by information concerning deleterious effects of radiation on membranes. Consequences of damage to structure and function of membranes are reviewed. Thereafter evidence relating to the possible involvement of membranes in radiation-induced cell killing is presented. (Auth.)

  9. The Impact of the Geometrical Structure of the DNA on Parameters of the Track-Event Theory for Radiation Induced Cell Kill.

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    Uwe Schneider

    Full Text Available When fractionation schemes for hypofractionation and stereotactic body radiotherapy are considered, a reliable cell survival model at high dose is needed for calculating doses of similar biological effectiveness. An alternative to the LQ-model is the track-event theory which is based on the probabilities for one- and two two-track events. A one-track-event (OTE is always represented by at least two simultaneous double strand breaks. A two-track-event (TTE results in one double strand break. Therefore at least two two-track-events on the same or different chromosomes are necessary to produce an event which leads to cell sterilization. It is obvious that the probabilities of OTEs and TTEs must somehow depend on the geometrical structure of the chromatin. In terms of the track-event theory the ratio ε of the probabilities of OTEs and TTEs includes the geometrical dependence and is obtained in this work by simple Monte Carlo simulations.For this work it was assumed that the anchors of loop forming chromatin are most sensitive to radiation induced cell deaths. Therefore two adjacent tetranucleosomes representing the loop anchors were digitized. The probability ratio ε of OTEs and TTEs was factorized into a radiation quality dependent part and a geometrical part: ε = εion ∙ εgeo. εgeo was obtained for two situations, by applying Monte Carlo simulation for DNA on the tetranucleosomes itself and for linker DNA. Low energy electrons were represented by randomly distributed ionizations and high energy electrons by ionizations which were simulated on rays. εion was determined for electrons by using results from nanodosimetric measurements. The calculated ε was compared to the ε obtained from fits of the track event model to 42 sets of experimental human cell survival data.When the two tetranucleosomes are in direct contact and the hits are randomly distributed εgeo and ε are 0.12 and 0.85, respectively. When the hits are simulated on rays

  10. N-acetyl cysteine protects against ionizing radiation-induced DNA damage but not against cell killing in yeast and mammals

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    Reliene, Ramune [Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 (United States); Department of Medicine, Center for Human Nutrition, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 (United States); Pollard, Julianne M. [Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 (United States); Biomedical Physics Interdepartmental Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 (United States); Sobol, Zhanna; Trouiller, Benedicte [Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 (United States); Gatti, Richard A. [Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 (United States); Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 (United States); Schiestl, Robert H., E-mail: rschiestl@mednet.ucla.edu [Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 (United States); Biomedical Physics Interdepartmental Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 (United States); Department of Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 (United States); Department of Environmental Health Sciences, School of Public Health, University of California Los Angeles, Los Angeles, CA 90095 (United States)

    2009-06-01

    Ionizing radiation (IR) induces DNA strand breaks leading to cell death or deleterious genome rearrangements. In the present study, we examined the role of N-acetyl-L-cysteine (NAC), a clinically proven safe agent, for it's ability to protect against {gamma}-ray-induced DNA strand breaks and/or DNA deletions in yeast and mammals. In the yeast Saccharomyces cerevisiae, DNA deletions were scored by reversion to histidine prototrophy. Human lymphoblastoid cells were examined for the frequency of {gamma}-H2AX foci formation, indicative of DNA double strand break formation. DNA strand breaks were also measured in mouse peripheral blood by the alkaline comet assay. In yeast, NAC reduced the frequency of IR-induced DNA deletions. However, NAC did not protect against cell death. NAC also reduced {gamma}-H2AX foci formation in human lymphoblastoid cells but had no protective effect in the colony survival assay. NAC administration via drinking water fully protected against DNA strand breaks in mice whole-body irradiated with 1 Gy but not with 4 Gy. NAC treatment in the absence of irradiation was not genotoxic. These data suggest that, given the safety and efficacy of NAC in humans, NAC may be useful in radiation therapy to prevent radiation-mediated genotoxicity, but does not interfere with efficient cancer cell killing.

  11. Radiation-induced cell damage

    International Nuclear Information System (INIS)

    Felix, W.D.; Schneiderman, M.H.

    1976-01-01

    The addition of irradiated crystals of galactose to Chinese hamster ovary cells resulted in mitotic delay, whereas exposure to nonirradiated crystals resulted in no detectable delay. The inference from this preliminary data is that free radicals or other transient irradiation products have reacted with external cellular components

  12. Radiation- induced aneuploidy in mammalian germ cells

    International Nuclear Information System (INIS)

    Tease, C.

    1989-01-01

    The ability of ionizing radiation to induce aneuploidy in mammalian germ cells has been investigated experimentally in the laboratory mouse using a variety of cytogenetic and genetic methods. These studies have provided unambiguous evidence of induced nondisjunction in both male and female germ cells when the effect of irradiation is screened in meiotic cells or preimplantation embryos. In contrast, however, cytogenetic analyses of post-implantation embryos and genetic assays for induced chromosome gains have not found a significant radiation effect. These apparently contradictory findings may be reconciled if (a) radiation induces tertiary rather than primary trisomy, or (b) induces embryo-lethal genetic damage, such as deletions, in addition to numerical anomalies. Either or both of these explanations may account for the apparent loss during gestation of radiation-induced trisomic embryos. Extrapolating from the information so far available, it seems unlikely that environmental exposure to low doses if low dose rate radiation will result in a detectable increase in the rate of aneuploidy in the human population. (author)

  13. Ionizing radiation-induced cell death

    International Nuclear Information System (INIS)

    Szumiel, I.

    1994-01-01

    Selected aspects of radiation-induced cell death, connected with signal transduction pathways are reviewed. Cell death is defined as insufficiency of the cellular signal transducing system to maintain the cell's physiological functions. The insufficiency may be due to impaired signal reception and/or transduction, lack or erroneous transcription activation, and eventual cellular ''misexpression'' of the signal. The molecular basis of this insufficiency would be damage to genomic (but also other cellular) structures and closing of specific signalling pathways or opening of others (like those leading to apoptosis). I describe experimental data that suggest an important role of RAS/NFI and p53/p105 Rb proteins in cell cycle control-coupled responses to DNA damage. (Author)

  14. Cell kinetic studies on radiation induced leukemogenesis

    International Nuclear Information System (INIS)

    Nakao, Isamu; Suzuki, Gen; Imai, Yasufumi; Kawase, Yoshiko; Nose, Masako; Hirashima, Kunitake; Bessho, Masami

    1989-01-01

    The purpose of this study was threefold: (1) to determine the clonal origin of radiation-induced thymic lymphoma in mice with cellular mosaicism for phosphoglycerate kinase; (2) to determine the incidence and latent period of myeloid leukemia and thymic lymphoma induced by whole-body exposure to median doses (3.0 Gy or less) in RFM/MsNrs-2 mice; and (3) to examine the influence of human recombinant interleukin-2 (hrIL-2). Thymic lymphoma was of a single cell origin. The incidence of radiation-induced myeloid leukemia and thymic lymphoma in RFM mice increased in a dose dependent fashion. Mean latent periods of both myeloid leukemia and thymic lymphoma after irradiation became shorter in proportion to radiation doses. When hrIL-2 was injected to RFM mice receiving 3.0 Gy, mean survivals were shorter in thymoma-bearing mice than the control mice. This suggested that hrIL-2 shortens the promotion step of thymoma. Administration of hrIL-2 failed to alter the incidence of myeloid leukemia or the mean survival of mice having myeloid leukemia, indicating that the protocol of hrIL-2 administration was not so sufficient as to alter the myeloid leukemogenesis. (Namekawa, K)

  15. Ionizing radiation induces stemness in cancer cells.

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    Laura Ghisolfi

    Full Text Available The cancer stem cell (CSC model posits the presence of a small number of CSCs in the heterogeneous cancer cell population that are ultimately responsible for tumor initiation, as well as cancer recurrence and metastasis. CSCs have been isolated from a variety of human cancers and are able to generate a hierarchical and heterogeneous cancer cell population. CSCs are also resistant to conventional chemo- and radio-therapies. Here we report that ionizing radiation can induce stem cell-like properties in heterogeneous cancer cells. Exposure of non-stem cancer cells to ionizing radiation enhanced spherogenesis, and this was accompanied by upregulation of the pluripotency genes Sox2 and Oct3/4. Knockdown of Sox2 or Oct3/4 inhibited radiation-induced spherogenesis and increased cellular sensitivity to radiation. These data demonstrate that ionizing radiation can activate stemness pathways in heterogeneous cancer cells, resulting in the enrichment of a CSC subpopulation with higher resistance to radiotherapy.

  16. Characterization of radiation-induced Apoptosis in rodent cell lines

    International Nuclear Information System (INIS)

    Guo, Min; Chen, Changhu; Ling, C.C.

    1997-01-01

    For REC:myc(ch1), Rat1 and Rat1:myc b cells, we determined the events in the development of radiation-induced apoptosis to be in the following order: cell division followed by chromatin condensation, membrane blebbing, loss of adhesion and the uptake of vital dye. Experimental data which were obtained using 4 He ions of well defined energies and which compared the dependence of apoptosis and clonogenic survival on 4 He range strongly suggested that in our cells both apoptosis and loss of clonogenic survival resulted from radiation damage to the cell nucleus. Corroboratory evidence was that BrdU incorporation sensitized these cells to radiation-induced apoptosis. Comparing the dose response for apoptosis and the clonogenic survival curves for Rat1 and Rat1:myc b cells, we concluded that radiation-induced cell inactivation as assayed by clonogenic survival, and that a modified linear-quadratic model, proposed previously, modeled such a contribution effectively. In the same context, the selective increase in radiation-induced apoptosis. Comparing the dose response for apoptosis and the clonogenic survival curves for Rat1 and Rat1:myc b cells, we concluded that radiation-induced apoptosis contributed to the overall radiation-induced cell inactivation as assayed by clonogenic survival, and that a modified linear-quadratic model, proposed previously, modeled such a contribution effectively. In the same context, the selective increase in radiation-induced apoptosis during late S and G 2 phases reduced the relative radioresistance observed for clonogenic survival during late S and G 2 phases. 30 refs., 8 figs

  17. Promotion of initiated cells by radiation-induced cell inactivation.

    Science.gov (United States)

    Heidenreich, W F; Paretzke, H G

    2008-11-01

    Cells on the way to carcinogenesis can have a growth advantage relative to normal cells. It has been hypothesized that a radiation-induced growth advantage of these initiated cells might be induced by an increased cell replacement probability of initiated cells after inactivation of neighboring cells by radiation. Here Monte Carlo simulations extend this hypothesis for larger clones: The effective clonal expansion rate decreases with clone size. This effect is stronger for the two-dimensional than for the three-dimensional situation. The clones are irregular, far from a circular shape. An exposure-rate dependence of the effective clonal expansion rate could come in part from a minimal recovery time of the initiated cells for symmetric cell division.

  18. 8-aminoadenosine enhances radiation-induced cell death in human lung carcinoma A549 cells

    International Nuclear Information System (INIS)

    Meike, Shunsuke; Yamamori, Tohru; Yasui, Hironobu; Eitaki, Masato; Inanami, Osamu; Matsuda, Akira

    2011-01-01

    The combination of a chemotherapeutic agent and radiation is widely applied to enhance cell death in solid tumor cells in cancer treatment. The purine analogue 8-aminoadenosine (8-NH 2 -Ado) is known to be a transcription inhibitor that has proved very effective in multiple myeloma cell lines and primary indolent leukemia cells. In this report, to examine whether 8-NH 2 -Ado had the ability to enhance the radiation-induced cell killing in solid tumor cells, human lung adenocarcinoma A549 cells were irradiated in the presence and absence of 8-NH 2 -Ado. 8-NH 2 -Ado significantly increased reproductive cell death and apoptosis in A549 cells exposed to X-rays. When peptide inhibitors against caspase-3, -8, and -9 were utilized to evaluate the involvement of caspases, all inhibitors suppressed the enhancement of radiation-induced apoptosis, suggesting that not only mitochondria-mediated apoptotic signal transduction pathways but also death receptor-mediated pathways were involved in this enhancement of apoptosis. In addition, in the cells exposed to the treatment combining X-irradiation and 8-NH 2 -Ado, reduction of the intracellular ATP concentration was essential for survival, and down-regulation of the expression of antiapoptotic proteins such as survivin and X-linked inhibitor of apoptosis protein (XIAP) was observed. These results indicate that 8-NH 2 -Ado has potential not only as an anti-tumor drug for leukemia and lymphoma but also as a radiosensitizing agent for solid tumors. (author)

  19. Radiation induced processes in moss cells

    International Nuclear Information System (INIS)

    Doehren, R. v.

    1975-01-01

    The moss F.h. shows apical growth in the protonema cells which spread radially from the spor. Every apical daughter cell during the state of 'Caulonema' and just before in the state of 'Caulonema Primanen' initiates cell division as soon as more than twice the length of the mother cell is reached. All this allows to follow radiation effects in single cells conveniently. UV irradiation on the range of 254 nm and 280 nm delivered at different parts of the cell area delays cell division markedly may suppress it, and is able to stop the process of growing in relation to the delivered dose and to the irradiated area as well. In case of irradiation of the area next to where the membrane is just being formed - that is to say next to the phragmoplast - the new membrane will be wrongly oriented. In particular giant cells are occurring in the case of nucleus irradiation during early prophase. (orig./GSE) [de

  20. Immobilization of yeast cells by radiation-induced polymerization

    International Nuclear Information System (INIS)

    Fujimura, T.; Kaetsu, I.

    1982-01-01

    Radiation-induced polymerization method was applied to the immobilization of yeast cells. The effects of irradiation, cooling and monomer, which are neccessary for polymerization, were recovered completely by subsequent aerobical incubation of yeast cells. The ethanol productive in immobilized yeast cells increased with the increase of aerobical incubation period. The growth of yeast cells in immobilized yeast cells was indicated. The maximum ethanol productivity in immobilized yeast cell system was around three times as much as that in free yeast cell system. (orig.)

  1. Seven cases of radiation-induced cutaneous squamous cell carcinoma

    International Nuclear Information System (INIS)

    Sugita, Kazunari; Yamamoto, Osamu; Suenaga, Yoshinori

    2000-01-01

    We report 7 cases of radiation-induced skin cancer. The diagnosis was based on the history of radiotherapy for benign skin diseases (5 cases) and of occupational exposures to medical doctors (2 cases). All cases were squamous cell carcinomas which arose from chronic radiodermatitis. The estimated latent period of these tumors ranged from 6 to 64 years, with an average of 29.9 years. After surgical treatments of the lesions, no local recurrences were observed in all cases. Benign skin diseases had sometimes been treated with low-energy radiation before the 1960s. Considering the estimated latent period, the peak time point of developing risk of radiation-induced skin cancer by such treatment has been already passed, however, the danger of it should not be ignored in future. In association with multiplicity of radiation usage, occupational exposure of radiation may develop the risk of occurrence of skin cancer in future. Therefore, we should recognize that radiation-induced skin cancer is not in the past. In the cases of chronic skin diseases showing warty keratotic growth, erosion and ulcer, we should include chronic radio-dermatitis in the differential diagnosis. It is necessary to recall all patients about the history of radiotherapy or radiation exposure. Rapid histopathological examination is mandatory because of the suspicion of radiation-induced skin cancer. (author)

  2. Seven cases of radiation-induced cutaneous squamous cell carcinoma

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    Sugita, Kazunari; Yamamoto, Osamu; Suenaga, Yoshinori [Univ. of Occupational and Environmental Health, Kitakyushu, Fukuoka (Japan). School of Medicine

    2000-09-01

    We report 7 cases of radiation-induced skin cancer. The diagnosis was based on the history of radiotherapy for benign skin diseases (5 cases) and of occupational exposures to medical doctors (2 cases). All cases were squamous cell carcinomas which arose from chronic radiodermatitis. The estimated latent period of these tumors ranged from 6 to 64 years, with an average of 29.9 years. After surgical treatments of the lesions, no local recurrences were observed in all cases. Benign skin diseases had sometimes been treated with low-energy radiation before the 1960s. Considering the estimated latent period, the peak time point of developing risk of radiation-induced skin cancer by such treatment has been already passed, however, the danger of it should not be ignored in future. In association with multiplicity of radiation usage, occupational exposure of radiation may develop the risk of occurrence of skin cancer in future. Therefore, we should recognize that radiation-induced skin cancer is not in the past. In the cases of chronic skin diseases showing warty keratotic growth, erosion and ulcer, we should include chronic radio-dermatitis in the differential diagnosis. It is necessary to recall all patients about the history of radiotherapy or radiation exposure. Rapid histopathological examination is mandatory because of the suspicion of radiation-induced skin cancer. (author)

  3. Radiation-induced gene amplification in rodent and human cells

    International Nuclear Information System (INIS)

    Luecke-Huhle, C.; Gloss, B.; Herrlich, P.

    1990-01-01

    Ionizing and UV radiations induce amplification of SV40 DNA sequences integrated in the genome of Chinese hamster cells and increase amplification of the dihydrofolate reductase (DHFR) gene during methotrexate selection in human skin fibroblasts of a patient with ataxia telangiectasia. Various types of external (60-Co-γ-rays, 241-Am-α-particles, UV) or internal radiation (caused by the decay of 125 I incorporated into DNA in form of I-UdR) were applied. By cell fusion experiments it could be shown that SV40 gene amplification is mediated by one or several diffusible trans-acting factors induced or activated in a dose dependent manner by all types of radiation. One of these factors binds to a 10 bp sequence within the minimal origin of replication of SV40. In vivo competition with an excess of a synthetic oligonucleotide comprising this sequence blocks radiation-induced amplification. (author) 25 refs.; 8 figs

  4. Effect of sulfhydryls on potentiation of radiation-induced cell lethality by substituted anthraquinones

    International Nuclear Information System (INIS)

    Kimler, B.F.

    1984-01-01

    The effects of various substituted anthraquinones (SAQ's) and Adriamycin (ADR) were investigated in cultured Chinese hamster V79 cells. These drugs cause a potentiation of radiation-induced cell lethality, albeit by different mechanisms. One possibility is that these components operate through the production of free radicals which then produce DNA strand breaks and crosslinks. If so, then one should be able to change the degree of cell kill by modifying sulfhydryl (SH) levels such that free radical processes are altered. Diamide, buthionine-S, R-sulfoximine, and N-ethylmaleimide (NEM) were used to reduce intracellular SH levels. Cysteamine and dithiotheitol were used to increase SH levels. In general, altered SH levels did not affect SAQ-induced cytotoxicity at low drug concentrations. When drug-tested cells were also irradiated, survival levels were generally those predicted from assuming purely additive interactions. On the other hand, survival after treatment with high concentrations of ADR and one other SAQ were decreased by concomitant treatment with NEM. Since altered SH levels do not produce changes in the potentiation of radiation-induced cell lethality by SAQs, it is concluded that free radicals are not involved in this potentiation. A free radical-mediated process may be involved in the cytotoxicity induced by ADR and other SAQs; however, it is not a simple process

  5. Repair mechanisms in radiation-induced cell transformation

    International Nuclear Information System (INIS)

    Elkind, M.M.; Han, A.; Hill, C.K.; Buonaguro, F.

    1983-01-01

    Our data with both low- and high-LET radiations are qualitatively similar to results obtained in vivo. This is evident, for example, in the reductions in cell transformation for protracted exposures of γ-rays. The consistencies between our results with cells and the data of others with animals lend support to Gray's hypothesis that tumorigenesis is the net effect of a low probability inductive process, and a high probability killing process. An important prediction can be made when spontaneous frequency is appreciable (e.g., 43% in the case of reticulum cell sarcoma in RFM mice). For small doses, tumorigenesis would drop provided that: (a) the cells responsible for the spontaneous incidence are present at the time of exposure; and (b) the progenitor cells of the tumor are not resistant to cell killing

  6. Mechanisms of radiation-induced neoplastic cell transformation

    International Nuclear Information System (INIS)

    Yang, T.C.H.; Tobias, C.A.

    1984-04-01

    Studies with cultured mammalian cells demonstrated clearly that radiation can transform cells directly and can enhance the cell transformation by oncogenic DNA viruses. In general, high-LET heavy-ion radiation can be more effective than X and gamma rays in inducing neoplastic cell transformation. Various experimental results indicate that radiation-induced DNA damage, most likely double-strand breaks, is important for both the initiation of cell transformation and for the enhancement of viral transformation. Some of the transformation and enhancement lesions can be repaired properly in the cell, and the amount of irrepairable lesions produced by a given dose depends on the quality of radiation. An inhibition of repair processes with chemical agents can increase the transformation frequency of cells exposed to radiation and/or oncogenic viruses, suggesting that repair mechanisms may play an important role in the radiation transformation. The progression of radiation-transformed cells appears to be a long and complicated process that can be modulated by some nonmutagenic chemical agents, e.g., DMSO. Normal cells can inhibit the expression of transforming properties of tumorigenic cells through an as yet unknown mechanism. The progression and expression of transformation may involve some epigenetic changes in the irradiated cells. 38 references, 15 figures, 1 table

  7. Mechanisms of radiation-induced neoplastic cell transformation

    Energy Technology Data Exchange (ETDEWEB)

    Yang, T.C.H.; Tobias, C.A.

    1984-04-01

    Studies with cultured mammalian cells demonstrated clearly that radiation can transform cells directly and can enhance the cell transformation by oncogenic DNA viruses. In general, high-LET heavy-ion radiation can be more effective than X and gamma rays in inducing neoplastic cell transformation. Various experimental results indicate that radiation-induced DNA damage, most likely double-strand breaks, is important for both the initiation of cell transformation and for the enhancement of viral transformation. Some of the transformation and enhancement lesions can be repaired properly in the cell, and the amount of irrepairable lesions produced by a given dose depends on the quality of radiation. An inhibition of repair processes with chemical agents can increase the transformation frequency of cells exposed to radiation and/or oncogenic viruses, suggesting that repair mechanisms may play an important role in the radiation transformation. The progression of radiation-transformed cells appears to be a long and complicated process that can be modulated by some nonmutagenic chemical agents, e.g., DMSO. Normal cells can inhibit the expression of transforming properties of tumorigenic cells through an as yet unknown mechanism. The progression and expression of transformation may involve some epigenetic changes in the irradiated cells. 38 references, 15 figures, 1 table.

  8. Regulation of radiation-induced protein kinase Cδ activation in radiation-induced apoptosis differs between radiosensitive and radioresistant mouse thymic lymphoma cell lines

    International Nuclear Information System (INIS)

    Nakajima, Tetsuo; Yukawa, Osami; Tsuji, Hideo; Ohyama, Harumi; Wang, Bing; Tatsumi, Kouichi; Hayata, Isamu; Hama-Inaba, Hiroko

    2006-01-01

    Protein kinase Cδ (PKCδ) has an important role in radiation-induced apoptosis. The expression and function of PKCδ in radiation-induced apoptosis were assessed in a radiation-sensitive mouse thymic lymphoma cell line, 3SBH5, and its radioresistant variant, XR223. Rottlerin, a PKCδ-specific inhibitor, completely abolished radiation-induced apoptosis in 3SBH5. Radiation-induced PKCδ activation correlated with the degradation of PKCδ, indicating that PKCδ activation through degradation is involved in radiation-induced apoptosis in radiosensitive 3SBH5. In radioresistant XR223, radiation-induced PKCδ activation was lower than that in radiosensitive 3SBH5. Cytosol PKCδ levels in 3SBH5 decreased markedly after irradiation, while those in XR223 did not. There was no apparent change after irradiation in the membrane fractions of either cell type. In addition, basal cytosol PKCδ levels in XR223 were higher than those in 3SBH5. These results suggest that the radioresistance in XR223 to radiation-induced apoptosis is due to a difference in the regulation of radiation-induced PKCδ activation compared to that of 3SBH5. On the other hand, Atm -/- mouse thymic lymphoma cells were more radioresistant to radiation-induced apoptosis than wild-type mouse thymic lymphoma cells. Irradiated wild-type cells, but not Atm -/- cells, had decreased PKCδ levels, indicating that the Atm protein is involved in radiation-induced apoptosis through the induction of PKCδ degradation. The decreased Atm protein levels induced by treatment with Atm small interfering RNA had no effect on radiation-induced apoptosis in 3SBH5 cells. These results suggest that the regulation of radiation-induced PKCδ activation, which is distinct from the Atm-mediated cascade, determines radiation sensitivity in radiosensitive 3SBH5 cells

  9. Radiation-induced spindle cell sarcoma: A rare case report

    Directory of Open Access Journals (Sweden)

    Khan Mubeen

    2009-01-01

    Full Text Available Ionizing radiation has been known to induce malignant transformation in human beings. Radiation-induced sarcomas are a late sequel of radiation therapy. Most sarcomas have been reported to occur after exposure to a radiation dose of 55 Gray (Gy and above, with a dose ranging from 16 to 112 Gys. Spindle cell sarcomas, arising after radiotherapy given to treat the carcinoma of head and neck region is a very uncommon sequel. This is a rare case report of spindle cell sarcoma of left maxilla, in a 24-year-old male, occurring as a late complication of radiotherapy with Cobalt-60 given for the treatment of retinoblastoma of the left eye 21 years back.

  10. Relationship between radiation induced activation of DNA repair genes and radiation induced apoptosis in human cell line A431

    International Nuclear Information System (INIS)

    Bom, Hee Seung; Min, Jung Jun; Kim, Kyung Keun; Choi, Keun Hee

    2000-01-01

    The purpose of this study was to evaluate the relationship between radiation-induced acivation of DNA repair genes and radiation induced apoptosis in A431 cell line. Five and 25 Gys of gamma radiation were given to A431 cells by a Cs-137 cell irradiator. Apoptosis was evaluated by flow cytometry using annexin V-fluorescein isothiocyanate and propidium iodide staining. The expression of DNA repair genes was evaluated by both Northern and Western blot analyses. The number of apoptotic cells increased with the increased radiation dose. It increased most significantly at 12 hours after irradiation. Expression of p53, p21, and ℎRAD50 reached the highest level at 12 hours after 5 Gy irradiation. In response to 25 Gy irradiation, ℎRAD50 and p21 were expressed maximally at 12 hours, but p53 and GADD45 genes showed the highest expression level after 12 hours. Induction of apoptosis and DNA repair by ionizing radiation were closely correlated. The peak time of inducing apoptosis and DNA repair was 12 hours in this study model. ℎRAD50, a recently discovered DNA repair gene, was also associated with radiation-induced apoptosis.=20

  11. Radiation-induced bystander effects in cultured human stem cells.

    Directory of Open Access Journals (Sweden)

    Mykyta V Sokolov

    2010-12-01

    Full Text Available The radiation-induced "bystander effect" (RIBE was shown to occur in a number of experimental systems both in vitro and in vivo as a result of exposure to ionizing radiation (IR. RIBE manifests itself by intercellular communication from irradiated cells to non-irradiated cells which may cause DNA damage and eventual death in these bystander cells. It is known that human stem cells (hSC are ultimately involved in numerous crucial biological processes such as embryologic development; maintenance of normal homeostasis; aging; and aging-related pathologies such as cancerogenesis and other diseases. However, very little is known about radiation-induced bystander effect in hSC. To mechanistically interrogate RIBE responses and to gain novel insights into RIBE specifically in hSC compartment, both medium transfer and cell co-culture bystander protocols were employed.Human bone-marrow mesenchymal stem cells (hMSC and embryonic stem cells (hESC were irradiated with doses 0.2 Gy, 2 Gy and 10 Gy of X-rays, allowed to recover either for 1 hr or 24 hr. Then conditioned medium was collected and transferred to non-irradiated hSC for time course studies. In addition, irradiated hMSC were labeled with a vital CMRA dye and co-cultured with non-irradiated bystander hMSC. The medium transfer data showed no evidence for RIBE either in hMSC and hESC by the criteria of induction of DNA damage and for apoptotic cell death compared to non-irradiated cells (p>0.05. A lack of robust RIBE was also demonstrated in hMSC co-cultured with irradiated cells (p>0.05.These data indicate that hSC might not be susceptible to damaging effects of RIBE signaling compared to differentiated adult human somatic cells as shown previously. This finding could have profound implications in a field of radiation biology/oncology, in evaluating radiation risk of IR exposures, and for the safety and efficacy of hSC regenerative-based therapies.

  12. The process and promotion of radiation-induced cell death

    International Nuclear Information System (INIS)

    Sasaki, Hiroshi

    1998-01-01

    Radiation-induced cell death is divided into reproductive and interphase death, whose process can be revealed by time-lapse observations. Pedigree analyses of progenies derived from a surviving progenitor cell have shown that moribund cells appear in clusters among cells which are apparently undamaged (lethal sectoring). Sister cell fusion, which likely results from chromosome bridge, is the most frequently observed cell abnormality leading to reproductive death. While interphase death does not occur unless the dose exceeds 10 Gy for low LET radiation such as X-rays, high-LET radiation is very effective at inducing interphase death (RBE: ≅3 at 230 keV/μm). Expression or fixation of potentially lethal damage (PLD) is closely associated with cell cycle events and enhanced by inducing premature chromosome condensation (PCC) at a nonpermissive temperature in tsBN2 cells with a ts-defect in RCC1 protein (a regulator of chromatin condensation) which monitors the completion of DNA replication. Furthermore, higher-order structural changes in nuclear matrix such as induced by leptomycin B, an inhibitor of CRM1 (chromosome region maintenance) protein, also play an important role in the fixation of PLD. (author)

  13. Radiation-induced apoptosis in F9 teratocarcinoma cells

    International Nuclear Information System (INIS)

    Langley, R.E.; Palayoor, S.T.; Coleman, C.N.; Bump, E.A.

    1994-01-01

    We have found that F9 murine teratocarcinoma cells undergo morphological changes and internucleosomal DNA fragmentation characteristic of apoptosis after exposure to ionizing radiation. We studied the time course, radiation dose-response, and the effects of protein and RNA synthesis inhibitors on this process. The response is dose dependent in the range 2-12 Gy. Internucleosomal DNA fragmentation can be detected as early as 6 h postirradiation and is maximal by 48 h. Cycloheximide, a protein synthesis inhibitor, and 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole, an RNA synthesis inhibitor, both induced internucleosomal DNA fragmentation in the unirradiated cells and enhanced radiation-induced DNA fragmentation. F9 cells can be induced to differentiate into cells resembling endoderm with retinoic acid. After irradiation, differentiated F9 cells exhibit less DNA fragmentation than stem cells. This indicates that ionizing radiation can induce apoptosis in non-lymphoid tumours. We suggest that embryonic tumour cells may be particularly susceptible to agents that induce apoptosis. (Author)

  14. Radiation-induced apoptosis in F9 teratocarcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Langley, R E; Palayoor, S T; Coleman, C N; Bump, E A [Joint Center for Radiation Therapy and Dana Farber Cancer Inst., Boston (United States)

    1994-05-01

    We have found that F9 murine teratocarcinoma cells undergo morphological changes and internucleosomal DNA fragmentation characteristic of apoptosis after exposure to ionizing radiation. We studied the time course, radiation dose-response, and the effects of protein and RNA synthesis inhibitors on this process. The response is dose dependent in the range 2-12 Gy. Internucleosomal DNA fragmentation can be detected as early as 6 h postirradiation and is maximal by 48 h. Cycloheximide, a protein synthesis inhibitor, and 5,6-dichloro-1-[beta]-D-ribofuranosylbenzimidazole, an RNA synthesis inhibitor, both induced internucleosomal DNA fragmentation in the unirradiated cells and enhanced radiation-induced DNA fragmentation. F9 cells can be induced to differentiate into cells resembling endoderm with retinoic acid. After irradiation, differentiated F9 cells exhibit less DNA fragmentation than stem cells. This indicates that ionizing radiation can induce apoptosis in non-lymphoid tumours. We suggest that embryonic tumour cells may be particularly susceptible to agents that induce apoptosis. (Author).

  15. Effect of bFGF on radiation-induced apoptosis of vascular endothelial cells

    International Nuclear Information System (INIS)

    Gu Qingyang; Wang Dewen; Li Yuejuan; Peng Ruiyun; Dong Bo; Wang Zhaohai; Liu Jie; Deng Hua; Jiang Tao

    2003-01-01

    Objective: To study the effect of bFGF on radiation-induced apoptosis vascular endothelial cells. Methods: A cell line PAE (porcine aortic endothelial cells) and primary cultured HUVEC (human umbilical vein endothelial cells) were irradiated with 60 Co γ-rays to establish cell apoptosis models. Flow cytometry with annexin-V-FITC + PI labeling was used to evaluate cell apoptosis. Different amounts of bFGF were used to study their effects on radiation-induced endothelial cell apoptosis. Results and Conclusions: It is found that bFGF could inhibit radiation-induced endothelial cell apoptosis in a considerable degree

  16. Mechanisms of radiation-induced changes in mammalian cell properties

    International Nuclear Information System (INIS)

    Elkind, M.M.; Han, A.; Ben-Hur, E.; Hill, C.K.; Myers, C.; Suzuki, F.; Utsumi, H.; Liu, C.M.; Theriot, L.D.

    1981-01-01

    The primary focus of this research is to determine the presence or absence of repair processes relative to linear or so-called single-hit dose effects. Experimental techniques and protocols are developed to test if repair processes contribute to the linear components of the induction of cell killing, mutation, and transformation and, if the slopes of such linear components are dependent upon dose rate. Principal methods are those cell culture techniques for assessing survival, altered phenotype, and transformation. Chinese hamster cells incubated in medium containing 90% D 2 O are inhibited from repairing potentially lethal x-ray and neutron damage (fisson-spectrum neutrons). The sector of damage whose repair is affected by D 2 O medium partially overlaps with that affected by anisotonic buffer. As in the instance of anisotonic buffer, enhanced cell killing due to D 2 O medium does not prevent cells from repairing sublethal damage when incubation in normal medium is resumed. Usng lt of human risk associated with nuclearing collective dose commitment will result in more attention being paid to potential releases of radionuclides at relatively short times after disposal

  17. Characterization of a Novel Radiation-Induced Sarcoma Cell Line

    Czech Academy of Sciences Publication Activity Database

    Lang, J.; Zhu, W.Z.; Nokes, B.; Sheth, S.G.; Novák, Petr; Fuchs, L.; Watts, G.; Futscher, B. W.; Mineyev, N.; Ring, A.

    2015-01-01

    Roč. 111, č. 6 (2015), s. 669-682 ISSN 0022-4790 Institutional support: RVO:60077344 Keywords : Sarcoma * radiation-induced * breast * cancer Subject RIV: FD - Oncology ; Hematology Impact factor: 3.151, year: 2015

  18. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells

    Science.gov (United States)

    Song, Chang W.; Lee, Hyemi; Dings, Ruud P. M.; Williams, Brent; Powers, John; Santos, Troy Dos; Choi, Bo-Hwa; Park, Heon Joo

    2012-01-01

    The anti-cancer effects of metformin, the most widely used drug for type 2 diabetes, alone or in combination with ionizing radiation were studied with MCF-7 human breast cancer cells and FSaII mouse fibrosarcoma cells. Clinically achievable concentrations of metformin caused significant clonogenic death in cancer cells. Importantly, metformin was preferentially cytotoxic to cancer stem cells relative to non-cancer stem cells. Metformin increased the radiosensitivity of cancer cells in vitro, and significantly enhanced the radiation-induced growth delay of FSaII tumors (s.c.) in the legs of C3H mice. Both metformin and ionizing radiation activated AMPK leading to inactivation of mTOR and suppression of its downstream effectors such as S6K1 and 4EBP1, a crucial signaling pathway for proliferation and survival of cancer cells, in vitro as well as in the in vivo tumors. Conclusion: Metformin kills and radiosensitizes cancer cells and eradicates radioresistant cancer stem cells by activating AMPK and suppressing mTOR. PMID:22500211

  19. Is radiation-induced cell death in mouse testis apoptosis?

    International Nuclear Information System (INIS)

    Hasegawa, Masatoshi; Wilson, Gene; Yun Zhang; Russell, Lonnie D.; Meistrich, Marvin L.

    1996-01-01

    Purpose: Radiation-induced death of spermatogonia and other germ cells in the testis has been claimed to be by an apoptotic mechanism, but these processes have been incompletely characterized. We investigated irradiated mouse testis by multiple techniques to determine whether the mode of cell death of spermatogonia can be classified as apoptosis. Materials and Methods: Adult male C57BL/6 and p53 knockout mice were irradiated with single doses of 0.5, 2.5 or 5.0 Gy. Four, 6, 8, 12, 18 or 24 hours after irradiation, testes were fixed in Bouin's solution or in 10% formalin. Slides were stained with hematoxylin and eosin or TdT-mediated dUTP-biotin nick end labeling (TUNEL). Some testes were perfusion-fixed with 5% glutaraldehyde for electron microscopy. Gel electrophoresis of DNA was also performed to identify DNA fragmentation. The number of sperm heads was counted 29 days after irradiation to evaluate the effect of radiation on the eventual survival of the differentiated spermatogonia. Results: The earliest sign of histological damage was an increase in the numbers of abnormal spermatogonia in the seminiferous tubules, particularly in stage I-VI of the seminiferous epithelial cycle. The numbers of abnormal spermatogonia began to increase at 6 hours, reached a peak 12 hours after irradiation, and then declined. The total number of spermatogonia began to decrease at 12 hours after irradiation, resulting in a 60% decline in sperm produced 29 days after 0.5 Gy. Although changes were greatest following 5.0 Gy irradiation, even 0.5 Gy induced marked changes. However, these changes were not induced in p53 knockout mice. By both light and electron microscopy, spermatogonia showed some condensation of nuclear chromatin, but margination of chromatin with clear delineation and nuclear fragmentation was rare. Many of the abnormal spermatogonia showed a positive TUNEL reaction, which was also at a maximum at 12 hours after irradiation. In addition, some TUNEL-positive and

  20. Comparison of gamma radiation - induced effects in two human prostate cancer cells

    International Nuclear Information System (INIS)

    Vucic, V.; Adzic, M.; Ruzdijic, S.; Radojcic, M.B. . E-mail address of corresponding author: vesnav@vin.bg.ac.yu; Vucic, V.)

    2005-01-01

    In this study, the effects of gamma radiation on two hormone refractory human prostate cancer cell lines, DU 145 and PC-3, were followed. It was shown that gamma radiation induced significant inhibition of cell proliferation and viability in dose dependent manner. Antiproliferative effects of radiation were similar in both cell lines, and more pronounced than cytotoxic effects. In addition to that, PC-3 cell line was more resistant to radiation -induced cytotoxicity. (author)

  1. Mutagenesis in mammalian cells can be modulated by radiation-induced voltage-dependent potassium channels

    International Nuclear Information System (INIS)

    Saad, A.H.; Zhou, L.Y.; Lambe, E.K.; Hahn, G.M.

    1994-01-01

    In mammalian cells, little is known about the initial events whose ultimate consequence is mutagenesis or DNA repair. The role the plasma membrane may play as an initiator of such a pathway is not understood. We show, for the first time, that membrane voltage-dependent potassium (K + ) currents, activated by ionizing radiation play a significant role in radiation mutagenesis. Specifically, we show that the frequency of mutation at the HGPRT locus is increased as expected to 37.6±4.0 mutations per 100,000 survivors by 800 cGy of ionizing radiation from a spontaneous frequency of 1.5±1.5. This increase, however, is abolished if either K + channel blocker, CsCl or BaCl 2 , is present for 2h following irradiation of the cells. RbCl, chemically similar to CsCl but known not to block K + channels, is ineffective in reducing the mutation frequency. Treatment of cells with CsCl or BaCl 2 had no effect on radiation-induced cell killing

  2. Effects of ceramide inhibition on radiation-induced apoptosis in human leukemia MOLT-4 cells

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Eriko; Inanami, Osamu; Asanuma, Taketoshi; Kuwabara, Mikinori [Hokkaido Univ., Graduate School of Veterinary Medicine, Sapporo, Hokkaido (Japan)

    2006-03-15

    In the present study, using inhibitors of ceramide synthase (fumonisin B{sub 1}), ketosphinganine synthetase (L-cycloserine), acid sphingomyelinase (D609 and desipramine) and neutral sphingomyelinase (GW4869), the role of ceramide in X-ray-induced apoptosis was investigated in MOLT-4 cells. The diacylglycerol kinase (DGK) assay showed that the intracellular concentration of ceramide increased time-dependently after X irradiation of cells, and this radiation-induced accumulation of ceramide did not occur prior to the appearance of apoptotic cells. Treatment with D609 significantly inhibited radiation-induced apoptosis, but did not inhibit the increase of intracellular ceramide. Treatment with desipramine or GW4869 prevented neither radiation-induced apoptosis nor the induced increase of ceramide. On the other hand, fumonisin B{sub 1} and L-cycloserine had no effect on the radiation-induced induction of apoptosis, in spite of significant inhibition of the radiation-induced ceramide. From these results, it was suggested that the increase of the intracellular concentration of ceramide was not essential for radiation-induced apoptosis in MOLT-4 cells. (author)

  3. Effects of ceramide inhibition on radiation-induced apoptosis in human leukemia MOLT-4 cells

    International Nuclear Information System (INIS)

    Takahashi, Eriko; Inanami, Osamu; Asanuma, Taketoshi; Kuwabara, Mikinori

    2006-01-01

    In the present study, using inhibitors of ceramide synthase (fumonisin B 1 ), ketosphinganine synthetase (L-cycloserine), acid sphingomyelinase (D609 and desipramine) and neutral sphingomyelinase (GW4869), the role of ceramide in X-ray-induced apoptosis was investigated in MOLT-4 cells. The diacylglycerol kinase (DGK) assay showed that the intracellular concentration of ceramide increased time-dependently after X irradiation of cells, and this radiation-induced accumulation of ceramide did not occur prior to the appearance of apoptotic cells. Treatment with D609 significantly inhibited radiation-induced apoptosis, but did not inhibit the increase of intracellular ceramide. Treatment with desipramine or GW4869 prevented neither radiation-induced apoptosis nor the induced increase of ceramide. On the other hand, fumonisin B 1 and L-cycloserine had no effect on the radiation-induced induction of apoptosis, in spite of significant inhibition of the radiation-induced ceramide. From these results, it was suggested that the increase of the intracellular concentration of ceramide was not essential for radiation-induced apoptosis in MOLT-4 cells. (author)

  4. Spatially Fractionated Radiation Induces Cytotoxicity and Changes in Gene Expression in Bystander and Radiation Adjacent Murine Carcinoma Cells

    Science.gov (United States)

    Asur, Rajalakshmi S.; Sharma, Sunil; Chang, Ching-Wei; Penagaricano, Jose; Kommuru, Indira M.; Moros, Eduardo G.; Corry, Peter M.; Griffin, Robert J.

    2012-01-01

    Radiation-induced bystander effects have been extensively studied at low doses, since evidence of bystander induced cell killing and other effects on unirradiated cells were found to be predominant at doses up to 0.5 Gy. Therefore, few studies have examined bystander effects induced by exposure to higher doses of radiation, such as spatially fractionated radiation (GRID) treatment. In the present study, we evaluate the ability of GRID treatment to induce changes in GRID adjacent (bystander) regions, in two different murine carcinoma cell lines following exposure to a single irradiation dose of 10 Gy. Murine SCK mammary carcinoma cells and SCCVII squamous carcinoma cells were irradiated using a brass collimator to create a GRID pattern of nine circular fields 12 mm in diameter with a center-to-center distance of 18 mm. Similar to the typical clinical implementation of GRID, this is approximately a 50:50 ratio of direct and bystander exposure. We also performed experiments by irradiating separate cultures and transferring the medium to unirradiated bystander cultures. Clonogenic survival was evaluated in both cell lines to determine the occurrence of radiation-induced bystander effects. For the purpose of our study, we have defined bystander cells as GRID adjacent cells that received approximately 1 Gy scatter dose or unirradiated cells receiving conditioned medium from irradiated cells. We observed significant bystander killing of cells adjacent to the GRID irradiated regions compared to sham treated controls. We also observed bystander killing of SCK and SCCVII cells cultured in conditioned medium obtained from cells irradiated with 10 Gy. Therefore, our results confirm the occurrence of bystander effects following exposure to a high-dose of radiation and suggest that cell-to-cell contact is not required for these effects. In addition, the gene expression profile for DNA damage and cellular stress response signaling in SCCVII cells after GRID exposure was studied

  5. Modelling radiation-induced cell death and tumour re-oxygenation: local versus global and instant versus delayed cell death

    International Nuclear Information System (INIS)

    Gago-Arias, Araceli; Espinoza, Ignacio; Sánchez-Nieto, Beatriz; Aguiar, Pablo; Pardo-Montero, Juan

    2016-01-01

    The resistance of hypoxic cells to radiation, due to the oxygen dependence of radiosensitivity, is well known and must be taken into account to accurately calculate the radiation induced cell death. A proper modelling of the response of tumours to radiation requires deriving the distribution of oxygen at a microscopic scale. This usually involves solving the reaction-diffusion equation in tumour voxels using a vascularization distribution model. Moreover, re-oxygenation arises during the course of radiotherapy, one reason being the increase of available oxygen caused by cell killing, which can turn hypoxic tumours into oxic. In this work we study the effect of cell death kinetics in tumour oxygenation modelling, analysing how it affects the timing of re-oxygenation, surviving fraction and tumour control. Two models of cell death are compared, an instantaneous cell killing, mimicking early apoptosis, and a delayed cell death scenario in which cells can die shortly after being damaged, as well as long after irradiation. For each of these scenarios, the decrease in oxygen consumption due to cell death can be computed globally (macroscopic voxel average) or locally (microscopic). A re-oxygenation model already used in the literature, the so called full re-oxygenation, is also considered. The impact of cell death kinetics and re-oxygenation on tumour responses is illustrated for two radiotherapy fractionation schemes: a conventional schedule, and a hypofractionated treatment. The results show large differences in the doses needed to achieve 50% tumour control for the investigated cell death models. Moreover, the models affect the tumour responses differently depending on the treatment schedule. This corroborates the complex nature of re-oxygenation, showing the need to take into account the kinetics of cell death in radiation response models. (paper)

  6. PAI-1-dependent endothelial cell death determines severity of radiation-induced intestinal injury.

    Directory of Open Access Journals (Sweden)

    Rym Abderrahmani

    Full Text Available Normal tissue toxicity still remains a dose-limiting factor in clinical radiation therapy. Recently, plasminogen activator inhibitor type 1 (SERPINE1/PAI-1 was reported as an essential mediator of late radiation-induced intestinal injury. However, it is not clear whether PAI-1 plays a role in acute radiation-induced intestinal damage and we hypothesized that PAI-1 may play a role in the endothelium radiosensitivity. In vivo, in a model of radiation enteropathy in PAI-1 -/- mice, apoptosis of radiosensitive compartments, epithelial and microvascular endothelium was quantified. In vitro, the role of PAI-1 in the radiation-induced endothelial cells (ECs death was investigated. The level of apoptotic ECs is lower in PAI-1 -/- compared with Wt mice after irradiation. This is associated with a conserved microvascular density and consequently with a better mucosal integrity in PAI-1 -/- mice. In vitro, irradiation rapidly stimulates PAI-1 expression in ECs and radiation sensitivity is increased in ECs that stably overexpress PAI-1, whereas PAI-1 knockdown increases EC survival after irradiation. Moreover, ECs prepared from PAI-1 -/- mice are more resistant to radiation-induced cell death than Wt ECs and this is associated with activation of the Akt pathway. This study demonstrates that PAI-1 plays a key role in radiation-induced EC death in the intestine and suggests that this contributes strongly to the progression of radiation-induced intestinal injury.

  7. Radiation-induced cell death in embryogenic cells of coniferous plants

    International Nuclear Information System (INIS)

    Watanabe, Yoshito; Homma-Takeda, Shino; Yukawa, Masae; Nishimura, Yoshikazu; Sasamoto, Hamako; Takahagi, Masahiko

    2004-01-01

    Reproductive processes are particularly radiosensitive in plant development, which was clearly illustrated in reduction of seed formation in native coniferous plants around Chernobyl after the nuclear accident. For the purpose to investigate the effects of ionizing radiation on embryonic formation in coniferous plants, we used an embryo-derived embryogenic cell culture of a Japanese native coniferous plant, Japanese cedar (Cryplomeria japonica). The embryogenic cells were so radiosensitive that most of the cells died by X-ray irradiation of 5 Gy. This indicated that the embryogenic cells are as radiosensitive as some mammalian cells including lymphocytes. We considered that this type of radiosensitive cell death in the embryogenic cells should be responsible for reproductive damages of coniferous plants by low dose of ionizing radiation. The cell death of the embryogenic cells was characteristic of nuclear DNA fragmentation, which is typically observed in radiation-induced programmed cell death, i.e. apoptosis, in mammalian cells. On the other hand, cell death with nuclear DNA fragmentation did not develop by X-ray irradiation in vegetative cells including meristematic cells of Japanese cedar. This suggests that an apoptosis-like programmed cell death should develop cell-specifically in embryogenic cells by ionizing radiation. The abortion of embryogenic cells may work to prevent transmission of radiation-induced genetic damages to the descendants. (author)

  8. Stem Cell Therapy to Reduce Radiation-Induced Normal Tissue Damage

    NARCIS (Netherlands)

    Coppes, Rob P.; van der Goot, Annemieke; Lombaert, Isabelle M. A.

    Normal tissue damage after radiotherapy is still a major problem in cancer treatment. Stem cell therapy may provide a means to reduce radiation-induced side effects and improve the quality of life of patients. This review discusses the current status in stem cell research with respect to their

  9. RhoA GTPase regulates radiation-induced alterations in endothelial cell adhesion and migration

    International Nuclear Information System (INIS)

    Rousseau, Matthieu; Gaugler, Marie-Hélène; Rodallec, Audrey; Bonnaud, Stéphanie; Paris, François; Corre, Isabelle

    2011-01-01

    Highlights: ► We explore the role of RhoA in endothelial cell response to ionizing radiation. ► RhoA is rapidly activated by single high-dose of radiation. ► Radiation leads to RhoA/ROCK-dependent actin cytoskeleton remodeling. ► Radiation-induced apoptosis does not require the RhoA/ROCK pathway. ► Radiation-induced alteration of endothelial adhesion and migration requires RhoA/ROCK. -- Abstract: Endothelial cells of the microvasculature are major target of ionizing radiation, responsible of the radiation-induced vascular early dysfunctions. Molecular signaling pathways involved in endothelial responses to ionizing radiation, despite being increasingly investigated, still need precise characterization. Small GTPase RhoA and its effector ROCK are crucial signaling molecules involved in many endothelial cellular functions. Recent studies identified implication of RhoA/ROCK in radiation-induced increase in endothelial permeability but other endothelial functions altered by radiation might also require RhoA proteins. Human microvascular endothelial cells HMEC-1, either treated with Y-27632 (inhibitor of ROCK) or invalidated for RhoA by RNA interference were exposed to 15 Gy. We showed a rapid radiation-induced activation of RhoA, leading to a deep reorganisation of actin cytoskeleton with rapid formation of stress fibers. Endothelial early apoptosis induced by ionizing radiation was not affected by Y-27632 pre-treatment or RhoA depletion. Endothelial adhesion to fibronectin and formation of focal adhesions increased in response to radiation in a RhoA/ROCK-dependent manner. Consistent with its pro-adhesive role, ionizing radiation also decreased endothelial cells migration and RhoA was required for this inhibition. These results highlight the role of RhoA GTPase in ionizing radiation-induced deregulation of essential endothelial functions linked to actin cytoskeleton.

  10. Spontaneous and radiation induced cell death in HeLa S3 human carcinoma

    International Nuclear Information System (INIS)

    Zaric, B.; Milosavljevic, B.; Radojcic, M.

    2001-01-01

    Radiation biologists have classified radiation-induced cell death based on cell proliferative capacity to either mitotic or interphase death. Cytologists have revealed two morphologically and biochemically diverse forms of cell death, apoptosis and necrosis. While the knowledge of the former is already well exploited by radiologists, cell susceptibility to apoptosis and necrosis is still under investigation. We studied characteristics of spontaneous cell death, and dose dependence and time course of radiation-induced cell death of human uterine cervix epitheloid carcinoma HeLaS 3 in culture. Cells were irradiated with 2-40 Gy of γ-rays. The effect on growth, viability, morphology and genomic DNA structure were followed 24-72 h after irradiation. Cell viability was evaluated by trypan-blue exclusion assay and cell morphology by in situ DNA staining with propidium iodide. Cell genomic DNA fragmentation pattern was determined by electrophoresis on 2% agarose gels. At all cell densities 25-35% cells were PI positive and their DNA was fragmented to a high molecular size (≥20 kbp), but the internucleosomal ladder was not observed. A significant decrease in viability to 33% was observed 72 h post 40 Gy irradiation. It corresponded to 55% of PI positive cells. A smear of smaller DNA fragments (0.1-1 kbp), 24 h after 10-20 Gy irradiation was considered as proof that the dominant form of radiation-induced cell death was necrosis. It was concluded that the dominant form of radiation-induced cell death in HeLaS 3 population was necrosis and the radiation dose which caused 50% of cell death after 72 h (termed ND 50 ) was between 30-40 Gy. (author)

  11. Stem cells and the repair of radiation-induced salivary gland damage

    NARCIS (Netherlands)

    Coppes, R. P.; Stokman, M. A.

    Hyposalivation underlying xerostomia after radiotherapy is still a major problem in the treatment of head and neck cancer. Stem cell therapy may provide a means to reduce radiation-induced hyposalivation and improve the quality of life of patients. This review discusses the current status in

  12. Cell survival and radiation induced chromosome aberrations. Pt. 2

    International Nuclear Information System (INIS)

    Bauchinger, M.; Schmid, E.; Braselmann, H.

    1986-01-01

    Human peripheral lymphocytes were irradiated in whole blood with 0.5-4.0 Gy of 220 kVp X-rays and the frequency of chromosome aberrations was determined in 1st or 2nd division metaphases discriminated by fluorescence plus giemsa staining. Using the empirical distributions of aberrations among cells, cell survival and transmission of aberrations were investigated. Considering both daughter cells, we found that 20% of fragments and 55% of dicentrics or ring chromosomes are lost during the 1st cell division; i.e. cell survival rate from 1st to 2nd generation is mainly influenced by anaphase bridging of these two-hit aberrations. Cell survival to 2nd mitosis was calculated considering this situation and compared with the survival derived from the fraction of M1 cells without unstable aberrations. The resulting shouldered survival curves showed significantly different slopes, indicating that cell reproductive death is overestimated in the latter approach. (orig.)

  13. Radiation induced formation of giant cells (Saccharomyces uvarum). Pt. 1

    Energy Technology Data Exchange (ETDEWEB)

    Baumstark-Khan, C; Schnitzler, L; Rink, H

    1984-02-01

    X-irradiated yeast cells (Saccharomyces uvarum) grown in liquid media stop mitosis and form giant cells. Chitin ring formation, being a prerequisite for cell separation, was studied by fluorescence microscopy using Calcofluor White, a chitin specific dye. Experiments with inhibitors of DNA synthesis (hydroxyurea) and chitin synthesis (polyoxin D) demonstrate chitin ring formation to be dependent on DNA synthesis, whereas bud formation is independent of DNA synthesis and chitin ring formation respectively. Basing on these results the formation of X-ray induced giant cells implies one DNA replication which in turn induces the formation of only one chitin ring between mother cell and giant bud. Obviously no septum can be formed. Thus cell separation does not occur, but the bud already formed, produces another bud demonstrating that bud formation itself is independent of DNA synthesis.

  14. Radiation induced formation of giant cells (Saccharomyces uvarum). Pt. 1

    International Nuclear Information System (INIS)

    Baumstark-Khan, C.; Schnitzler, L.; Rink, H.

    1984-01-01

    X-irradiated yeast cells (Saccharomyces uvarum) grown in liquid media stop mitosis and form giant cells. Chitin ring formation, being a prerequisite for cell separation, was studied by fluorescence microscopy using Calcofluor White, a chitin specific dye. Experiments with inhibitors of DNA synthesis (hydroxyurea) and chitin synthesis (polyoxin D) demonstrate chitin ring formation to be dependent on DNA synthesis, whereas bud formation is independent of DNA synthesis and chitin ring formation respectively. Basing on these results the formation of X-ray induced giant cells implies one DNA replication which in turn induces the formation of only one chitin ring between mother cell and giant bud. Obviously no septum can be formed. Thus cell separation does not occur, but the bud already formed, produces another bud demonstrating that bud formation itself is independent of DNA synthesis. (orig.)

  15. Radiation-induced motility alterations in medulloblastoma cells

    International Nuclear Information System (INIS)

    Rieken, Stefan; Rieber, Juliane; Brons, Stephan

    2015-01-01

    Photon irradiation has been repeatedly suspected of increasing tumor cell motility and promoting locoregional recurrence of disease. This study was set up to analyse possible mechanisms underlying the potentially radiation-altered motility in medulloblastoma cells. Medulloblastoma cell lines D425 and Med8A were analyzed in migration and adhesion experiments with and without photon and carbon ion irradiation. Expression of integrins was determined by quantitative FACS analysis. Matrix metalloproteinase concentrations within cell culture supernatants were investigated by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using Student's t-test. Both photon and carbon ion irradiation significantly reduced chemotactic medulloblastoma cell transmigration through 8-μm pore size membranes, while simultaneously increasing adherence to fibronectin- and collagen I- and IV-coated surfaces. Correspondingly, both photon and carbon ion irradiation downregulate soluble MMP9 concentrations, while upregulating cell surface expression of proadhesive extracellular matrix protein-binding integrin α 5 . The observed phenotype of radiation-altered motility is more pronounced following carbon ion than photon irradiation. Both photon and (even more so) carbon ion irradiation are effective in inhibiting medulloblastoma cell migration through downregulation of matrix metalloproteinase 9 and upregulation of proadhesive cell surface integrin α 5 , which lead to increased cell adherence to extracellular matrix proteins. (author)

  16. Base substitutions, frameshifts, and small deletions constitute ionizing radiation-induced point mutations in mammalian cells

    International Nuclear Information System (INIS)

    Grosovsky, A.J.; de Boer, J.G.; de Jong, P.J.; Drobetsky, E.A.; Glickman, B.W.

    1988-01-01

    The relative role of point mutations and large genomic rearrangements in ionizing radiation-induced mutagenesis has been an issue of long-standing interest. Recent studies using Southern blotting analysis permit the partitioning of ionizing radiation-induced mutagenesis in mammalian cells into detectable deletions and major genomic rearrangements and into point mutations. The molecular nature of these point mutations has been left unresolved; they may include base substitutions as well as small deletions, insertions, and frame-shifts below the level of resolution of Southern blotting analysis. In this investigation, we have characterized a collection of ionizing radiation-induced point mutations at the endogenous adenine phosphoribosyltransferase (aprt) locus of Chinese hamster ovary cells at the DNA sequence level. Base substitutions represented approximately equal to 2/3 of the point mutations analyzed. Although the collection of mutants is relatively small, every possible type of base substitution event has been recovered. These mutations are well distributed throughout the coding sequence with only one multiple occurrence. Small deletions represented the remainder of characterized mutants; no insertions have been observed. Sequence-directed mechanisms mediated by direct repeats could account for some of the observed deletions, while others appear to be directly attributable to radiation-induced strand breakage

  17. Ionizing radiation induces apoptosis in hematopoietic stem and progenitor cells

    International Nuclear Information System (INIS)

    Meng, A.; Zhou, D.; Geiger, H.; Zant, G.V.

    2003-01-01

    The aims of this study was to determine if ionizing radiation (IR) induces apoptosis in hematopoietic stem (HSC) and progenitor cells. Lin-cells were isolated from mouse bone marrow (BM) and pretreated with vehicle or 100 μM z-VAD 1 h prior to exposure to 4 Gy IR. The apoptotic and/or necrotic responses of these cells to IR were analyzed by measuring the annexin V and/or 7-AAD staining in HSC and progenitor populations using flow cytometry, and hematopoietic function of these cells was determined by CAFC assay. Exposure of Lin-cells to IR selectively decreased the numbers of HSC and progenitors in association with an increase in apoptosis in a time-dependent manner. Pretreatment of Lin- cells with z-VAD significantly inhibited IR-induced apoptosis and the decrease in the numbers of HSC and progenitors. However, IR alone or in combination with z-VAD did not lead to a significant increase in necrotic cell death in either HSC or progenitors. In addition, pretreatment of BM cells with z-VAD significantly attenuated IR-induced reduction in the frequencies of day-7, -28 and -35 CAFC. Exposure of HSC and progenitors to IR induces apoptosis. The induction of HSC and progenitor apoptosis contributes to IR-induced suppression of their hematopoietic function

  18. Radiation-induced mitotic catastrophe in PARG-deficient cells

    Energy Technology Data Exchange (ETDEWEB)

    Ame, J.Ch.; Fouquerel, E.; Dantzer, F.; De Murcia, G.; Schreiber, V. [IREBS-FRE3211 du CNRS, Universite de Strasbourg, ESBS, Bd Sebastien Brant, BP 10413, 67412 Illkirch Cedex (France); Gauthier, L.R.; Boussin, F.D. [Laboratoire de Radiopathologie/INSERM U967, CEA-DSV-IRCM, 92265 Fontenay aux Roses, Cedex 6 (France); Biard, D. [CEA-DSV-IRCM/INSERM U935, Institut A. Lwoff-CNRS, BP 8, 94801 Villejuif cedex (France)

    2009-07-01

    Poly(ADP-ribosyl)ation is a post-translational modification of proteins involved in the regulation of chromatin structure, DNA metabolism, cell division and cell death. Through the hydrolysis of poly(ADP-ribose) (PAR), Poly(ADP-ribose) glyco-hydrolase (PARG) has a crucial role in the control of life-and-death balance following DNA insult. Comprehension of PARG function has been hindered by the existence of many PARG isoforms encoded by a single gene and displaying various subcellular localizations. To gain insight into the function of PARG in response to irradiation, we constitutively and stably knocked down expression of PARG isoforms in HeLa cells. PARG depletion leading to PAR accumulation was not deleterious to undamaged cells and was in fact rather beneficial, because it protected cells from spontaneous single-strand breaks and telomeric abnormalities. By contrast, PARG-deficient cells showed increased radiosensitivity, caused by defects in the repair of single- and double-strand breaks and in mitotic spindle checkpoint, leading to alteration of progression of mitosis. Irradiated PARG-deficient cells displayed centrosome amplification leading to mitotic supernumerary spindle poles, and accumulated aberrant mitotic figures, which induced either polyploidy or cell death by mitotic catastrophe. Our results suggest that PARG could be a novel potential therapeutic target for radiotherapy. (authors)

  19. Radiation-induced cell death by chromatin loss

    International Nuclear Information System (INIS)

    Campbell, I.R.; Warenius, H.M.

    1989-01-01

    A model is proposed which relates reproductive death of cells caused by radiation to loss of chromatin at cell division. This loss of chromatin can occur through chromosomal deletions or through the formation of asymmetrical chromosomal exchanges. It is proposed that smaller doses of radiation produce fewer chromatin breaks, which are more likely to be accurately repaired, compared with larger doses. Consequently, smaller doses of radiation are less efficient in causing cell death, leading to a shoulder on the cell survival curve. Experimental evidence supports this model, and the fit between the derived formula and experimental cell survival curves is good. The derived formula approximates to the linear-quadratic equation at low doses of radiation. (author)

  20. Radiation-induced genetic effects in germ cells of mammals

    International Nuclear Information System (INIS)

    Van Buul, P.P.W.

    1993-01-01

    The aim of the project is to gain information on the effects of ionizing radiation on germ cells of rodents and primates as measured by induced chromosomal translocations. Different aspects of the very significant interspecies differences between the mouse and the rhesus monkey (Macaca mulatta) for translocation induction in spermatogonial stem cells were studied. In addition, possible mechanisms for the well established reduced transmission of induced mouse translocations were investigated. (R.P.) 6 refs

  1. Ionizing radiation induces heritable disruption of epithelial cell interactions

    Science.gov (United States)

    Park, Catherine C.; Henshall-Powell, Rhonda L.; Erickson, Anna C.; Talhouk, Rabih; Parvin, Bahram; Bissell, Mina J.; Barcellos-Hoff, Mary Helen; Chatterjee, A. (Principal Investigator)

    2003-01-01

    Ionizing radiation (IR) is a known human breast carcinogen. Although the mutagenic capacity of IR is widely acknowledged as the basis for its action as a carcinogen, we and others have shown that IR can also induce growth factors and extracellular matrix remodeling. As a consequence, we have proposed that an additional factor contributing to IR carcinogenesis is the potential disruption of critical constraints that are imposed by normal cell interactions. To test this hypothesis, we asked whether IR affected the ability of nonmalignant human mammary epithelial cells (HMEC) to undergo tissue-specific morphogenesis in culture by using confocal microscopy and imaging bioinformatics. We found that irradiated single HMEC gave rise to colonies exhibiting decreased localization of E-cadherin, beta-catenin, and connexin-43, proteins necessary for the establishment of polarity and communication. Severely compromised acinar organization was manifested by the majority of irradiated HMEC progeny as quantified by image analysis. Disrupted cell-cell communication, aberrant cell-extracellular matrix interactions, and loss of tissue-specific architecture observed in the daughters of irradiated HMEC are characteristic of neoplastic progression. These data point to a heritable, nonmutational mechanism whereby IR compromises cell polarity and multicellular organization.

  2. Sucralfate protects intestinal epithelial cells from radiation-induced apoptosis in rats

    International Nuclear Information System (INIS)

    Matsuu-Matsuyama, Mutsumi; Shichijo, Kazuko; Okaichi, Kumio

    2006-01-01

    Radiotherapy for malignant pelvic disease is often followed by acute radiation colitis (ARC). It has been reported that sucralfate treatment has a protective effect against ARC, though the mechanisms of action are unknown. The effects of sucralfate on X-ray radiation-induced apoptosis was studied at 4 Gy in the colonic crypt cells of rats. Sucralfate enemas given prior to radiation resulted in the following: reduction in number of apoptotic colonic crypt cells; reduction in number of caspase-3 positive cells; decreases in p53 accumulation and p21 expression; decreases of Bax/Bcl-2 ratio. The protective effects of sucralfate against ARC may be partially due to the suppression of radiation-induced apoptosis by way of p53 in the colon and the protection of the colonic epithelial stem cell region. (author)

  3. Radiation induced cell death in cervical squamous cell carcinoma. An immunohistochemical and ultrastructural study

    International Nuclear Information System (INIS)

    Atari, Eio; Toda, Takayoshi; Sadi, A.M.; Egawa, Haruhiko; Moromizato, Hidehiko; Mamadi, T.; Kiyuna, Masaya

    1998-01-01

    To study the process of cell death in cervical squamous cell carcinoma (SCC) after radiation, an ultrastructural and immunohistochemical study was performed. Paraffin-embedded tissue blocks of biopsy samples pre- and post-radiation stage III SCC (n=15) were collected. Irradiation caused varying ultrastructural changes including nuclear and cytoplasmic disorganization suggesting cell necrosis. Immunohistochemically, the pre-radiation specimens showed no positive reaction for tumor necrosis factor-alpha (TNF-α), tumor necrosis factor-receptor (TNF-γ) or Fas. C-fos, p53 and bcl-2 showed positive reactions in only a few non-irradiated specimens. All of the irradiated specimens showed a positive reaction for TNF-α, and variable positive reactions were observed for TNF-γ, Fas, p53, c-fos and bcl-2. These results suggest that TNF-α, TNF-γ, and c-fos are responsible for radiation induced cell death in cervical SCC. (author)

  4. Clinicopathological evaluation of radiation induced basal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Meibodi Naser

    2008-01-01

    Full Text Available Background: Development of skin neoplasms is one of the most important chronic complications of radiation therapy. Basal cell carcinoma (BCC is the most frequent carcinoma occurring at the region of the body to which radiotherapy was delivered. Aim: The aim of this study was to evaluate clinical and histological aspects of basal cell carcinoma in patients with a history of radiotherapy. Materials and Methods: Medical records and microscopic slides of 80 patients with basal cell carcinoma who had received radiotherapy (1996-2006 were reviewed in pathology department of Imam Reza hospital of Mashhad, Iran. Collected data were analyzed statistically using descriptive test. Results: 60 men and 20 women were included, majority of them in their sixties. Plaque was the most common clinical pattern of basal cell carcinoma. Fifty one percent of the patients had pigmented and 42.5% had multiple lesions. Scalp was the most common site of involvement. Histologically, macronodular and pigmented carcinoma were the most predominant forms of basal cell carcinoma. Discussion: Majority of patients had scalp involvement and multiple lesions. Nodular and pigmented forms were the most common histological findings. We suggest the need for close supervision in patients with a history of radio therapy in the past.

  5. Radiation-induced genetic effects in germ cells of mammals

    International Nuclear Information System (INIS)

    Van der Schans, G.P.

    1993-01-01

    The objectives of the project are a better understanding of the fundamental principles that determine the radiation sensitivity in humans, with specific attention for the role of DNA repair in germ cells. The induction and repair of damage in DNA of germ cells of the Syrian golden hamster exposed to ionizing radiation is studied at biologically relevant doses. It has also been investigated which aspects of DNA sequence or chromosomal organisation are important with respect to their influence on the repairability of DNA damage. (R.P.) 10 refs

  6. Study of microflora status of radiation-induced peripheral blood T cell and its subgroup changes

    International Nuclear Information System (INIS)

    Ding Hao; Wang Shengzi; Wang Shuyi; Lu Shenbin; Guo Ming; Tian Jie

    2009-01-01

    Objective: To observe the differences of the radiation-induced peripheral blood T cell and its subgroup changes between SPF and CV rats after nasopharyngeal radiation with gradient doses and explore the microflora factors in the pathogenesis of abnormal radiation-induced immunity status. Methods: 8 from each SPF and CV rats were chosen for oropharyngeal bacteria cultivation and determination and the spleen organ coefficients. The rest were irradiated with 6MX linear accelerator in the nasopharyngeal fields at dose of 0, 10, 20, 30 Gy, 5 in each group. 24 ∼ 36 h later, blood T lymphocytes and their subgroups were detected by FCM. Results: The bacteria of CV rats were pathogen mostly and the one from SPF rats was Proteus mirabilis uniquely. Spleen organ coefficients between two groups showed no statistical difference. CD + 3 , CD + 4 lymphocytes and the ratio of CD + 4 / CD + 8 of CV rats decreased dramatically after radiation is in close relation with radiation doses while The CD + 8 lymphocyte increased a bit. The CD + 3 , CD + 4 , CD + 8 lymphocytes and the ratio of CD + 4 / CD + 8 of SPF rats remained in a stable level. Conclusions: There exists the difference of radiation-induced injuries of immune system in relation with different microflora status. Micro-flora plays an important role in the radiation-induced immune system abnormity. (authors)

  7. Anti-apoptotic peptides protect against radiation-induced cell death

    International Nuclear Information System (INIS)

    McConnell, Kevin W.; Muenzer, Jared T.; Chang, Kathy C.; Davis, Chris G.; McDunn, Jonathan E.; Coopersmith, Craig M.; Hilliard, Carolyn A.; Hotchkiss, Richard S.; Grigsby, Perry W.; Hunt, Clayton R.

    2007-01-01

    The risk of terrorist attacks utilizing either nuclear or radiological weapons has raised concerns about the current lack of effective radioprotectants. Here it is demonstrated that the BH4 peptide domain of the anti-apoptotic protein Bcl-xL can be delivered to cells by covalent attachment to the TAT peptide transduction domain (TAT-BH4) and provide protection in vitro and in vivo from radiation-induced apoptotic cell death. Isolated human lymphocytes treated with TAT-BH4 were protected against apoptosis following exposure to 15 Gy radiation. In mice exposed to 5 Gy radiation, TAT-BH4 treatment protected splenocytes and thymocytes from radiation-induced apoptotic cell death. Most importantly, in vivo radiation protection was observed in mice whether TAT-BH4 treatment was given prior to or after irradiation. Thus, by targeting steps within the apoptosis signaling pathway it is possible to develop post-exposure treatments to protect radio-sensitive tissues

  8. Dying cells protect survivors from radiation-induced cell death in Drosophila.

    Directory of Open Access Journals (Sweden)

    Amber Bilak

    2014-03-01

    Full Text Available We report a phenomenon wherein induction of cell death by a variety of means in wing imaginal discs of Drosophila larvae resulted in the activation of an anti-apoptotic microRNA, bantam. Cells in the vicinity of dying cells also become harder to kill by ionizing radiation (IR-induced apoptosis. Both ban activation and increased protection from IR required receptor tyrosine kinase Tie, which we identified in a genetic screen for modifiers of ban. tie mutants were hypersensitive to radiation, and radiation sensitivity of tie mutants was rescued by increased ban gene dosage. We propose that dying cells activate ban in surviving cells through Tie to make the latter cells harder to kill, thereby preserving tissues and ensuring organism survival. The protective effect we report differs from classical radiation bystander effect in which neighbors of irradiated cells become more prone to death. The protective effect also differs from the previously described effect of dying cells that results in proliferation of nearby cells in Drosophila larval discs. If conserved in mammals, a phenomenon in which dying cells make the rest harder to kill by IR could have implications for treatments that involve the sequential use of cytotoxic agents and radiation therapy.

  9. Low-Dose Radiation Induces Genes Promoting Cell Survival

    International Nuclear Information System (INIS)

    Liu, Shu-Zheng; Chen, Dong; Mu, Ying

    1999-01-01

    Apoptosis is an important process controlling homeostasis of the body. It is influenced by stimuli constantly arising from the external and internal environment of the organism. It is well known that radiation could induce apoptosis of cells in vitro and in vivo. However, the dose-effect relationship of apoptosis extending to the low-dose range has scarcely been studied. Here, the molecular basis of the phenomenon is explored by examining the changes in expression of some of the proapoptotic and antiapoptotic genes

  10. Selenoprotein P Inhibits Radiation-Induced Late Reactive Oxygen Species Accumulation and Normal Cell Injury

    Energy Technology Data Exchange (ETDEWEB)

    Eckers, Jaimee C.; Kalen, Amanda L.; Xiao, Wusheng; Sarsour, Ehab H.; Goswami, Prabhat C., E-mail: prabhat-goswami@uiowa.edu

    2013-11-01

    Purpose: Radiation is a common mode of cancer therapy whose outcome is often limited because of normal tissue toxicity. We have shown previously that the accumulation of radiation-induced late reactive oxygen species (ROS) precedes cell death, suggesting that metabolic oxidative stress could regulate cellular radiation response. The purpose of this study was to investigate whether selenoprotein P (SEPP1), a major supplier of selenium to tissues and an antioxidant, regulates late ROS accumulation and toxicity in irradiated normal human fibroblasts (NHFs). Methods and Materials: Flow cytometry analysis of cell viability, cell cycle phase distribution, and dihydroethidium oxidation, along with clonogenic assays, were used to measure oxidative stress and toxicity. Human antioxidant mechanisms array and quantitative real-time polymerase chain reaction assays were used to measure gene expression during late ROS accumulation in irradiated NHFs. Sodium selenite addition and SEPP1 overexpression were used to determine the causality of SEPP1 regulating late ROS accumulation and toxicity in irradiated NHFs. Results: Irradiated NHFs showed late ROS accumulation (4.5-fold increase from control; P<.05) that occurs after activation of the cell cycle checkpoint pathways and precedes cell death. The mRNA levels of CuZn- and Mn-superoxide dismutase, catalase, peroxiredoxin 3, and thioredoxin reductase 1 increased approximately 2- to 3-fold, whereas mRNA levels of cold shock domain containing E1 and SEPP1 increased more than 6-fold (P<.05). The addition of sodium selenite before the radiation treatment suppressed toxicity (45%; P<.05). SEPP1 overexpression suppressed radiation-induced late ROS accumulation (35%; P<.05) and protected NHFs from radiation-induced toxicity (58%; P<.05). Conclusion: SEPP1 mitigates radiation-induced late ROS accumulation and normal cell injury.

  11. Identification of novel senescence-associated genes in ionizing radiation-induced senescent carcinoma cells

    International Nuclear Information System (INIS)

    Lee, Jae Seon; Kim, Bong Cho; Han, Na Kyung; Hong, Mi Na; Park, Su Min; Yoo, Hee Jung; Chu, In Sun; Lee, Sun Hee

    2009-01-01

    Cellular senescence is considered as a defense mechanism to prevent tumorigenesis. Ionizing radiation (IR) induces stress-induced premature senescence as well as apoptosis in various cancer cells. Senescent cells undergo functional and morphological changes including large and flattened cell shape, senescence-associated β-galactosidase (SA-βGal) activity, and altered gene expressions. Even with the recent findings of several gene expression profiles and supporting functional data, it is obscure that mechanism of IR-induced premature senescence in cancer cells. We performed microarray analysis to identify the common regulated genes in ionizing radiation-induced prematurely senescent human carcinoma cell lines

  12. Override of the radiation-induced mitotic block in human tumour cells by methylxanthines and its relationship to the potentiation of cytotoxicity

    International Nuclear Information System (INIS)

    Musk, S.R.R.; Steel, G.G.

    1990-01-01

    Caffeine, theophylline, theobromine and paraxanthine, were tested for ability to override mitotic block induced by ionizing radiation in the human bladder carcinoma cell line RT112. All were found to partially override the block, at a concentration of 1mM in the order caffeine > theophylline > theobromine = paraxanthine. At a concentration of 1 mM only caffeine was found to potentiate cell killing as well as causing block override; at higher concentrations all had a significant effect on survival but little or no further influence on the degree of block override. It is concluded that override of a mitotic block is not in itself sufficient to cause increased killing when irradiated cells are incubated in the presence of caffeine, and that caffeine exerts its potentiating effect by directly inhibiting repair of damage in DNA or by causing override of radiation-induced inhibition of DNA synthesis. (author)

  13. Override of the radiation-induced mitotic block in human tumour cells by methylxanthines and its relationship to the potentiation of cytotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Musk, S.R.R.; Steel, G.G. (Institute of Cancer Research, Sutton (UK). Surrey Branch)

    1990-06-01

    Caffeine, theophylline, theobromine and paraxanthine, were tested for ability to override mitotic block induced by ionizing radiation in the human bladder carcinoma cell line RT112. All were found to partially override the block, at a concentration of 1mM in the order caffeine > theophylline > theobromine = paraxanthine. At a concentration of 1 mM only caffeine was found to potentiate cell killing as well as causing block override; at higher concentrations all had a significant effect on survival but little or no further influence on the degree of block override. It is concluded that override of a mitotic block is not in itself sufficient to cause increased killing when irradiated cells are incubated in the presence of caffeine, and that caffeine exerts its potentiating effect by directly inhibiting repair of damage in DNA or by causing override of radiation-induced inhibition of DNA synthesis. (author).

  14. A case of radiation-induced squamous cell carcinoma of an 87-year-old physician

    International Nuclear Information System (INIS)

    Tanaka, Eiichiro; Takatsuka, Sumiko; Takenouchi, Tatsuya

    2005-01-01

    We reported a case of radiation-induced squamous cell carcinoma on the bilateral middle finger of an 87-year-old physician. He had exposed his hands to radiation without defense when he took an X-ray photograph. Squamous papules and ulcers occurred on both of his hands 10-years ago. The ulcer on the right middle finger enlarged rapidly after a one-month duration. A biopsy specimen showing squamous cell carcinoma derived from chronic radiation dermatitis, and disarticulation at the proximal interpharyngeal joint (PIP) joint of the right middle finger was performed. Six month later, hyperkeratotic tumor newly occurred on the opposite middle finger, and were operated on in the same way. The remaining lesions of chronic radiation dermatitis were treated by topical bleomycin hydrochloride. Since medical workers carelessly exposed their skin to radiation several decades ago, attention to late occurrence of radiation-induced skin cancer is needed. (author)

  15. Mesenchymal Stem Cells Adopt Lung Cell Phenotype in Normal and Radiation-induced Lung Injury Conditions.

    Science.gov (United States)

    Maria, Ola M; Maria, Ahmed M; Ybarra, Norma; Jeyaseelan, Krishinima; Lee, Sangkyu; Perez, Jessica; Shalaby, Mostafa Y; Lehnert, Shirley; Faria, Sergio; Serban, Monica; Seuntjens, Jan; El Naqa, Issam

    2016-04-01

    Lung tissue exposure to ionizing irradiation can invariably occur during the treatment of a variety of cancers leading to increased risk of radiation-induced lung disease (RILD). Mesenchymal stem cells (MSCs) possess the potential to differentiate into epithelial cells. However, cell culture methods of primary type II pneumocytes are slow and cannot provide a sufficient number of cells to regenerate damaged lungs. Moreover, effects of ablative radiation doses on the ability of MSCs to differentiate in vitro into lung cells have not been investigated yet. Therefore, an in vitro coculture system was used, where MSCs were physically separated from dissociated lung tissue obtained from either healthy or high ablative doses of 16 or 20 Gy whole thorax irradiated rats. Around 10±5% and 20±3% of cocultured MSCs demonstrated a change into lung-specific Clara and type II pneumocyte cells when MSCs were cocultured with healthy lung tissue. Interestingly, in cocultures with irradiated lung biopsies, the percentage of MSCs changed into Clara and type II pneumocytes cells increased to 40±7% and 50±6% at 16 Gy irradiation dose and 30±5% and 40±8% at 20 Gy irradiation dose, respectively. These data suggest that MSCs to lung cell differentiation is possible without cell fusion. In addition, 16 and 20 Gy whole thorax irradiation doses that can cause varying levels of RILD, induced different percentages of MSCs to adopt lung cell phenotype compared with healthy lung tissue, providing encouraging outlook for RILD therapeutic intervention for ablative radiotherapy prescriptions.

  16. Modulation of radiation-induced apoptosis and G{sub 2}/M block in murine T-lymphoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Palayoor, S.T.; Macklis, R.M.; Bump, E.A.; Coleman, C.N. [Harvard Medical School, Boston, MA (United States)

    1995-03-01

    Radiation-induced apoptosis in lymphocyte-derived cell lines is characterized by endonucleolytic cleavage of cellular DNA within hours after radiation exposure. We have studied this phenomenon qualitatively (DNA gel electrophoresis) and quantitatively (diphenylamine reagent assay) in murine EL4 T-lymphoma cells exposed to {sup 137}Cs {gamma} irradiation. Fragmentation was discernible within 18-24 h after exposure. It increased with time and dose and reached a plateau after 8 Gy of {gamma} radiation. We studied the effect of several pharmacological agents on the radiation-induced G{sub 2}/M block and DNA fragmentation. The agents which reduced the radiation-induced G{sub 2}/M-phase arrest (caffeine, theobromine, theophylline and 2-aminopurine) enhanced the degree of DNA fragmentation at 24 h. In contrast, the agents which sustained the radiation-induced G{sub 2}/M-phase arrest (TPA, DBcAMP, IBMX and 3-aminobenzamide) inhibited the DNA fragmentation at 24 h. These studies on EL4 lymphoma cells are consistent with the hypothesis that cells with radiation-induced genetic damage are eliminated by apoptosis subsequent to a G{sub 2}/M block. Furthermore, it may be possible to modulate the process of radiation-induced apoptosis in lymphoma cells with pharmacological agents that modify the radiation-induced G{sub 2}/M block, and to use this effect in the treatment of patients with malignant disease. 59 refs., 7 figs.

  17. Modulation of radiation-induced apoptosis and G2/M block in murine T-lymphoma cells

    International Nuclear Information System (INIS)

    Palayoor, S.T.; Macklis, R.M.; Bump, E.A.; Coleman, C.N.

    1995-01-01

    Radiation-induced apoptosis in lymphocyte-derived cell lines is characterized by endonucleolytic cleavage of cellular DNA within hours after radiation exposure. We have studied this phenomenon qualitatively (DNA gel electrophoresis) and quantitatively (diphenylamine reagent assay) in murine EL4 T-lymphoma cells exposed to 137 Cs γ irradiation. Fragmentation was discernible within 18-24 h after exposure. It increased with time and dose and reached a plateau after 8 Gy of γ radiation. We studied the effect of several pharmacological agents on the radiation-induced G 2 /M block and DNA fragmentation. The agents which reduced the radiation-induced G 2 /M-phase arrest (caffeine, theobromine, theophylline and 2-aminopurine) enhanced the degree of DNA fragmentation at 24 h. In contrast, the agents which sustained the radiation-induced G 2 /M-phase arrest (TPA, DBcAMP, IBMX and 3-aminobenzamide) inhibited the DNA fragmentation at 24 h. These studies on EL4 lymphoma cells are consistent with the hypothesis that cells with radiation-induced genetic damage are eliminated by apoptosis subsequent to a G 2 /M block. Furthermore, it may be possible to modulate the process of radiation-induced apoptosis in lymphoma cells with pharmacological agents that modify the radiation-induced G 2 /M block, and to use this effect in the treatment of patients with malignant disease. 59 refs., 7 figs

  18. Effects of smoke and tea on radiation-induced bone marrow cell mutation and marrow inhibition

    International Nuclear Information System (INIS)

    Gao Yong; Zhang Weiguang

    2004-01-01

    Objective: To provide scientific information for the prevention and treatment of the radiation damage by analyzing the effects of smoke and tea on radiation-induced bone marrow cell mutation and marrow inhibition. Methods: 7 group mice were exposed to smoke and/or tea and/or radiation respectively. There were also b blank control group and a cyclophosphamide positive control group. The frequencies of micronucleated polychromatic erythrocytes (MPCE), the ratio of polychromatic erythrocytes (PCE) to mature erythrocytes (RBC) in marrow, and the count of peripheral blood hemoleukocyte were observed. Results: The frequencies of MPCE in the groups irradiated with γ-rays were significantly higher than that in the blank control group (P<0.05 or 0.01). The smoke + radiation group's frequency was significantly higher than single radiation group (P<0.05). The ratios of PCE to RBC in the groups irradiated were significantly lower than that in the blank control group (P<0.01). The counts of peripheral blood hemoleukocyte in the groups irradiated were significantly lower than the blank control group (P<0.01). Conclusion: Radiation were able to cause marrow cell mutation and induce marrow inhibition. Smoke increases the effect of radiation-induced marrow cell mutation. Tea and smoke could not affect radiation-induced bone marrow inhibition

  19. Trans-differentiation of neural stem cells: a therapeutic mechanism against the radiation induced brain damage.

    Directory of Open Access Journals (Sweden)

    Kyeung Min Joo

    Full Text Available Radiation therapy is an indispensable therapeutic modality for various brain diseases. Though endogenous neural stem cells (NSCs would provide regenerative potential, many patients nevertheless suffer from radiation-induced brain damage. Accordingly, we tested beneficial effects of exogenous NSC supplementation using in vivo mouse models that received whole brain irradiation. Systemic supplementation of primarily cultured mouse fetal NSCs inhibited radiation-induced brain atrophy and thereby preserved brain functions such as short-term memory. Transplanted NSCs migrated to the irradiated brain and differentiated into neurons, astrocytes, or oligodendrocytes. In addition, neurotrophic factors such as NGF were significantly increased in the brain by NSCs, indicating that both paracrine and replacement effects could be the therapeutic mechanisms of NSCs. Interestingly, NSCs also differentiated into brain endothelial cells, which was accompanied by the restoration the cerebral blood flow that was reduced from the irradiation. Inhibition of the VEGF signaling reduced the migration and trans-differentiation of NSCs. Therefore, trans-differentiation of NSCs into brain endothelial cells by the VEGF signaling and the consequential restoration of the cerebral blood flow would also be one of the therapeutic mechanisms of NSCs. In summary, our data demonstrate that exogenous NSC supplementation could prevent radiation-induced functional loss of the brain. Therefore, successful combination of brain radiation therapy and NSC supplementation would provide a highly promising therapeutic option for patients with various brain diseases.

  20. Ionizing radiation induces senescence and differentiation of human dental pulp stem cells.

    Science.gov (United States)

    Havelek, R; Soukup, T; Ćmielová, J; Seifrtová, M; Suchánek, J; Vávrová, J; Mokrý, J; Muthná, D; Řezáčová, M

    2013-01-01

    Head and neck cancer is one of the most common cancers in Europe. Many current anti-cancer treatments, including ionizing radiation, induce apoptosis via DNA damage. Unfortunately, such treatments are non-selective to cancer cells and produce similar toxicity in normal cells, including adult stem cells. One of the fundamental properties of an adult stem cell is that it does not have any tissue-specific structures that allow it to perform specialized functions. However, under certain stimuli, unspecialized adult stem cells can give rise to specialized cells to generate replacements for cells that are lost during one's life or due to injury or disease. Nevertheless, specialization of stem cells must be controlled by specific milieu and also initiated at the proper time, making the entire process beneficial for tissue recovery and maintaining it for a long time. In this paper we assess whether irradiated dental pulp stem cells have maintained open their options to mature into specialized cells, or whether they have lost their unspecialized (immature) state following irradiation. Our findings showed radiation-induced premature differentiation of dental pulp stem cells towards odonto-/osteoblast lineages in vitro. Matrix calcification was visualized from Day 6 or Day 9 following irradiation of cells expressing low or high levels of CD146, respectively.

  1. Radiation induced bystander effect on hepatoma HepG2 cells under hypoxia condition

    International Nuclear Information System (INIS)

    Zhang Jianghong; Jin Yizun; Shao Chunlin; Prise KM

    2009-01-01

    Objective: To investigate radiation induced bystander effect and its mechanism on hepatoma HepG2 cells under hypoxia condition. Methods: Non-irradiated bystander hepatoma cells were co-cultured with irradiated cells or treated with the conditioned medium (CM) from irradiated cells, then micronuclei (MN) were measured for both irradiated cells and bystander cells. Results: The MN yield of irradiated HepG2 cells under hypoxic condition was significantly lower than that under normoxia, the oxygen enhancement ratio of HepG2 cells of MN was 1.6. For both hypoxic and normoxic condition, the MN yield of bystander cells were obviously enhanced to a similar high level after co-culturing with irradiated cells or with CM treatment, and it also correlated with the irradiation dose. When the hypoxic HepG2 cells were treated with either DMSO, a scavenger of reactive oxygen species (ROS), or aminoguanidine, an iNOS inhibitor, the yield of bystander MN was partly diminished, and the reducing rate of DMSO was 42.2%-46.7%, the reducing rate of aminoguanidine was 42% . Conclusion: ROS, NO and their downstream signal factors are involved in the radiation induced bystander effect of hypoxic HepG2 cells. (authors)

  2. The effects of herbs on the radiation-induced apoptosis in intestinal crypt cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung Ho; An, Mi Ra; Nah, Seung Yeol; Lee, Jong Hwan; Kim, Jae Ha; Shin, Dong Ho [Chonnam National Univ., Gwangju (Korea, Republic of); Jo, Sung Kee [KAERI, Daejeon (Korea, Republic of); Jang, Jong Sik [Sangju National Univ., Sangju (Korea, Republic of)

    2001-03-15

    This study was performed to determine the effect of several herbs on radiation-induced apoptosis in jejunal crypt cells. Longyanrou(Euphoris logana), Suanzaoren(Zizyphus vulgaris), Yuanzhi(Polygala tenuifolia), Rensan(Panax ginseng), Fuling(Poria cocos), Muxiang(Saussurea lappa), Chuanxiong(Cnidium offcinale), Baishaoyao(Paeonia lactifolia), Shengma(Cimicifuga heracleifolia), Chaihu(Bupleurum falcatum) and Dongchongxiacao(Paecilomyces japonica) reduced the frequency of radiation-induced apoptosis(p<0.05). Although the mechanisms of this effect remain to be elucidated, these results indicated that Longyanrou, Suanzaoren, Yuanzhi, Rensan, Fuling, Muxiang, Chuanxiong, Baishaoyao, Shengma, Chaihu and Dongchongxiacao might be useful inhibitors of apoptosis, especially since these are relative nontoxic natural products.

  3. Radiation-induced enhancement of enzymatic cell lysis of Micrococcus radiodurans

    International Nuclear Information System (INIS)

    Watanabe, H.; Takehisa, M.; Iizuka, H.

    1981-01-01

    The intact cells of M. radiodurans were rendered sensitive to the action of lytic enzyme (P2-2 enzyme) by irradiation. The radiation-induced enhancement of cell lysis with P2-2 enzyme was completely prevented by the addition of t-butanol and irradiation at liquid nitrogen temperature. These results indicate that the enhancement is due to indirect action resulting from OH radicals. Cell lysis by lysozyme was enhanced only when the cells were irradiated under N 2 O. The enhancement of cell lysis with lysozyme was also prevented by adding alcohols. On the other hand, when lipid components in cells were removed by extraction with n-butanol, the radiation-induced enhancement of cell lysis with P2-2 enzyme and lysozyme was not observed. From these results it is concluded that the enhancement of enzymatic cell lysis by irradiation is attributable to alteration in the lipid-rich layer of the cell wall caused by OH radicals

  4. Radiation-induced enhancement of enzymatic cell lysis of Micrococcus radiodurans

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, H.; Takehisa, M. [Japan Atomic Energy Research Inst., Takasaki, Gunma, Takasaki Radiation Chemistry Research Establishment (Japan); Iizuka, H.

    1981-10-15

    The intact cells of M. radiodurans were rendered sensitive to the action of lytic enzyme (P2-2 enzyme) by irradiation. The radiation-induced enhancement of cell lysis with P2-2 enzyme was completely prevented by the addition of t-butanol and irradiation at liquid nitrogen temperature. These results indicate that the enhancement is due to indirect action resulting from OH radicals. Cell lysis by lysozyme was enhanced only when the cells were irradiated under N{sub 2}O. The enhancement of cell lysis with lysozyme was also prevented by adding alcohols. On the other hand, when lipid components in cells were removed by extraction with n-butanol, the radiation-induced enhancement of cell lysis with P2-2 enzyme and lysozyme was not observed. From these results it is concluded that the enhancement of enzymatic cell lysis by irradiation is attributable to alteration in the lipid-rich layer of the cell wall caused by OH radicals.

  5. Radiation induced bystander effects in modification of cellular radio-sensitivity in human cancer cells

    International Nuclear Information System (INIS)

    Pandey, B.N.

    2012-01-01

    Radiation-induced Bystander Effect is manifestation of radiation effects in non-irradiated cells in the population. The phenomenon may have significant implication in risk of radiation induced cancer incidence and outcome of cancer radiotherapy. To understand the bystander interaction in tumor cells, we have studied secretion of diffusible factors from control and irradiated tumor cells of different origin. Our results showed a good correlation between magnitude of secretion of diffusible factors and survival of tumor cells. These diffusible factors are shown to affect proliferation and survival of tumor cells involving regulation of kinases and genes/proteins involved in apoptotic machinery. Our experiments using pharmacological inhibitors showed involvement of activating transcription factor 2 (ATF-2) signaling in survival of tumor cells after treatment with diffusible factors. These factors seem to be involved in exerting radio-resistance in tumor cells. Furthermore, in proton microbeam irradiation studies showed induction of double strand break measured as gH2AX foci in human lung carcinoma cells, which was found to propagate to bystander tumor cells during post-irradiation incubation. Implication of these observations in outcome of cancer radiotherapy scenario would be discussed. (author)

  6. Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice

    Directory of Open Access Journals (Sweden)

    Pasupathi Sundaramoorthy

    2017-11-01

    Full Text Available Abstract Background Radiation exposure poses a significant threat to public health. Hematopoietic injury is one of the major manifestations of acute radiation sickness. Protection and/or mitigation of hematopoietic stem cells (HSCs from radiation injury is an important goal in the development of medical countermeasure agents (MCM. We recently identified thioredoxin (TXN as a novel molecule that has marked protective and proliferative effects on HSCs. In the current study, we investigated the effectiveness of TXN in rescuing mice from a lethal dose of total body radiation (TBI and in enhancing hematopoietic reconstitution following a lethal dose of irradiation. Methods We used in-vivo and in-vitro methods to understand the biological and molecular mechanisms of TXN on radiation mitigation. BABL/c mice were used for the survival study and a flow cytometer was used to quantify the HSC population and cell senescence. A hematology analyzer was used for the peripheral blood cell count, including white blood cells (WBCs, red blood cells (RBCs, hemoglobin, and platelets. Colony forming unit (CFU assay was used to study the colongenic function of HSCs. Hematoxylin and eosin staining was used to determine the bone marrow cellularity. Senescence-associated β-galactosidase assay was used for cell senescence. Western blot analysis was used to evaluate the DNA damage and senescence protein expression. Immunofluorescence staining was used to measure the expression of γ-H2AX foci for DNA damage. Results We found that administration of TXN 24 h following irradiation significantly mitigates BALB/c mice from TBI-induced death: 70% of TXN-treated mice survived, whereas only 25% of saline-treated mice survived. TXN administration led to enhanced recovery of peripheral blood cell counts, bone marrow cellularity, and HSC population as measured by c-Kit+Sca-1+Lin– (KSL cells, SLAM + KSL cells and CFUs. TXN treatment reduced cell senescence and radiation-induced

  7. Radiation-induced apoptosis in sensitive and resistant cells isolated from a mouse lymphoma

    International Nuclear Information System (INIS)

    Story, M.D.; Voehringer, D.W.; Malone, C.G.; Hobbs, M.L.; Meyn, R.E.

    1994-01-01

    Cells were isolated from a mouse lymphoma (LY-TH) and grown in vitro. They were susceptible to radiation-induced apoptosis after low doses with the appearance of endonucleolytically fragmented DNA 1 h after irradiation. Four hours after receiving 5 Gy, 80% of the DNA was endonucleolytically cleaved. Apoptosis induction by DNA double-strand break (dsb) formation was more effective compared with induction by single-strand break (ssb) formation. After long-term culturing, LY-TH cultures became refractory to apoptosis. Apoptosis-permissive cells (LY-as, cloned from LY-TH cells) were three times more radiosensitive than clonally expanded apoptosis-refractory cells (LY-ar). Low dose-rate irradiation and maintenance at 25 o C for 5 h postirradiation was sparing in LY-ar but not LY-as cells, suggesting a repair deficiency in LY-as cells. Analysis of dsb rejoining kinetics revealed no difference in the initial phase of dsb rejoining. After 1 h, however, relative dsbs in the LY-as variant increased as endonucleolytic cleavage was initiated. Signalling for radiation-induced apoptosis in LY-as cells was independent of the DNA dsb repair pathway and appeared determined by initial events, whereas in LY-ar cells, because of an inhibition in the apoptotic pathway, survival was enhanced and modifiable by repair processes. (author)

  8. Protection against radiation-induced oxidative stress in cultured human epithelial cells by treatment with antioxidant agents

    International Nuclear Information System (INIS)

    Wan, X. Steven; Ware, Jeffrey H.; Zhou, Zhaozong; Donahue, Jeremiah J.; Guan, Jun; Kennedy, Ann R.

    2006-01-01

    Purpose: To evaluate the protective effects of antioxidant agents against space radiation-induced oxidative stress in cultured human epithelial cells. Methods and Materials: The effects of selected concentrations of N-acetylcysteine, ascorbic acid, sodium ascorbate, co-enzyme Q10, α-lipoic acid, L-selenomethionine, and vitamin E succinate on radiation-induced oxidative stress were evaluated in MCF10 human breast epithelial cells exposed to radiation with X-rays, γ-rays, protons, or high mass, high atomic number, and high energy particles using a dichlorofluorescein assay. Results: The results demonstrated that these antioxidants are effective in protecting against radiation-induced oxidative stress and complete or nearly complete protection was achieved by treating the cells with a combination of these agents before and during the radiation exposure. Conclusion: The combination of antioxidants evaluated in this study is likely be a promising countermeasure for protection against space radiation-induced adverse biologic effects

  9. Transmission of persistent ionizing radiation-induced foci through cell division in human primary cells

    Energy Technology Data Exchange (ETDEWEB)

    Vaurijoux, Aurelie, E-mail: aurelie.vaurijoux@irsn.fr [Institut de Radioprotection et de Sureté Nucléaire (IRSN), Laboratoire de Dosimétrie Biologique, BP 17, 92262 Fontenay aux roses cedex (France); Voisin, Pascale; Freneau, Amelie [Institut de Radioprotection et de Sureté Nucléaire (IRSN), Laboratoire de Dosimétrie Biologique, BP 17, 92262 Fontenay aux roses cedex (France); Barquinero, Joan Francesc [Universitat Autònoma de Barcelona, Faculty of Biosciences, 08193 Cerdanyola del Vallès (Spain); Gruel, Gaetan [Institut de Radioprotection et de Sureté Nucléaire (IRSN), Laboratoire de Dosimétrie Biologique, BP 17, 92262 Fontenay aux roses cedex (France)

    2017-03-15

    Highlights: • Persistent IRIF do not permanently block cell proliferation. • Persistent IRIF are transmitted in part and sometimes asymmetrically to daughter cells. • IRIF differ in their nature before and after the first cell division. - Abstract: Unrepaired DNA double-strand breaks (DSBs) induced by ionizing radiation are associated with lethal effects and genomic instability. After the initial breaks and chromatin destabilization, a set of post-translational modifications of histones occurs, including phosphorylation of serine 139 of histone H2AX (γH2AX), which leads to the formation of ionizing radiation-induced foci (IRIF). DSB repair results in the disappearance of most IRIF within hours after exposure, although some remain 24 h after irradiation. Their relation to unrepaired DSBs is generally accepted but still controversial. This study evaluates the frequency and kinetics of persistent IRIF and analyzes their impact on cell proliferation. We observed persistent IRIF up to 7 days postirradiation, and more than 70% of cells exposed to 5 Gy had at least one of these persistent IRIF 24 h after exposure. Moreover we demonstrated that persistent IRIF did not block cell proliferation definitively. The frequency of IRIF was lower in daughter cells, due to asymmetric distribution of IRIF between some of them. We report a positive association between the presence of IRIF and the likelihood of DNA missegregation. Hence, the structure formed after the passage of a persistent IRI focus across the S and G2 phases may impede the correct segregation of the affected chromosome's sister chromatids. The ensuing abnormal resolution of anaphase might therefore cause the nature of IRIF in daughter-cell nuclei to differ before and after the first cell division. The resulting atypical chromosomal assembly may be lethal or result in a gene dosage imbalance and possibly enhanced genomic instability, in particular in the daughter cells.

  10. Transmission of persistent ionizing radiation-induced foci through cell division in human primary cells

    International Nuclear Information System (INIS)

    Vaurijoux, Aurelie; Voisin, Pascale; Freneau, Amelie; Barquinero, Joan Francesc; Gruel, Gaetan

    2017-01-01

    Highlights: • Persistent IRIF do not permanently block cell proliferation. • Persistent IRIF are transmitted in part and sometimes asymmetrically to daughter cells. • IRIF differ in their nature before and after the first cell division. - Abstract: Unrepaired DNA double-strand breaks (DSBs) induced by ionizing radiation are associated with lethal effects and genomic instability. After the initial breaks and chromatin destabilization, a set of post-translational modifications of histones occurs, including phosphorylation of serine 139 of histone H2AX (γH2AX), which leads to the formation of ionizing radiation-induced foci (IRIF). DSB repair results in the disappearance of most IRIF within hours after exposure, although some remain 24 h after irradiation. Their relation to unrepaired DSBs is generally accepted but still controversial. This study evaluates the frequency and kinetics of persistent IRIF and analyzes their impact on cell proliferation. We observed persistent IRIF up to 7 days postirradiation, and more than 70% of cells exposed to 5 Gy had at least one of these persistent IRIF 24 h after exposure. Moreover we demonstrated that persistent IRIF did not block cell proliferation definitively. The frequency of IRIF was lower in daughter cells, due to asymmetric distribution of IRIF between some of them. We report a positive association between the presence of IRIF and the likelihood of DNA missegregation. Hence, the structure formed after the passage of a persistent IRI focus across the S and G2 phases may impede the correct segregation of the affected chromosome's sister chromatids. The ensuing abnormal resolution of anaphase might therefore cause the nature of IRIF in daughter-cell nuclei to differ before and after the first cell division. The resulting atypical chromosomal assembly may be lethal or result in a gene dosage imbalance and possibly enhanced genomic instability, in particular in the daughter cells.

  11. Hydrolysis of fish protein by Bacillus megaterium cells immobilized in radiation induced polymerized wood

    International Nuclear Information System (INIS)

    Ghosh, S.; Alur, M.D.; Nerkar, D.P.

    1992-01-01

    The immobilization of Bacillus megaterium cells in radiation-induced polymerized wood was studied for hydrolysis of trash fish protein. The optimum conditions and reaction kinetics for hydrolysis of protein by free and immobilized cells were found to be similar. Maximum hydrolysis occurred at 50 o C and at pH 7.5 with 15-20% (w/v) of immobilized matrix. The soluble content of the resultant hydrolysate about 2.4% (w/v). (author). 10 refs., 4 figs

  12. Immobilization of yeast cells on hydrogel carriers obtained by radiation-induced polymerization

    International Nuclear Information System (INIS)

    Luzhao Xin; Carenza, M.; Kaetsu, Isao; Kumakura, Minoru; Yoshida, Masaru; Fujimura, Takashi

    1992-01-01

    Polymer hydrogels were obtained by radiation-induced copolymerization at -78 o C of aqueous solutions of acrylic and methacrylic esters. The matrices were characterized by equilibrium water content measurements, by optical microscopy observations and by scanning electron microscopy analysis. Yeast cells were immobilized on these hydrogels and the ethanol productivity by batch fermentation was determined. Matrix hydrophilicity and porosity were found to deeply influence the adhesion of yeast cells and, hence, the ethanol productivity. The latter as well as other physico-chemical properties were also affected by the presence of a crosslinking agent added in small amounts to the polymerizating mixture. (author)

  13. Microrna-31 mediates radiation induced apoptosis selectively in malignant tumour cells with dysfunctional P53

    International Nuclear Information System (INIS)

    Kumar, Ashish; Mukherjee, Prabuddho; Babu, Bincy; Chandna, Sudhir

    2016-01-01

    The protein p53 has been recognized as an important radio-responsive protein which functions mainly through transcriptional control of its target genes and microRNAs that target multiple response pathways. In this study, we investigate a putative link between p53 functionality and microRNA-31 expression that largely contributes to cellular transformation/malignancy and also establishes the role of miR-31 in radiation-induced cell death. The expression of miR-31 is found to be attenuated in cells in successive stages of cancer progression

  14. Nicaraven attenuates radiation-induced injury in hematopoietic stem/progenitor cells in mice.

    Directory of Open Access Journals (Sweden)

    Miho Kawakatsu

    Full Text Available Nicaraven, a chemically synthesized hydroxyl radical-specific scavenger, has been demonstrated to protect against ischemia-reperfusion injury in various organs. We investigated whether nicaraven can attenuate radiation-induced injury in hematopoietic stem/progenitor cells, which is the conmen complication of radiotherapy and one of the major causes of death in sub-acute phase after accidental exposure to high dose radiation. C57BL/6 mice were exposed to 1 Gy γ-ray radiation daily for 5 days in succession (a total of 5 Gy, and given nicaraven or a placebo after each exposure. The mice were sacrificed 2 days after the last radiation treatment, and the protective effects and relevant mechanisms of nicaraven in hematopoietic stem/progenitor cells with radiation-induced damage were investigated by ex vivo examination. We found that post-radiation administration of nicaraven significantly increased the number, improved the colony-forming capacity, and decreased the DNA damage of hematopoietic stem/progenitor cells. The urinary levels of 8-oxo-2'-deoxyguanosine, a marker of DNA oxidation, were significantly lower in mice that were given nicaraven compared with those that received a placebo treatment, although the levels of intracellular and mitochondrial reactive oxygen species in the bone marrow cells did not differ significantly between the two groups. Interestingly, compared with the placebo treatment, the administration of nicaraven significantly decreased the levels of the inflammatory cytokines IL-6 and TNF-α in the plasma of mice. Our data suggest that nicaraven effectively diminished the effects of radiation-induced injury in hematopoietic stem/progenitor cells, which is likely associated with the anti-oxidative and anti-inflammatory properties of this compound.

  15. Radiation-induced apoptosis in differentially modulated by PTK inhibitora in K562 cells

    International Nuclear Information System (INIS)

    Lee, Hyung Sik; Moon, Chang Woo; Hur, Won Joo; Jeong, Su Jin; Jeong Min Ho; Lee, Jeong Hyeon; Lim, Young Jin; Park, Heon Joo

    2000-01-01

    The effect of PTK inhibitors (herbimycin A and genistein) on the induction of radiation-induced apoptosis in Ph-positive K562 leukemia cell line was investigated. K562 cells in exponential growth phase were irradiated with a linear accelerator at room temperature. For 6 MV X-ray irradiation and drug treatment, cultures were initiated at 2x10 6 cells/ml. The cells were irradiated with 10Gy. Stock solutions of herbimycin A and genistein were prepared in dimethyl sulphoxide (DMSO). After incubation at 37 .deg. for 0-48 h, the extent of apoptosis was determined using agarose gel electrophoresis and TUNEL assay. The progression of cells through the cell cycle after irradiation and drug treatment was also determined with flow cytometry. Western blot analysis was used to monitor bcl-2, bcl-X-L and bax protein levels. Treatment with 10 Gy X-irradiation did not result in the induction of apoptosis. The HMA alone (500 nM) also failed to induce apoptosis. By contrast, incubation of K562 cells with HMA after irradiation resulted in a substantial induction of nuclear condensation and fragmentation by agarose gel electrophoresis and TUNEL assay. Genistein failed to enhance the ability of X-irradiation to induce DNA fragmentation. Enhancement of apoptosis by HMA was not attributable to downregulation of the bcl-2 or bcl-X-L anti-apoptotic proteins. When the cells were irradiated and maintained with HMA, the percentage of cells in G2/M phase decreased to 30-40% at 48 h. On the other hand, cells exposed to 10 Gy X-irradiation alone or maintained with genistein did not show marked cell cycle redistribution. We have shown that nanomolar concentrations of the PTK inhibitor HMA synergize with X-irradiation in inducing the apoptosis in Ph (+) K562 leukemia cell line. While, genistein, a PTK inhibitor which is not selective for p210 bcr/abl failed to enhance the radiation induced apoptosis in K562 cells. It is unlikely that the ability of HMA to enhance apoptosis in K562 cells is

  16. Radiation-induced alterations of histone post-translational modification levels in lymphoblastoid cell lines

    International Nuclear Information System (INIS)

    Maroschik, Belinda; Gürtler, Anne; Krämer, Anne; Rößler, Ute; Gomolka, Maria; Hornhardt, Sabine; Mörtl, Simone; Friedl, Anna A

    2014-01-01

    Radiation-induced alterations in posttranslational histone modifications (PTMs) may affect the cellular response to radiation damage in the DNA. If not reverted appropriately, altered PTM patterns may cause long-term alterations in gene expression regulation and thus lead to cancer. It is therefore important to characterize radiation-induced alterations in PTM patterns and the factors affecting them. A lymphoblastoid cell line established from a normal donor was used to screen for alterations in methylation levels at H3K4, H3K9, H3K27, and H4K20, as well as acetylation at H3K9, H3K56, H4K5, and H4K16, by quantitative Western Blot analysis at 15 min, 1 h and 24 h after irradiation with 2 Gy and 10 Gy. The variability of alterations in acetylation marks was in addition investigated in a panel of lymphoblastoid cell lines with differing radiosensitivity established from lung cancer patients. The screening procedure demonstrated consistent hypomethylation at H3K4me3 and hypoacetylation at all acetylation marks tested. In the panel of lymphoblastoid cell lines, however, a high degree of inter-individual variability became apparent. Radiosensitive cell lines showed more pronounced and longer lasting H4K16 hypoacetylation than radioresistant lines, which correlates with higher levels of residual γ-H2AX foci after 24 h. So far, the factors affecting extent and duration of radiation-induced histone alterations are poorly defined. The present work hints at a high degree of inter-individual variability and a potential correlation of DNA damage repair capacity and alterations in PTM levels

  17. Three-dimensional culture conditions lead to decreased radiation induced cytotoxicity in human mammary epithelial cells

    International Nuclear Information System (INIS)

    Sowa, Marianne B.; Chrisler, William B.; Zens, Kyra D.; Ashjian, Emily J.; Opresko, Lee K.

    2010-01-01

    For both targeted and non-targeted exposures, the cellular responses to ionizing radiation have predominantly been measured in two-dimensional monolayer cultures. Although convenient for biochemical analysis, the true interactions in vivo depend upon complex interactions between cells themselves and the surrounding extracellular matrix. This study directly compares the influence of culture conditions on radiation induced cytotoxicity following exposure to low-LET ionizing radiation. Using a three-dimensional (3D) human mammary epithelial tissue model, we have found a protective effect of 3D cell culture on cell survival after irradiation. The initial state of the cells (i.e., 2D versus 3D culture) at the time of irradiation does not alter survival, nor does the presence of extracellular matrix during and after exposure to dose, but long term culture in 3D which offers significant reduction in cytotoxicity at a given dose (e.g. ∼4-fold increased survival at 5 Gy). The cell cycle delay induced following exposure to 2 and 5 Gy was almost identical between 2D and 3D culture conditions and cannot account for the observed differences in radiation responses. However the amount of apoptosis following radiation exposure is significantly decreased in 3D culture relative to the 2D monolayer after the same dose. A likely mechanism of the cytoprotective effect afforded by 3D culture conditions is the down regulation of radiation induced apoptosis in 3D structures.

  18. Flow cytometric determination of radiation-induced chromosome damage and its correlation with cell survival

    International Nuclear Information System (INIS)

    Welleweerd, J.; Wilder, M.E.; Carpenter, S.G.; Raju, M.R.

    1984-01-01

    Chinese hamster M3-1 cells were irradiated with several doses of x rays or α particles from 238 Pu. Propidium iodide-stained chromosome suspensions were prepared at different times after irradiation; cells were also assayed for survival. The DNA histograms of these chromosomes showed increased background counts with increased doses of radiation. This increase in background was cell-cycle dependent and was correlated with cell survival. The correlation between radiation-induced chromosome damage and cell survival was the same for X rays and α particles. Data are presented which indicate that flow cytometric analysis of chromosomes of irradiated cell populations can be a useful adjunct to classical cytogenic analysis of irradiation-induced chromosomal damage by virtue of its ability to express and measure chromosomal damage not seen by classical cytogenic methods

  19. Monoclonal TCR-redirected tumor cell killing.

    Science.gov (United States)

    Liddy, Nathaniel; Bossi, Giovanna; Adams, Katherine J; Lissina, Anna; Mahon, Tara M; Hassan, Namir J; Gavarret, Jessie; Bianchi, Frayne C; Pumphrey, Nicholas J; Ladell, Kristin; Gostick, Emma; Sewell, Andrew K; Lissin, Nikolai M; Harwood, Naomi E; Molloy, Peter E; Li, Yi; Cameron, Brian J; Sami, Malkit; Baston, Emma E; Todorov, Penio T; Paston, Samantha J; Dennis, Rebecca E; Harper, Jane V; Dunn, Steve M; Ashfield, Rebecca; Johnson, Andy; McGrath, Yvonne; Plesa, Gabriela; June, Carl H; Kalos, Michael; Price, David A; Vuidepot, Annelise; Williams, Daniel D; Sutton, Deborah H; Jakobsen, Bent K

    2012-06-01

    T cell immunity can potentially eradicate malignant cells and lead to clinical remission in a minority of patients with cancer. In the majority of these individuals, however, there is a failure of the specific T cell receptor (TCR)–mediated immune recognition and activation process. Here we describe the engineering and characterization of new reagents termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs). Four such ImmTACs, each comprising a distinct tumor-associated epitope-specific monoclonal TCR with picomolar affinity fused to a humanized cluster of differentiation 3 (CD3)-specific single-chain antibody fragment (scFv), effectively redirected T cells to kill cancer cells expressing extremely low surface epitope densities. Furthermore, these reagents potently suppressed tumor growth in vivo. Thus, ImmTACs overcome immune tolerance to cancer and represent a new approach to tumor immunotherapy.

  20. Protective effect of mild endoplasmic reticulum stress on radiation-induced bystander effects in hepatocyte cells

    Science.gov (United States)

    Xie, Yuexia; Ye, Shuang; Zhang, Jianghong; He, Mingyuan; Dong, Chen; Tu, Wenzhi; Liu, Peifeng; Shao, Chunlin

    2016-01-01

    Radiation-induced bystander effect (RIBE) has important implications for secondary cancer risk assessment during cancer radiotherapy, but the defense and self-protective mechanisms of bystander normal cells are still largely unclear. The present study found that micronuclei (MN) formation could be induced in the non-irradiated HL-7702 hepatocyte cells after being treated with the conditioned medium from irradiated hepatoma HepG2 cells under either normoxia or hypoxia, where the ratio of the yield of bystander MN induction to the yield of radiation-induced MN formation under hypoxia was much higher than that of normoxia. Nonetheless, thapsigargin induced endoplasmic reticulum (ER) stress and dramatically suppressed this bystander response manifested as the decrease of MN and apoptosis inductions. Meanwhile, the interference of BiP gene, a major ER chaperone, amplified the detrimental RIBE. More precisely, thapsigargin provoked ER sensor of PERK to initiate an instantaneous and moderate ER stress thus defensed the hazard form RIBE, while BiP depletion lead to persistently destroyed homeostasis of ER and exacerbated cell injury. These findings provide new insights that the mild ER stress through BiP-PERK-p-eIF2α signaling pathway has a profound role in protecting cellular damage from RIBE and hence may decrease the potential secondary cancer risk after cancer radiotherapy. PMID:27958308

  1. Lithium delays the radiation-induced apoptotic process in external granule cells of mouse cerebellum

    International Nuclear Information System (INIS)

    Inouye, Minoru; Yamamura, Hideki; Nakano, Atsuhiro.

    1995-01-01

    Proliferating cells of the external granular layer (EGL) in the developing cerebellum are highly sensitive to ionizing radiation. We examined the effect of lithium, an inhibitor of intracellular signaling, on the manifestation of radiation-induced apoptosis. Newborn mice were exposed to 0.5 Gy gamma-irradiation alone, or first were treated with lithium (10 μmol/g, SC) then given 0.5 Gy irradiation 2 hr later. The EGL was examined histologically for apoptosis at various times after treatment. Apoptotic cells increased rapidly, peaked (about 14%) 6 hr after irradiation, then decreased gradually to the control level by 24 hr. Prior treatment with lithium delayed the manifestation of apoptosis, the peak appearing at 12 hr. The disappearance of dead cells was delayed for about one day. The lithium concentration in the whole brain increased rapidly, being 30 μg/g at the time of irradiation and remaining at more than 40 μg/g for 40 hr. Lithium is reported to inhibit guanine-nucleotide binding to G proteins as well as phosphoinositide turnover. Of the variety of lesions induced by radiation, DNA double strand breaks are the most important source of cell lethality. The present findings, however, suggest that cyclic AMP-mediated and/or phosphoinositide-mediated signaling systems regulate radiation-induced apoptosis. (author)

  2. Lithium delays the radiation-induced apoptotic process in external granule cells of mouse cerebellum.

    Science.gov (United States)

    Inouye, M; Yamamura, H; Nakano, A

    1995-09-01

    Proliferating cells of the external granular layer (EGL) in the developing cerebellum are highly sensitive to ionizing radiation. We examined the effect of lithium, an inhibitor of intracellular signaling, on the manifestation of radiation-induced apoptosis. Newborn mice were exposed to 0.5 Gy gamma-irradiation alone, or first were treated with lithium (10 mumol/g, SC) then given 0.5 Gy irradiation 2 hr later. The EGL was examined histologically for apoptosis at various times after treatment. Apoptotic cells increased rapidly, peaked (about 14%) 6 hr after irradiation, then decreased gradually to the control level by 24 hr. Prior treatment with lithium delayed the manifestation of apoptosis, the peak appearing at 12 hr. The disappearance of dead cells was delayed for about one day. The lithium concentration in the whole brain increased rapidly, being 30 micrograms/g at the time of irradiation and remaining at more than 40 micrograms/g for 40 hr. Lithium is reported to inhibit guanine-nucleotide binding to G proteins as well as phosphoinositide turnover. Of the variety of lesions induced by radiation, DNA double strand breaks are the most important source of cell lethality. The present findings, however, suggest that cyclic AMP-mediated and/or phosphoinositidemediated signaling systems regulate radiation-induced apoptosis.

  3. Lithium delays the radiation-induced apoptotic process in external granule cells of mouse cerebellum

    Energy Technology Data Exchange (ETDEWEB)

    Inouye, Minoru; Yamamura, Hideki [Nagoya Univ. (Japan). Research Inst. of Environmental Medicine; Nakano, Atsuhiro

    1995-09-01

    Proliferating cells of the external granular layer (EGL) in the developing cerebellum are highly sensitive to ionizing radiation. We examined the effect of lithium, an inhibitor of intracellular signaling, on the manifestation of radiation-induced apoptosis. Newborn mice were exposed to 0.5 Gy gamma-irradiation alone, or first were treated with lithium (10 {mu}mol/g, SC) then given 0.5 Gy irradiation 2 hr later. The EGL was examined histologically for apoptosis at various times after treatment. Apoptotic cells increased rapidly, peaked (about 14%) 6 hr after irradiation, then decreased gradually to the control level by 24 hr. Prior treatment with lithium delayed the manifestation of apoptosis, the peak appearing at 12 hr. The disappearance of dead cells was delayed for about one day. The lithium concentration in the whole brain increased rapidly, being 30 {mu}g/g at the time of irradiation and remaining at more than 40 {mu}g/g for 40 hr. Lithium is reported to inhibit guanine-nucleotide binding to G proteins as well as phosphoinositide turnover. Of the variety of lesions induced by radiation, DNA double strand breaks are the most important source of cell lethality. The present findings, however, suggest that cyclic AMP-mediated and/or phosphoinositide-mediated signaling systems regulate radiation-induced apoptosis. (author).

  4. Umbelliferone suppresses radiation induced DNA damage and apoptosis in hematopoietic cells of mice

    International Nuclear Information System (INIS)

    Jayakumar, S.; Bhilwade, H.N.; Chaubey, R.C.

    2012-01-01

    Radiotherapy is one of the major modes of treatment for different types of cancers. But the success of radiotherapy is limited by injury to the normal cells. Protection of the normal cells from radiation damage by radioprotectors can increase therapeutic efficiency. These radioprotectors can also be used during nuclear emergency situations. Umbelliferone (UMB) is a wide spread natural product of the coumarin family. It occurs in many plants from the Apiaceae family. In the present study radioprotective effect of UMB was investigated in vitro and in vivo. Anti genotoxic effect of Umbelliferone was tested by treating the splenic lymphocytes with various doses of UMB (6.5 μM - 50 μM) prior to radiation (6Gy) exposure. After the radiation exposure, extent of DNA damage was assessed by comet assay at 5 mm and two hours after radiation exposure. At both the time points, it was observed that the pretreatment of UMB reduced the radiation induced DNA damage to a significant extent in comparison to radiation control. UMB pretreatment also significantly reduced the radiation induced apoptosis enumerated by propidium iodide staining assay. Results of clonogenic survival assay using intestinal cell line showed that pretreatment with UMB significantly protected against radiation induced loss of colony forming units. To assess the anti genotoxic role of umbelliferone in vivo two different doses of UMB (20 mg/Kg and 40 mg/Kg of body weight) were injected into Swiss mice or with vehicle and exposed to radiation. Thirty minutes after the radiation comet assay was performed in peripheral leukocytes. Frequency of micro nucleated erythrocytes was scored in bone marrow cells. It was observed that UMB alone did not cause any significant increase in DNA damage in comparison to control. Animals which are exposed to radiation alone showed significant increase in DNA damage and micronuclei frequency. But animals treated with UMB prior to the radiation exposure showed significant decrease

  5. Cell to Cell Variability of Radiation-Induced Foci: Relation between Observed Damage and Energy Deposition.

    Science.gov (United States)

    Gruel, Gaëtan; Villagrasa, Carmen; Voisin, Pascale; Clairand, Isabelle; Benderitter, Marc; Bottollier-Depois, Jean-François; Barquinero, Joan Francesc

    2016-01-01

    Most studies that aim to understand the interactions between different types of photon radiation and cellular DNA assume homogeneous cell irradiation, with all cells receiving the same amount of energy. The level of DNA damage is therefore generally determined by averaging it over the entire population of exposed cells. However, evaluating the molecular consequences of a stochastic phenomenon such as energy deposition of ionizing radiation by measuring only an average effect may not be sufficient for understanding some aspects of the cellular response to this radiation. The variance among the cells associated with this average effect may also be important for the behaviour of irradiated tissue. In this study, we accurately estimated the distribution of the number of radiation-induced γH2AX foci (RIF) per cell nucleus in a large population of endothelial cells exposed to 3 macroscopic doses of gamma rays from 60Co. The number of RIF varied significantly and reproducibly from cell to cell, with its relative standard deviation ranging from 36% to 18% depending on the macroscopic dose delivered. Interestingly, this relative cell-to-cell variability increased as the dose decreased, contrary to the mean RIF count per cell. This result shows that the dose effect, in terms of the number of DNA lesions indicated by RIF is not as simple as a purely proportional relation in which relative SD is constant with dose. To analyse the origins of this observed variability, we calculated the spread of the specific energy distribution for the different target volumes and subvolumes in which RIF can be generated. Variances, standard deviations and relative standard deviations all changed similarly from dose to dose for biological and calculated microdosimetric values. This similarity is an important argument that supports the hypothesis of the conservation of the association between the number of RIF per nucleus and the specific energy per DNA molecule. This comparison allowed us to

  6. Cell to Cell Variability of Radiation-Induced Foci: Relation between Observed Damage and Energy Deposition.

    Directory of Open Access Journals (Sweden)

    Gaëtan Gruel

    Full Text Available Most studies that aim to understand the interactions between different types of photon radiation and cellular DNA assume homogeneous cell irradiation, with all cells receiving the same amount of energy. The level of DNA damage is therefore generally determined by averaging it over the entire population of exposed cells. However, evaluating the molecular consequences of a stochastic phenomenon such as energy deposition of ionizing radiation by measuring only an average effect may not be sufficient for understanding some aspects of the cellular response to this radiation. The variance among the cells associated with this average effect may also be important for the behaviour of irradiated tissue. In this study, we accurately estimated the distribution of the number of radiation-induced γH2AX foci (RIF per cell nucleus in a large population of endothelial cells exposed to 3 macroscopic doses of gamma rays from 60Co. The number of RIF varied significantly and reproducibly from cell to cell, with its relative standard deviation ranging from 36% to 18% depending on the macroscopic dose delivered. Interestingly, this relative cell-to-cell variability increased as the dose decreased, contrary to the mean RIF count per cell. This result shows that the dose effect, in terms of the number of DNA lesions indicated by RIF is not as simple as a purely proportional relation in which relative SD is constant with dose. To analyse the origins of this observed variability, we calculated the spread of the specific energy distribution for the different target volumes and subvolumes in which RIF can be generated. Variances, standard deviations and relative standard deviations all changed similarly from dose to dose for biological and calculated microdosimetric values. This similarity is an important argument that supports the hypothesis of the conservation of the association between the number of RIF per nucleus and the specific energy per DNA molecule. This

  7. Pharmacological manipulation of radiation induced apoptosis in a cervical carcinoma cell line

    International Nuclear Information System (INIS)

    Kamradt, M.; Mohideen, N.; Krueger, E.; Sokolova, I.A.; Khodarev, N.N; Vaughan, A.T.M.

    1997-01-01

    Purpose: Radiotherapy is a curative option in the treatment of early stage cervical carcinoma and radioresistant tumors limit local control and survival. Therefore, it is important to understand mechanisms by which cells evade death after irradiation. Of these, the process of apoptosis offers a useful model system to study. Tumors of the cervix offer a unique opportunity in that most contain an HPV genome expressing the E6 and E7 gene products under the control of a glucocorticoid responsive promoter. The HPV E6 and E7 proteins target p53 and/or Rb, both of which are involved in cell cycle control and in the apoptotic process. It was previously determined that treatment with the corticosteroid dexamethasone increased transcription of E6 and E7 and decreased p53 protein levels which corresponded with increased radioresistance and decreased apoptosis in C4-1 cervical carcinoma cells. The goal of this study is to demonstrate pharmacological manipulation of apoptosis within an HPV +ve cervical cell line. Methods: The HPV 18 +ve and p53 wildtype human cervical cell line C4-1 was used in this study. Apoptosis was induced by exposure to 6 Gy of gamma radiation and the ability of cells to undergo apoptosis was determined by morphology and the ability to form internucleosomal fragments using a DNA laddering technique. Cells were exposed to 0.01 to 1 μM dexamethasone in the presence or absence of 1 μM Mifepristone (RU486), a steroid antagonist and analyzed using the DNA laddering assay. In addition, cells that were irradiated in the presence of dexamethasone and/or Mifepristone were collected and p53 protein levels determined by FACS analysis. Results: Apoptosis was observed at a low level in control cells and was increased by irradiation with 6 Gy as determined by DNA laddering and morphology. The presence of 0.01 to 1 μM dexamethasone reduced both the radiation induced DNA laddering and also that seen in control cells. Addition of 1 μM Mifepristone to dexamethasone

  8. Effect of Flavopiridol on Radiation-induced Apoptosis of Human Laryngeal and Lung Cancer Cells

    International Nuclear Information System (INIS)

    Kim, Suzy; Kwon, Eun Kyung; Lee, B. S.; Lee, Seung Hee; Park, B. S.; Wu, Hong Gyun

    2007-01-01

    Purpose: To investigate the flavopiridol effect on radiation-induced apoptosis and expression of apoptosisrelated genes of human laryngeal and lung cancer cells. Materials and Methods: A human laryngeal cancer cell line, AMC-HN3 and a human lung cancer cell line, NCI-H460, were used in the study. The cells were divided into four groups according to the type of treatment: 1) control groups; 2) cells that were only irradiated; 3) cells treated only with flavopiridol; 4) cells treated with flavopiridol and radiation simultaneously. The cells were irradiated with 10 Gy of X-rays using a 4 MV linear accelerator. Flavopiridol was administered to the media at a concentration of 100 nM for 24 hours. We compared the fraction of apoptotic cells of each group 24 hours after the initiation of treatment. The fraction of apoptotic cells was detected by measurement of the sub-G1 fractions from a flow cytometric analysis. The expression of apoptosis-regulating genes, including cleaved caspase-3, cleaved PARP (poly (ADP-ribose) polymerase), p53, p21, cyclin D1, and phosphorylated Akt (protein kinase B) were analyzed by Western blotting. Results: The sub-G1 fraction of cells was significantly increased in the combination treatment group, as compared to cells exposed to radiation alone or flavopiridol alone. Western blotting also showed an increased expression of cleaved caspase-3 and cleaved PARP expression in cells of the combination treatment group, as compared with cells exposed to radiation alone or flavopiridol alone. Treatment with flavopiridol down regulated cyclin D1 expression of both cell lines but its effect on p53 and p21 expression was different according to each individual cell line. Flavopiridol did not affect the expression of phophorylated Akt in both cell lines. Conclusion: Treatment with flavopiridol increased radiation-induced apoptosis of both the human laryngeal and lung cancer cell lines. Flavopiridol effects on p53 and p21 expression were different according

  9. Bone marrow stromal cell transplantation mitigates radiation-induced gastrointestinal syndrome in mice.

    Directory of Open Access Journals (Sweden)

    Subhrajit Saha

    Full Text Available Nuclear accidents and terrorism presents a serious threat for mass casualty. While bone-marrow transplantation might mitigate hematopoietic syndrome, currently there are no approved medical countermeasures to alleviate radiation-induced gastrointestinal syndrome (RIGS, resulting from direct cytocidal effects on intestinal stem cells (ISC and crypt stromal cells. We examined whether bone marrow-derived adherent stromal cell transplantation (BMSCT could restitute irradiated intestinal stem cells niche and mitigate radiation-induced gastrointestinal syndrome.Autologous bone marrow was cultured in mesenchymal basal medium and adherent cells were harvested for transplantation to C57Bl6 mice, 24 and 72 hours after lethal whole body irradiation (10.4 Gy or abdominal irradiation (16-20 Gy in a single fraction. Mesenchymal, endothelial and myeloid population were characterized by flow cytometry. Intestinal crypt regeneration and absorptive function was assessed by histopathology and xylose absorption assay, respectively. In contrast to 100% mortality in irradiated controls, BMSCT mitigated RIGS and rescued mice from radiation lethality after 18 Gy of abdominal irradiation or 10.4 Gy whole body irradiation with 100% survival (p<0.0007 and p<0.0009 respectively beyond 25 days. Transplantation of enriched myeloid and non-myeloid fractions failed to improve survival. BMASCT induced ISC regeneration, restitution of the ISC niche and xylose absorption. Serum levels of intestinal radioprotective factors, such as, R-Spondin1, KGF, PDGF and FGF2, and anti-inflammatory cytokines were elevated, while inflammatory cytokines were down regulated.Mitigation of lethal intestinal injury, following high doses of irradiation, can be achieved by intravenous transplantation of marrow-derived stromal cells, including mesenchymal, endothelial and macrophage cell population. BMASCT increases blood levels of intestinal growth factors and induces regeneration of the irradiated

  10. Automated studies of radiation-induced changes in 3T3 cell motility and morphology

    International Nuclear Information System (INIS)

    Thurston, G.; Palcic, B.

    1985-01-01

    The most common endpoint in radiobiological studies is cell survival, as measured by colony forming ability. There is substantial experimental evidence that cell survival is related to the amount of radiation damage to the DNA. Radiation induces other changes in cell behaviour and morphology that may not be due to DNA damage alone. For example, low doses of radiation (<100 rads) were found to alter the ''phagokinetic tracks'' of moving 3T3 cells. They reported abnormal cell motility as demonstrated by a more random pattern of motion. 3T3 cells were also noted to show changes in morphology after exposure to x-rays. The fibroblast adhesion routine is disrupted by low doses of radiation (cell settling, microspike extension, lamellipodia flow, then cell spreading). An automated microscope system, DMIPS, is being used to automatically track 3T3 cells as they move and to correlate their movement with their morphology. An effort is being made to quantitate, for a large number of cells, the changes in 3T3 cell motility induced by radiation. The DMIPS procedure is compared to the gold dust technique

  11. Involvement of ERK-Nrf-2 signaling in ionizing radiation induced cell death in normal and tumor cells.

    Directory of Open Access Journals (Sweden)

    Raghavendra S Patwardhan

    Full Text Available Prolonged oxidative stress favors tumorigenic environment and inflammation. Oxidative stress may trigger redox adaptation mechanism(s in tumor cells but not normal cells. This may increase levels of intracellular antioxidants and establish a new redox homeostasis. Nrf-2, a master regulator of battery of antioxidant genes is constitutively activated in many tumor cells. Here we show that, murine T cell lymphoma EL-4 cells show constitutive and inducible radioresistance via activation of Nrf-2/ERK pathway. EL-4 cells contained lower levels of ROS than their normal counterpart murine splenic lymphocytes. In response to radiation, the thiol redox circuits, GSH and thioredoxin were modified in EL-4 cells. Pharmacological inhibitors of ERK and Nrf-2 significantly enhanced radiosensitivity and reduced clonogenic potential of EL-4 cells. Unirradiated lymphoma cells showed nuclear accumulation of Nrf-2, upregulation of its dependent genes and protein levels. Interestingly, MEK inhibitor abrogated its nuclear translocation suggesting role of ERK in basal and radiation induced Nrf-2 activation in tumor cells. Double knockdown of ERK and Nrf-2 resulted in higher sensitivity to radiation induced cell death as compared to individual knockdown cells. Importantly, NF-kB which is reported to be constitutively active in many tumors was not present at basal levels in EL-4 cells and its inhibition did not influence radiosensitivity of EL-4 cells. Thus our results reveal that, tumor cells which are subjected to heightened oxidative stress employ master regulator cellular redox homeostasis Nrf-2 for prevention of radiation induced cell death. Our study reveals the molecular basis of tumor radioresistance and highlights role of Nrf-2 and ERK.

  12. Mitigation of radiation induced hematopoietic injury via regulation of Nrf-2 and increasing hematopoietic stem cells

    International Nuclear Information System (INIS)

    Patwardhan, R.S.; Sharma, Deepak; Checker, Rahul; Santosh Kumar, S.

    2014-01-01

    Therapeutic doses of ionizing radiation (IR) that can be delivered to tumors are restricted due to radiation induced damage to surrounding normal tissues thereby limiting the effectiveness of radiotherapy. Strategies to develop agents that selectively protect normal cells yielded limited success in the past. There is pressing need to develop safe, syndrome specific and effective radiation countermeasures to prevent or mitigate the harmful consequences of radiation exposure. Survival of bone marrow stem cells (HSCs) play a key role in protecting against IR induced hematopoietic injury. Many studies have shown manipulation of HSC frequency and/or survival as principal mechanism of radioprotection. It is known that, Nrf-2 plays crucial role in HSC survival and maintenance under oxidative stress conditions. In the present study, we have investigated the radioprotective ability of a flavonoid baicalein (5,6,7-trihydroxyflavone), extracted from the root of Scutellaria baicalensis Georgi, a medicinal plant traditionally used in Oriental medicine. There are numerous reports showing anti-inflammatory, anti-apoptotic, anti-oxidant, anti-cancer, anti-microbial, anti-mutagenic and neuroprotective properties of baicalein. Based on these reports, we have investigated the ability of baicalein to protect against radiation induced hematopoietic injury. Baicalein administration to mice protected against WBI induced mortality. Interestingly, the stem cell frequency increased in bone marrow cells obtained from baicalein administered mice as compared to vehicle treated mice. Baicalein treatment led to increased phospho-Nrf-2 levels in lineage negative BM-MNC. Administration of mice with Nrf-2 inhibitor prior to baicalein treatment led to significant abrogation of radioprotective ability of baicalein. This result suggests that, Nrf-2 may be playing a key role in baicalein mediated radioprotection. Here, we have shown that baicalein administration augments stem cell frequency, induces

  13. Methylglyoxal-bis(guanylhydrazone), a polyamine analogue, sensitized γ-radiation-induced cell death in HL-60 leukemia cells Sensitizing effect of MGBG on γ-radiation-induced cell death.

    Science.gov (United States)

    Kim, Jin Sik; Lee, Jin; Chung, Hai Won; Choi, Han; Paik, Sang Gi; Kim, In Gyu

    2006-09-01

    Methylglyoxal-bis(guanylhydrazone) (MGBG), a polyamine analogue, has been known to inhibit the biosynthesis of polyamines, which are important in cell proliferation. We showed that MGBG treatment significantly affected γ-radiation-induced cell cycle transition (G(1)/G(0)→S→G(2)/M) and thus γ-radiation-induced cell death. As determined by micronuclei and comet assay, we showed that it sensitized the cytotoxic effect induced by γ-radiation. One of the reasons is that polyamine depletion by MGBG treatment did not effectively protect against the chemical (OH) or physical damage to DNA caused by γ-radiation. Through in vitro experiment, we confirmed that DNA strand breaks induced by γ-radiation was prevented more effectively in the presence of polyamines (spermine and spermidine) than in the absence of polyamines. MGBG also blocks the cell cycle transition caused by γ-radiation (G(2) arrest), which helps protect cells by allowing time for DNA repair before entry into mitosis or apoptosis, via the down regulation of cyclin D1, which mediates the transition from G(1) to S phase of cell cycle, and ataxia telangiectasia mutated, which is involved in the DNA sensing, repair and cell cycle check point. Therefore, the abrogation of G(2) arrest sensitizes cells to the effect of γ-radiation. As a result, γ-radiation-induced cell death increased by about 2.5-3.0-fold in cells treated with MGBG. However, exogenous spermidine supplement partially relieved this γ-radiation-induced cytotoxicity and cell death. These findings suggest a potentially therapeutic strategy for increasing the cytotoxic efficacy of γ-radiation.

  14. Effect of cell cycle stage, dose rate and repair of sublethal damage of radiation-induced apoptosis in F9 teratocarcinoma cells

    International Nuclear Information System (INIS)

    Langley, R.E.; Quartuccio, S.G.; Kennealey, P.T.

    1995-01-01

    There are at least two different models of cell death after treatment with ionizing radiation. The first is a failure to undergo sustained cell division despite metabolic survival, and we refer to this end point as open-quotes classical reproductive cell death.close quotes The second is a process that results in loss of cell integrity. This second category includes cellular necrosis as well as apoptosis. Earlier studies in our laboratory showed that the predominant mechanism of cell death for irradiated F9 cell is apoptosis, and there is no indication that these cells die by necrosis. We have therefore used cells of this cell line to reassess basic radiobiological principles with respect to apoptosis. Classical reproductive cell death was determined by staining colonies derived from irradiated cells and scoring colonies of less than 50 cells as reproductively dead and colonies of more than 50 cells as survivors. Cells that failed to produce either type of colony (detached from the plate or disintegrated) were scored as having undergone apoptosis. Using these criteria we found that the fraction of the radiation-killed F9 cells that died by apoptosis did not vary when cells were irradiated at different stages of the cell cycle despite large variations in overall survival. This suggests that the factors that influence radiation sensitivity throughout the cell cycle have an equal impact on apoptosis and classical reproductive cell death. There was no difference in cell survival between split doses and single doses of X rays, suggesting that sublethal damage repair is not a factor in radiation-induced apoptosis of F9 cells. Apoptosis was not affected by changes in dose rate in the range of 0.038-4.96 Gy/min. 48 refs., 6 figs., 1 tab

  15. Radiation-induced enlargement of granulocytic and macrophage progenitor cells in mouse bone marrow

    Energy Technology Data Exchange (ETDEWEB)

    Metcalf, D; Johnson, G R; Wilson, J [Walter and Eliza Hall Inst. of Medical Research, Parkville (Australia)

    1977-01-01

    The peak sedimentation velocity of C/sub 57/BL mouse bone marrow progenitors of granulocytes and macrophages (GM-colony-forming cells, GM-CFC's) increased from 4.3 mm/h to 7 to 8 mm/h by 2 days after 250 rad whole body irradiation and slowly returned to normal over the next 3 weeks. Preliminary irradiation and/or endotoxin injection did not prevent this radiation-induced change. Some change in sedimentation velocity was seen with as little as 100 rad irradiation. Neither buoyant density nor cell cycle changes could account for the sedimentation velocity data which therefore indicate a major volume increase in the GM-CFC's. This size enlargement affected all subpopulations of GM-CFC's which consequently maintained their size relationship with one another.

  16. Mesenchymal stem cell-conditioned medium prevents radiation-induced liver injury by inhibiting inflammation and protecting sinusoidal endothelial cells

    International Nuclear Information System (INIS)

    Chen Yixing; Zeng Zhaochong; Sun Jing; Huang Yan; Zhang Zhenyu; Zeng Haiying

    2015-01-01

    Current management of radiation-induced liver injury is limited. Sinusoidal endothelial cell (SEC) apoptosis and inflammation are considered to be initiating events in hepatic damage. We hypothesized that mesenchymal stem cells (MSCs) possess anti-apoptotic and anti-inflammatory actions during hepatic irradiation, acting via paracrine mechanisms. This study aims to examine whether MSC-derived bioactive components are protective against radiation-induced liver injury in rats. MSC-conditioned medium (MSC-CM) was generated from rat bone marrow–derived MSCs. The effect of MSC-CM on the viability of irradiated SECs was examined by flow cytometric analysis. Activation of the Akt and ERK pathways was analyzed by western blot. MSC-CM was also delivered to Sprague–Dawley rats immediately before receiving liver irradiation, followed by testing for pathological features, changes in serum hyaluronic acid, ALT, and inflammatory cytokine levels, and liver cell apoptosis. MSC-CM enhanced the viability of irradiated SECs in vitro and induced Akt and ERK phosphorylation in these cells. Infusion of MSC-CM immediately before liver irradiation provided a significant anti-apoptotic effect on SECs and improved the histopathological features of injury in the irradiated liver. MSC-CM also reduced the secretion and expression of inflammatory cytokines and increased the expression of anti-inflammatory cytokines. MSC-derived bioactive components could be a novel therapeutic approach for treating radiation-induced liver injury. (author)

  17. Do protons and X-rays induce cell-killing in human peripheral blood lymphocytes by different mechanisms?

    Science.gov (United States)

    Miszczyk, J; Rawojć, K; Panek, A; Borkowska, A; Prasanna, P G S; Ahmed, M M; Swakoń, J; Gałaś, A

    2018-02-01

    Significant progress has been made in the technological and physical aspects of dose delivery and distribution in proton therapy. However, mode of cell killing induced by protons is less understood in comparison with X-rays. The purpose of this study is to see if there is any difference in the mode of cell-killing, induced by protons and X-rays in an ex vivo human peripheral blood lymphocyte (HPBL) model. HPBL were irradiated with 60 MeV proton beam or 250-kVp X-rays in the dose range of 0.3-4.0 Gy. Frequency of apoptotic and necrotic cells was determined by the Fluorescein (FITC)-Annexin V labelling procedure, 1 and 4 h after irradiation. Chip-based DNA Ladder Assay was used to confirm radiation-induced apoptosis and necrosis. Chip-based DNA Ladder Assay was used to confirm radiation-induced apoptosis. Ex vivo irradiation of HPBL with proton beams of 60 MeV or 250 kVp X-rays resulted in apoptotic as well as necrotic modes of cell-killing, which were evident at both 1 and 4 h after irradiation in the whole dose and time range. Generally, our results indicated that protons cause relatively higher yields of cell death that appears to be necrosis compared to X-rays. The analysis also demonstrates that radiation type and dose play a critical role in mode of cell-killing. Obtained results suggest that X-rays and protons induce cell-killing by different modes. Such differences in cell-killing modes may have implications on the potential of a given therapeutic modality to cause immune modulation via programmed cell death (X-rays) or necrotic cell death (proton therapy). These studies point towards exploring for gene expression biomarkers related necrosis or apoptosis to predict immune response after proton therapy.

  18. Enhanced killing of mammalian cells by radiation combined with m-AMSA

    Energy Technology Data Exchange (ETDEWEB)

    Roberts, P B; Millar, B C [Institute of Cancer Research, Sutton (UK). Surrey Branch

    1980-11-01

    m-AMSA is an intercalating agent at present on Phase II trial as a chemotherapeutic drug. A 30 min exposure of Chinese hamster (Line V79-753B) cells to submicromolar concentrations of m-AMSA killed 50% of the cells. The survivors had an enhanced sensitivity to radiation-induced cell killing. Depending upon the conditions, m-AMSA enhanced the radiation effect by either a decrease in the survival-curve shoulder or by an increase in slope. m-AMSA may act partly by suppressing the accumulation of sublethal damage but, if so, recovery from damage as measured in split-dose experiments with cells pretreated with the drug is not affected. m-AMSA increased radiation lethality throughout the cell cycle, but a contribution to its radiation effect from selective toxicity to cells in a radioresistant phase of the cell cycle cannot be excluded. Radiation and the drug interacted to give increased cell killing, even when the exposures to each agent were separated in time. It is concluded that m-ASMA may behave like actinomycin D and adriamycin, and enhance clinical radiation responses. In vivo testing to determine the effect of m-AMSA on the therapeutic index is recommended.

  19. Enhanced killing of mammalian cells by radiation combined with m-AMSA

    International Nuclear Information System (INIS)

    Roberts, P.B.; Millar, B.C.

    1980-01-01

    m-AMSA is an intercalating agent at present on Phase II trial as a chemotherapeutic drug. A 30min exposure of Chinese hamster (Line V79-753B) cells to submicromolar concentrations of m-AMSA killed 50% of the cells. The survivors had an enhanced sensitivity to radiation-induced cell killing. Depending upon the conditions, m-AMSA enhanced the radiation effect by either a decrease in the survival-curve shoulder or by an increase in slope. m-AMSA may act partly by suppressing the accumulation of sublethal damage but, if so, recovery from damage as measured in split-dose experiments with cells pretreated with the drug is not affected. m-AMSA increased radiation lethality throughout the cell cycle, but a contribution to its radiation effect from selective toxicity to cells in a radioresistant phase of the cell cycle cannot be excluded. Radiation and the drug interacted to give increased cell killing, even when the exposures to each agent were separated in time. It is concluded that m-ASMA may behave like actinomycin D and adriamycin, and enhance clinical radiation responses. In vivo testing to determine the effect of m-AMSA on the therapeutic index is recommended. (author)

  20. Molecular mechanisms of radiation-induced cell proliferation in human carcinoma cells

    International Nuclear Information System (INIS)

    Schmidt-Ullrich, R.K.; Mikkelsen, R.; Valerie, K.; Todd, D.; Kavanagh, B.; Contessa, J.; Rorrer, K.; Chen, P.

    1996-01-01

    Purpose: At therapeutically applied ionizing radiation (IR) doses of 0.5 to 5 Gy, a certain proportion of cells will undergoes radiation-induced death while a varied proportion of cells will survive and be able of furnishing adaptive responses. One of these adaptive responses has been experimentally and clinically described as repopulation. Despite description of this phenomenon more than 20 years ago, the mechanisms of this response have remained relatively unknown until modern experimental techniques have been applied to studies on cellular radiation responses. materials and Methods: Human mammary, MCF-7 and MDA-MB-231, and squamous, A431, carcinoma cells (MCC and SCC), expressing epidermal growth factor-receptor (EGF-R) at widely varied levels, have been exposed under defined culture conditions to single and repeated IR at doses between 0.5 and 5 Gy. Cellular IR responses of activation and expression changes of growth regulatory genes and activation of signal transduction pathways were linked to IR-induced proliferation responses. Specifically, EGF-R activation and expression were assessed by levels of Tyr phosphorylation (Y p ) of the receptor protein and mRNA, respectively. Phospholipase (PL-C) activation was quantified by Y p levels and production of inositol-triphosphate (IP 3 ), elevation of cytoplasmic Ca 2+ by video-intensified florescence microscopy after Fura-2 loading. Mitogen-activated protein (MAP) kinase activation was measured by a MBP receptor assay. The EGF-R and signal transduction activation events were correlated with a proliferation response of irradiated cells as quantified by MTT assay. Results: The cell lines tested showed an about 3-fold stimulation of EGF-R Y p levels within 5 min of IR which was associated with a 2.5-fold upregulation of EGF-R after 24 hr. Repeated daily 2 Gy exposures of MCF-7 and MDA-cells resulted in up to 9-fold increases in EGF-R mRNA. EGF-R downstream signal transduction was evidenced by activation of the

  1. Radiation-induced decrease of CD8+ dendritic cells contributes to Th1/Th2 shift.

    Science.gov (United States)

    Liu, Hu; Li, Bailong; Jia, Xiaojing; Ma, Yan; Gu, Yifeng; Zhang, Pei; Wei, Qun; Cai, Jianming; Cui, Jianguo; Gao, Fu; Yang, Yanyong

    2017-05-01

    Exposure to ionizing radiation (IR) often reduce the helper T (Th) 1 like function, resulting in a Th1/Th2 imbalance, which could affect the efficacy of cancer radiotherapy. As the most potent antigen presenting cells, dendritic cells (DC) can be divided into several subsets with specialized function. However, there is no literature covering the changes of DC subsets and their roles in immune regulation in response to IR. In the present study, we were aimed to investigate the changes of DC subsets after IR and its relationship with Th1/Th2 immunity. We found a significant decrease of BDCA3+DC in the blood of patients treated with radiotherapy. CD8+DC, a mouse equivalent of human BDCA3+DC, was also found decreased in mice spleen, peripheral blood and lymph node tissues after irradiation. As CD8+DC mainly induce Th1 immunity, we tested the changes of Th1/Th2 response and found that IR caused a repression of Th1 immunity, indicating a possible role of CD8+DC in radiation-induced Th1/Th2 imbalance. We also found that a CD8+DC-inducing cytokine, Fms-like tyrosine kinase 3 ligand (FLT3 ligand), restored CD8+DC and reversed Th1/Th2 shift. And then we found that bone marrow cells from irradiated mice differentiated into less CD8+DC, which was also protected by FLT3 ligand. In conclusion, our data showed that IR induced a decrease of CD8+DC and Th1/Th2 shift, which was reversed by Flt3 ligand treatment, suggesting a novel mechanism for radiation-induced immunosuppression. Copyright © 2017. Published by Elsevier B.V.

  2. Role of ROS-mediated autophagy in radiation-induced bystander effect of hepatoma cells.

    Science.gov (United States)

    Wang, Xiangdong; Zhang, Jianghong; Fu, Jiamei; Wang, Juan; Ye, Shuang; Liu, Weili; Shao, Chunlin

    2015-05-01

    Autophagy plays a crucial role in cellular response to ionizing radiation, but it is unclear whether autophagy can modulate radiation-induced bystander effect (RIBE). Here, we investigated the relationship between bystander damage and autophagy in human hepatoma cells of HepG2. HepG2 cells were treated with conditioned medium (CM) collected from 3 Gy γ-rays irradiated hepatoma HepG2 cells for 4, 12, or 24 h, followed by the measurement of micronuclei (MN), intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and protein expressions of microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1 in the bystander HepG2 cells. In some experiments, the bystander HepG2 cells were respectively transfected with LC3 small interfering RNA (siRNA), Beclin-1 siRNA or treated with 1% dimethyl sulfoxide (DMSO). Additional MN and mitochondrial dysfunction coupled with ROS were induced in the bystander cells. The expressions of protein markers of autophagy, LC3-II/LC3-I and Beclin-1, increased in the bystander cells. The inductions of bystander MN and overexpressions of LC3 and Beclin-1 were significantly diminished by DMSO. However, when the bystander cells were transfected with LC3 siRNA or Beclin-1 siRNA, the yield of bystander MN was significantly enhanced. The elevated ROS have bi-functions in balancing the bystander effects. One is to cause MN and the other is to induce protective autophagy.

  3. Radiation-induced chromosome aberrations in bone marrow cells leading to acute myeloid leukemia in mouse

    International Nuclear Information System (INIS)

    Nobuhiko Ban; Tomoko Kusama

    1996-01-01

    It is well known that radiation-induced acute myeloid leukemia (RI-AML) in mice is charaterized by deletion and/or rearrangement of chromosome 2. While chromosome 2 has been suspected to be a target of RI-AML, radiation-sensitive site of the chromosome might be implicated in the leukemogenesis. There were few cytogenetical studies, however, focusing on chromosomal rearrangements shortly after irradiation, and little was known about the frequency and pattern of chromosome 2 aberrations during the early period. In this study, metaphase samples were prepared from whole-body irradiated mice 24 hours after irradiation, most of the cells considered to be in the first mitotic stage. Distribution of chromosomal breakpoints on the metaphase samples were analyzed to study the relationship between chromosome aberrations and RI-AML. (author)

  4. Radiation-induced bystander effects enhanced by elevated sodium chloride through sensitizing cells to bystander factors

    International Nuclear Information System (INIS)

    Zhu Lingyan; Han Wei; Chen Shaopeng; Zhao Ye; Jiang Erkang; Bao Lingzhi; Pei Bei; Yang Gen; Zhao Guoping; Wang Jun; Xu An; Wu Lijun

    2008-01-01

    Radiation-induced bystander effects (RIBE) have been demonstrated to occur widely in various cell lines. However, very little data is available on the genotoxic effects of RIBE combined with other factor(s). We reported previously that with a low dose of α-particle irradiation, the fraction of γ-H2AX foci-positive cells in non-irradiated bystander cells was significantly increased under elevated NaCl culture conditions. In this study, we further investigated the functional role of NaCl in the enhancement of RIBE using a specially designed co-culture system and micronucleus (MN) test. It was shown that the MN frequency was not increased significantly by elevated NaCl (9.0 g/L) alone or by medium exposure. However, with 1.0 cGy α-particle irradiation, the induced MN frequency increased significantly in both irradiated and non-irradiated bystander regions. Additional studies showed that elevated NaCl made the non-irradiated bystander cells more vulnerable to bystander factors. Furthermore, it was found that the induced MN frequency in cells both in irradiated and non-irradiated bystander regions was weakened when the hypertonic medium was changed to normotonic medium for 2 h before irradiation. Such observations were quite similar to the co-effect of NaCl and hydrogen peroxide (H 2 O 2 ), indicating that elevated NaCl might sensitize non-irradiated cells to bystander factors-induced oxidative stress

  5. Glutathione requirement for the rejoining of radiation-induced DNA breaks in misonidazole-treated cells

    International Nuclear Information System (INIS)

    Edgren, M.; Revesz, L.

    1985-01-01

    The role of glutathione (GSH) in the rejoining of radiation-induced single-strand DNA breaks (ssb) was studied in human fibroblast cultures sensitized to radiation by a 30 min treatment with 1 mM misonidazole (MISO). Hypoxically irradiated cells, deficient in GSH, either inherently, or due to a 16 h incubation with 1 mM buthionine sulphoximine (BSO), rejoined the breaks after MISO treatment at a lower rate and to a lesser extent than did GSH-proficient cells. Without MISO treatment, the hypoxically induced ssb were rejoined in the GSH-deficient cells as effectively as in the proficient cells. It is concluded that a large proportion of the breaks which arise after hypoxic irradiation in the presence of MISO are of a different type to those which arise in the absence of the drug, and require a particular GSH-dependent, enzymatic repair system. This requirement for rejoining in hypoxically irradiated, MISO-treated cells is similar to that seen earlier in MISO-untreated, oxically irradiated cells, and suggests that the ssb induced by radiation in the presence of MISO or oxygen are of a similar nature. (author)

  6. Identification of Secreted Proteins from Ionizing Radiation-Induced Senescent MCF7 Cells Using Comparative Proteomics

    International Nuclear Information System (INIS)

    Han, Na Kyung; Kim, Han Na; Hong, Mi Na; Park, Su Min; Lee, Jae Seon; Chi, Seong Gil

    2010-01-01

    Cellular senescence was first described by Hayflick and Moorhead in 1961 who observed that cultures of normal human fibroblasts had a limited replicative potential and eventually became irreversibly arrest. The majority of senescent cells assume a characteristic flattened and enlarged morphological change, senescence associated β-galactosidase positivity and over the years a large number of molecular phenotypes have been described, such as changes in gene expression, protein processing and chromatin organization. In contrast to apoptosis, senescence does not destroy the cells but leaves them metabolically and synthetically active and therefore able to affect their microenvironment. In particular, senescent fibroblasts and some cancer cells were found to secrete proteins with known or putative tumor-promoting functions such as growth factors or proteolytic enzymes. However, the knowledge about secreted proteins from senescent tumor cells and their functions to surrounding cells is still lacking. In this study, changes of senescence-associated secretory protein expression profile were observed in MCF7 human breast cancer cells exposed to gamma-ray radiation using two dimensional electrophoresis. Also, we identified up-regulated secretory proteins during ionizing radiation-induced cellular senescence

  7. Radiation-induced apoptosis of chicken lymphocyte B-cell line DT40

    International Nuclear Information System (INIS)

    Furusawa, Y.; Aoki, M.; Takakura, K.

    2003-01-01

    Full text: Ionizing radiation causes lesions of DNA, cell cycle arrest, induced cell death, and apoptosis in the irradiated cells. Then it is easy to expect that those events would be increased in a cell line which is defective in DNA repair system. However, induction of apoptosis by irradiation takes so complicated process when the cells are defective of DNA repair system. Indeed by many recent studies it has been clarified that DNA repair gene is also concerned with apoptotic event and some study shows the contrary data. Thus, the relationship between the genetics of apoptosis and that of DNA repair is still unclear. In this study two kinds of DNA repair proteins, Rad54 and Ku70, were focused. Proteins of Rad54 and Ku70 have important role at two type of DNA repair systems called homologous recombination repair and non-homologous end joining repair, respectively. 4 phenotypes of DT40, parent type, ku70-/-, rad54-/- and ku70-/-/rad54-/- were used to study the radiation-induced apoptosis (Previous study shows that survival fraction of 4 phenotypes of DT40 is decreased in the cell line, in which DNA repair gene is defective). From the results in this study, two things are clarifies. One is that the dependence of apoptotic index on phenotypes is so different between at low dose and at high dose irradiation. The other is that Ku70 has effective role to induce apoptosis in DT40 irradiated with high dose X-rays

  8. Identification of Secreted Proteins from Ionizing Radiation-Induced Senescent MCF7 Cells Using Comparative Proteomics

    Energy Technology Data Exchange (ETDEWEB)

    Han, Na Kyung; Kim, Han Na; Hong, Mi Na; Park, Su Min; Lee, Jae Seon [Korea Institue of Radiological and Medical Sciences, Seoul (Korea, Republic of); Chi, Seong Gil [Korea University, Seoul (Korea, Republic of)

    2010-05-15

    Cellular senescence was first described by Hayflick and Moorhead in 1961 who observed that cultures of normal human fibroblasts had a limited replicative potential and eventually became irreversibly arrest. The majority of senescent cells assume a characteristic flattened and enlarged morphological change, senescence associated beta-galactosidase positivity and over the years a large number of molecular phenotypes have been described, such as changes in gene expression, protein processing and chromatin organization. In contrast to apoptosis, senescence does not destroy the cells but leaves them metabolically and synthetically active and therefore able to affect their microenvironment. In particular, senescent fibroblasts and some cancer cells were found to secrete proteins with known or putative tumor-promoting functions such as growth factors or proteolytic enzymes. However, the knowledge about secreted proteins from senescent tumor cells and their functions to surrounding cells is still lacking. In this study, changes of senescence-associated secretory protein expression profile were observed in MCF7 human breast cancer cells exposed to gamma-ray radiation using two dimensional electrophoresis. Also, we identified up-regulated secretory proteins during ionizing radiation-induced cellular senescence

  9. Radiation-induced VEGF-C expression and endothelial cell proliferation in lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yu-Hsuan [National Taiwan University Hospital, Department of Oncology, Taipei (China); National Taiwan University, Pharmacological Institute, College of Medicine, Taipei (China); Pan, Shiow-Lin; Wang, Jing-Chi; Teng, Che-Ming [National Taiwan University, Pharmacological Institute, College of Medicine, Taipei (China); Kuo, Sung-Hsin [National Taiwan University Hospital, Department of Oncology, Taipei (China); National Taiwan University College of Medicine, Department of Internal Medicine, Taipei (China); Cheng, Jason Chia-Hsien [National Taiwan University Hospital, Department of Oncology, Taipei (China); National Taiwan University College of Medicine, Graduate Institute of Clinical Medicine, Taipei (China)

    2014-12-15

    The present study was undertaken to investigate whether radiation induces the expression of vascular endothelial growth factor C (VEGF-C) through activation of the PI3K/Akt/mTOR pathway,subsequently affecting endothelial cells. Radiotherapy-induced tumor micro-lymphatic vessel density (MLVD) was determined in a lung cancer xenograft model established in SCID mice. The protein expression and phosphorylation of members of the PI3K/Akt/mTOR pathway and VEGF-C secretion and mRNA expression in irradiated lung cancer cells were assessed by Western blot analysis, enzyme-linked immunosorbent assays (ELISAs), and reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, specific chemical inhibitors were used to evaluate the role of the PI3K/Akt/mTOR signaling pathway. Conditioned medium (CM) from irradiated control-siRNA or VEGF-C-siRNA-expressing A549 cells was used to evaluate the proliferation of endothelial cells by the MTT assay. Radiation increased VEGF-C expression in a dose-dependent manner over time at the protein but not at the mRNA level. Radiation also up-regulated the phosphorylation of Akt, mTOR, 4EBP, and eIF4E, but not of p70S6K. Radiation-induced VEGF-C expression was down-regulated by LY294002 and rapamycin (both p < 0.05). Furthermore, CM from irradiated A549 cells enhanced human umbilical vein endothelial cell (HUVEC) and lymphatic endothelial cell (LEC) proliferation, which was not observed with CM from irradiated VEGF-C-siRNA-expressing A549 cells. Radiation-induced activation of the PI3K/Akt/mTOR signaling pathway increases VEGF-C expression in lung cancer cells, thereby promoting endothelial cell proliferation. (orig.) [German] Die vorliegende Studie untersucht, ob die Strahlung die Expression von VEGF-C (vascular endothelial growth factor C) mittels Aktivierung des PI3K/Akt/mTOR-Signalwegs induziert und anschliessend die endothelialen Zellen beeinflusst. Die durch Strahlentherapie induzierte Mikrolymphgefaessdichte (MLVD) im Tumor wurde in

  10. Protection against hyperthermic cell killing by alanine

    International Nuclear Information System (INIS)

    Cunningham, A.; Henle, K.J.; Moss, A.J.; Nagle, W.A.

    1987-01-01

    Compounds capable of protecting cells against hyperthermia may provide new insights into potential mechanisms of thermotolerance and cellular heat death. The authors characterized heat protection by alanine and related compounds as a function of concentration, temperature and preincubation time. Alanine was added either to complete medium or to HBSS before hyperthermia. Maximal heat protection required 3 hr, 37 0 ; longer preincubation intervals resulted in lower levels of protection. Addition of alanine to medium after hyperthermia had no protective effect. Protection was concentration dependent with a 20- or 200-fold increase in cell survival after 40 min, 45 0 C at 60 mM in medium or in HBSS, respectively. Higher alanine concentrations up to 120mM did not significantly increase heat protection. A 45 0 -heat survival curve showed that 100mM alanine increased the D/sub q/ by approx. 12 min with little change in the D/sub o/. Hyperthermia of 1 hr at temperatures between 42 0 and 45 0 indicated that 100mM alanine shifted the isotoxic temperature by 0.5 Celsius degrees. Polymers of either L or D,L alanine and related compounds, like pyruvate, also protected cells against heat killing. These results indicate that heat protection by alanine shows characteristics that are not shared by polyhydroxy compounds

  11. [Protective effect of Liuweidihuang Pills against cellphone electromagnetic radiation-induced histomorphological abnormality, oxidative injury, and cell apoptosis in rat testes].

    Science.gov (United States)

    Ma, Hui-rong; Cao, Xiao-hui; Ma, Xue-lian; Chen, Jin-jin; Chen, Jing-wei; Yang, Hui; Liu, Yun-xiao

    2015-08-01

    To observe the effect of Liuweidihuang Pills in relieving cellphone electromagnetic radiation-induced histomorphological abnormality, oxidative injury, and cell apoptosis in the rat testis. Thirty adult male SD rats were equally randomized into a normal, a radiated, and a Liuweidihuang group, the animals in the latter two groups exposed to electromagnetic radiation of 900 MHz cellphone frequency 4 hours a day for 18 days. Meanwhile, the rats in the Liuweidihuang group were treated with the suspension of Liuweidihuang Pills at 1 ml/100 g body weight and the other rats intragastrically with the equal volume of purified water. Then all the rats were killed for observation of testicular histomorphology by routine HE staining, measurement of testicular malondialdehyde (MDA) and glutathione (GSH) levels by colorimetry, and determination of the expressions of bax and bcl-2 proteins in the testis tissue by immunohistochemistry. Compared with the normal controls, the radiated rats showed obviously loose structure, reduced layers of spermatocytes, and cavitation in the seminiferous tubules. Significant increases were observed in the MDA level (P radiated rats. In comparison with the radiated rats, those of the Liuweidihuang group exhibited nearly normal testicular structure, significantly lower MDA level (P electromagnetic radiation-induced histomorphological abnormality of the testis tissue and reduce its oxidative damage and cell apoptosis.

  12. Radiation-induced apoptosis in undifferentiated cells of the developing brain as a biological defense mechanism

    International Nuclear Information System (INIS)

    Inouye, Minioru; Tamaru, Masao.

    1994-01-01

    Undifferentiated neural (UN) cells of the developing mammalian brain are highly sensitive to the lethal effects of ionizing radiation. Nuclear and cytoplasmic condensation, transglutaminase activation, and internucleosomal DNA cleavage reveal radiation-induced cell death in the ventricular zone of the cerebral mantle and external granular layer of the cerebellum to be due to apoptosis. A statistically significant increase of cell mortality can be induced by 0.03 Gy X-irradiation, and the mortality increases linearly with increasing doses. It is not changed by split doses, probably because of the very slow repair of cellular damage and a lack of adaptive response. Although extensive apoptosis in the UN cell population results in microcephaly and mental retardation, it possesses the ability to recover from a considerable cell loss and to form the normal structure of the central nervous system. The number of cell deaths needed to induce tissue adnormalities in the adult murine brain rises in the range of 15-25% of the germinal cell population; with the threshold doses at about 0.3 Gy for cerebral anomalies and 1 Gy for cerebellar abnormalities. Threshold level is similarly suggested in prenatally exposed A-bomb survivors. High radiosensitivity of UN cells is assumed to be a manifestation of the ability of the cell to commit suicide when injured. Repeated replication of DNA and extensive gene expression are required in future proliferation and differentiation. Once an abnormality in DNA was induced and fixed in the UN cell, it would be greatly amplified and prove a danger in producing malformations and tumors. These cells would thus commit suicide for the benefit of the individual to eliminate their acquired genetic abnormalities rather than make DNA repair. UN cells in the developing brain are highly radiosensitive and readily involved in apoptosis. Paradoxically, however, this may be to protect individuals against teratogenesis and tumorigenesis. (J.P.N.)

  13. Radiation-induced apoptosis in undifferentiated cells of the developing brain as a biological defense mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Inouye, Minioru [Nagoya Univ. (Japan). Research Inst. of Environmental Medicine; Tamaru, Masao

    1994-12-31

    Undifferentiated neural (UN) cells of the developing mammalian brain are highly sensitive to the lethal effects of ionizing radiation. Nuclear and cytoplasmic condensation, transglutaminase activation, and internucleosomal DNA cleavage reveal radiation-induced cell death in the ventricular zone of the cerebral mantle and external granular layer of the cerebellum to be due to apoptosis. A statistically significant increase of cell mortality can be induced by 0.03 Gy X-irradiation, and the mortality increases linearly with increasing doses. It is not changed by split doses, probably because of the very slow repair of cellular damage and a lack of adaptive response. Although extensive apoptosis in the UN cell population results in microcephaly and mental retardation, it possesses the ability to recover from a considerable cell loss and to form the normal structure of the central nervous system. The number of cell deaths needed to induce tissue adnormalities in the adult murine brain rises in the range of 15-25% of the germinal cell population; with the threshold doses at about 0.3 Gy for cerebral anomalies and 1 Gy for cerebellar abnormalities. Threshold level is similarly suggested in prenatally exposed A-bomb survivors. High radiosensitivity of UN cells is assumed to be a manifestation of the ability of the cell to commit suicide when injured. Repeated replication of DNA and extensive gene expression are required in future proliferation and differentiation. Once an abnormality in DNA was induced and fixed in the UN cell, it would be greatly amplified and prove a danger in producing malformations and tumors. These cells would thus commit suicide for the benefit of the individual to eliminate their acquired genetic abnormalities rather than make DNA repair. UN cells in the developing brain are highly radiosensitive and readily involved in apoptosis. Paradoxically, however, this may be to protect individuals against teratogenesis and tumorigenesis. (J.P.N.).

  14. Prophylactic role of melatonin against radiation induced damage in mouse cerebellum with special reference to Purkinje cells

    Energy Technology Data Exchange (ETDEWEB)

    Sisodia, Rashmi; Kumari, Seema; Verma, Rajesh Kumar; Bhatia, A L [Neurobiology Laboratory, Department of Zoology, University of Rajasthan, Jaipur 302004 (India)

    2006-06-15

    Melatonin, a hormone with a proven antioxidative efficacy, crosses all morphophysiological barriers, including the blood-brain barrier, and distributes throughout the cell. The present study is an attempt to investigate the prophylactic influence of a chronic low level of melatonin against an acute radiation induced oxidative stress in the cerebellum of Swiss albino mice, with special reference to Purkinje cells. After 15 days of treatment the mice were sacrificed at various intervals from 1 to 30 days. Biochemical parameters included lipid peroxidation (LPO) and glutathione (GSH) levels as the endpoints. The quantitative study included alterations in number and volume of Purkinje cells. Swiss albino mice were orally administered a very low dose of melatonin (0.25 mg/mouse/day) for 15 consecutive days before single exposure to 4 Gy gamma radiation. Melatonin checked the augmented levels of LPO, by approximately 55%, by day 30 day post-exposure. Radiation induced depleted levels of GSH could be raised by 68.9% by day 30 post-exposure. Radiation exposure resulted in a reduction of the volume of Purkinje cells and their total number. The administration of melatonin significantly protected against the radiation induced decreases in Purkinje cell volume and number. Results indicate the antioxidative properties of melatonin resulting in its prophylactic property against radiation induced biochemical and cellular alterations in the cerebellum. The findings support the idea that melatonin may be used as an anti-irradiation drug due to its potent free radical scavenging and antioxidative efficacy.

  15. Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

    International Nuclear Information System (INIS)

    Xiong, Shanshan; Pan, Xiujie; Xu, Long; Yang, Zhihua; Guo, Renfeng; Gu, Yongqing; Li, Ruoxi; Wang, Qianjun; Xiao, Fengjun; Du, Li; Zhou, Pingkun; Zhu, Maoxiang

    2015-01-01

    Purpose: Radiation-induced pulmonary fibrosis results from thoracic radiation therapy and severely limits radiation therapy approaches. CD4 + CD25 + FoxP3 + regulatory T cells (Tregs) as well as epithelium-to-mesenchyme transition (EMT) cells are involved in pulmonary fibrosis induced by multiple factors. However, the mechanisms of Tregs and EMT cells in irradiation-induced pulmonary fibrosis remain unclear. In the present study, we investigated the influence of Tregs on EMT in radiation-induced pulmonary fibrosis. Methods and Materials: Mice thoraxes were irradiated (20 Gy), and Tregs were depleted by intraperitoneal injection of a monoclonal anti-CD25 antibody 2 hours after irradiation and every 7 days thereafter. Mice were treated on days 3, 7, and 14 and 1, 3, and 6 months post irradiation. The effectiveness of Treg depletion was assayed via flow cytometry. EMT and β-catenin in lung tissues were detected by immunohistochemistry. Tregs isolated from murine spleens were cultured with mouse lung epithelial (MLE) 12 cells, and short interfering RNA (siRNA) knockdown of β-catenin in MLE 12 cells was used to explore the effects of Tregs on EMT and β-catenin via flow cytometry and Western blotting. Results: Anti-CD25 antibody treatment depleted Tregs efficiently, attenuated the process of radiation-induced pulmonary fibrosis, hindered EMT, and reduced β-catenin accumulation in lung epithelial cells in vivo. The coculture of Tregs with irradiated MLE 12 cells showed that Tregs could promote EMT in MLE 12 cells and that the effect of Tregs on EMT was partially abrogated by β-catenin knockdown in vitro. Conclusions: Tregs can promote EMT in accelerating radiation-induced pulmonary fibrosis. This process is partially mediated through β-catenin. Our study suggests a new mechanism for EMT, promoted by Tregs, that accelerates radiation-induced pulmonary fibrosis

  16. Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, Shanshan; Pan, Xiujie; Xu, Long; Yang, Zhihua [Beijing Institute of Radiation Medicine, Beijing (China); Guo, Renfeng [Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan (United States); Gu, Yongqing; Li, Ruoxi; Wang, Qianjun; Xiao, Fengjun; Du, Li; Zhou, Pingkun [Beijing Institute of Radiation Medicine, Beijing (China); Zhu, Maoxiang, E-mail: zhumx@nic.bmi.ac.cn [Beijing Institute of Radiation Medicine, Beijing (China)

    2015-10-01

    Purpose: Radiation-induced pulmonary fibrosis results from thoracic radiation therapy and severely limits radiation therapy approaches. CD4{sup +}CD25{sup +}FoxP3{sup +} regulatory T cells (Tregs) as well as epithelium-to-mesenchyme transition (EMT) cells are involved in pulmonary fibrosis induced by multiple factors. However, the mechanisms of Tregs and EMT cells in irradiation-induced pulmonary fibrosis remain unclear. In the present study, we investigated the influence of Tregs on EMT in radiation-induced pulmonary fibrosis. Methods and Materials: Mice thoraxes were irradiated (20 Gy), and Tregs were depleted by intraperitoneal injection of a monoclonal anti-CD25 antibody 2 hours after irradiation and every 7 days thereafter. Mice were treated on days 3, 7, and 14 and 1, 3, and 6 months post irradiation. The effectiveness of Treg depletion was assayed via flow cytometry. EMT and β-catenin in lung tissues were detected by immunohistochemistry. Tregs isolated from murine spleens were cultured with mouse lung epithelial (MLE) 12 cells, and short interfering RNA (siRNA) knockdown of β-catenin in MLE 12 cells was used to explore the effects of Tregs on EMT and β-catenin via flow cytometry and Western blotting. Results: Anti-CD25 antibody treatment depleted Tregs efficiently, attenuated the process of radiation-induced pulmonary fibrosis, hindered EMT, and reduced β-catenin accumulation in lung epithelial cells in vivo. The coculture of Tregs with irradiated MLE 12 cells showed that Tregs could promote EMT in MLE 12 cells and that the effect of Tregs on EMT was partially abrogated by β-catenin knockdown in vitro. Conclusions: Tregs can promote EMT in accelerating radiation-induced pulmonary fibrosis. This process is partially mediated through β-catenin. Our study suggests a new mechanism for EMT, promoted by Tregs, that accelerates radiation-induced pulmonary fibrosis.

  17. HIV transcription is induced with some forms of cell killing

    International Nuclear Information System (INIS)

    Woloschak, G.E.; Schreck, S.; Chang-Liu, C.-M.; Libertin, C.R.

    1996-01-01

    Using HeLa cells stably transfected with an HIV-LTR-CAT construct', we demonstrated a peak in CAT induction that occurs in viable (but not necessarily cell-division-competent) cells 24 h following exposure to some cell-killing agents. Γ rays were the only cell-killing agent which did not induce HIV transcription; this can be attributed to the fact that γ-ray-induced apoptotic death requires function p53, which is missing in HeLa cells. For all other agents, HIV-LTR induction was dose-dependent and correlated with the amount of cell killing that occurred in the culture

  18. Radiation-Induced Dedifferentiation of Head and Neck Cancer Cells Into Cancer Stem Cells Depends on Human Papillomavirus Status

    International Nuclear Information System (INIS)

    Vlashi, Erina; Chen, Allen M.; Boyrie, Sabrina; Yu, Garrett; Nguyen, Andrea; Brower, Philip A.; Hess, Clayton B.; Pajonk, Frank

    2016-01-01

    Purpose: To test the hypothesis that the radiation response of cancer stem cells (CSCs) in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) differs and is not reflected in the radiation response of the bulk tumor populations, that radiation therapy (RT) can dedifferentiate non-stem HNSCC cells into CSCs, and that radiation-induced dedifferentiation depends on the HPV status. Methods and Materials: Records of a cohort of 162 HNSCC patients were reviewed, and their outcomes were correlated with their HPV status. Using a panel of HPV-positive and HPV-negative HNSCC cell lines expressing a reporter for CSCs, we characterized HPV-positive and HPV-negative lines via flow cytometry, sphere-forming capacity assays in vitro, and limiting dilution assays in vivo. Non-CSCs were treated with different doses of radiation, and the dedifferentiation of non-CSCs into CSCs was investigated via flow cytometry and quantitative reverse transcription–polymerase chain reaction for re-expression of reprogramming factors. Results: Patients with HPV-positive tumors have superior overall survival and local–regional control. Human papillomavirus–positive HNSCC cell lines have lower numbers of CSCs, which inversely correlates with radiosensitivity. Human papillomavirus–negative HNSCC cell lines lack hierarchy owing to enhanced spontaneous dedifferentiation. Non-CSCs from HPV-negative lines show enhanced radiation-induced dedifferentiation compared with HPV-positive lines, and RT induced re-expression of Yamanaka reprogramming factors. Conclusions: Supporting the favorable prognosis of HPV-positive HNSCCs, we show that (1) HPV-positive HNSCCs have a lower frequency of CSCs; (2) RT can dedifferentiate HNSCC cells into CSCs; and (3) radiation-induced dedifferentiation depends on the HPV status of the tumor.

  19. Radiation-Induced Dedifferentiation of Head and Neck Cancer Cells Into Cancer Stem Cells Depends on Human Papillomavirus Status

    Energy Technology Data Exchange (ETDEWEB)

    Vlashi, Erina, E-mail: evlashi@mednet.ucla.edu [Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California (United States); Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California (United States); Chen, Allen M.; Boyrie, Sabrina; Yu, Garrett; Nguyen, Andrea; Brower, Philip A. [Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California (United States); Hess, Clayton B. [Department of Radiation Oncology, University of California Davis, Sacramento, California (United States); Pajonk, Frank [Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California (United States); Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California (United States)

    2016-04-01

    Purpose: To test the hypothesis that the radiation response of cancer stem cells (CSCs) in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) differs and is not reflected in the radiation response of the bulk tumor populations, that radiation therapy (RT) can dedifferentiate non-stem HNSCC cells into CSCs, and that radiation-induced dedifferentiation depends on the HPV status. Methods and Materials: Records of a cohort of 162 HNSCC patients were reviewed, and their outcomes were correlated with their HPV status. Using a panel of HPV-positive and HPV-negative HNSCC cell lines expressing a reporter for CSCs, we characterized HPV-positive and HPV-negative lines via flow cytometry, sphere-forming capacity assays in vitro, and limiting dilution assays in vivo. Non-CSCs were treated with different doses of radiation, and the dedifferentiation of non-CSCs into CSCs was investigated via flow cytometry and quantitative reverse transcription–polymerase chain reaction for re-expression of reprogramming factors. Results: Patients with HPV-positive tumors have superior overall survival and local–regional control. Human papillomavirus–positive HNSCC cell lines have lower numbers of CSCs, which inversely correlates with radiosensitivity. Human papillomavirus–negative HNSCC cell lines lack hierarchy owing to enhanced spontaneous dedifferentiation. Non-CSCs from HPV-negative lines show enhanced radiation-induced dedifferentiation compared with HPV-positive lines, and RT induced re-expression of Yamanaka reprogramming factors. Conclusions: Supporting the favorable prognosis of HPV-positive HNSCCs, we show that (1) HPV-positive HNSCCs have a lower frequency of CSCs; (2) RT can dedifferentiate HNSCC cells into CSCs; and (3) radiation-induced dedifferentiation depends on the HPV status of the tumor.

  20. Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells.

    Science.gov (United States)

    Voos, Patrick; Fuck, Sebastian; Weipert, Fabian; Babel, Laura; Tandl, Dominique; Meckel, Tobias; Hehlgans, Stephanie; Fournier, Claudia; Moroni, Anna; Rödel, Franz; Thiel, Gerhard

    2018-01-01

    Impairment or stimulation of the immune system by ionizing radiation (IR) impacts on immune surveillance of tumor cells and non-malignant cells and can either foster therapy response or side effects/toxicities of radiation therapy. For a better understanding of the mechanisms by which IR modulates T-cell activation and alters functional properties of these immune cells, we exposed human immortalized Jurkat cells and peripheral blood lymphocytes (PBL) to X-ray doses between 0.1 and 5 Gy. This resulted in cellular responses, which are typically observed also in naïve T-lymphocytes in response of T-cell receptor immune stimulation or mitogens. These responses include oscillations of cytosolic Ca 2+ , an upregulation of CD25 surface expression, interleukin-2 and interferon-γ synthesis, elevated expression of Ca 2+ sensitive K + channels and an increase in cell diameter. The latter was sensitive to inhibition by the immunosuppressant cyclosporine A, Ca 2+ buffer BAPTA-AM, and the CDK1-inhibitor RO3306, indicating the involvement of Ca 2+ -dependent immune activation and radiation-induced cell cycle arrest. Furthermore, on a functional level, Jurkat and PBL cell adhesion to endothelial cells was increased upon radiation exposure and was highly dependent on an upregulation of integrin beta-1 expression and clustering. In conclusion, we here report that IR impacts on immune activation and functional properties of T-lymphocytes that may have implications in both toxic effects and treatment response to combined radiation and immune therapy in cancer patients.

  1. Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells

    Directory of Open Access Journals (Sweden)

    Patrick Voos

    2018-04-01

    Full Text Available Impairment or stimulation of the immune system by ionizing radiation (IR impacts on immune surveillance of tumor cells and non-malignant cells and can either foster therapy response or side effects/toxicities of radiation therapy. For a better understanding of the mechanisms by which IR modulates T-cell activation and alters functional properties of these immune cells, we exposed human immortalized Jurkat cells and peripheral blood lymphocytes (PBL to X-ray doses between 0.1 and 5 Gy. This resulted in cellular responses, which are typically observed also in naïve T-lymphocytes in response of T-cell receptor immune stimulation or mitogens. These responses include oscillations of cytosolic Ca2+, an upregulation of CD25 surface expression, interleukin-2 and interferon-γ synthesis, elevated expression of Ca2+ sensitive K+ channels and an increase in cell diameter. The latter was sensitive to inhibition by the immunosuppressant cyclosporine A, Ca2+ buffer BAPTA-AM, and the CDK1-inhibitor RO3306, indicating the involvement of Ca2+-dependent immune activation and radiation-induced cell cycle arrest. Furthermore, on a functional level, Jurkat and PBL cell adhesion to endothelial cells was increased upon radiation exposure and was highly dependent on an upregulation of integrin beta-1 expression and clustering. In conclusion, we here report that IR impacts on immune activation and functional properties of T-lymphocytes that may have implications in both toxic effects and treatment response to combined radiation and immune therapy in cancer patients.

  2. Chromosome painting analysis of radiation-induced aberrant cell clones in the mouse

    International Nuclear Information System (INIS)

    Spruill, M.D.; Nath, J.; Tucker, J.D.

    1997-01-01

    In a study of the persistence of radiation-induced translocations over the life span of the mouse, we observed a number of clonal cells in peripheral blood lymphocytes. The presence of clones caused the mean frequency of aberrations at various time points to be elevated which interfered with biodosimetry. For this reason, we have corrected our data for the presence of clones. Mice were given an acute dose of 0, 1, 2, 3 or 4 Gy 137 Cs at 8 weeks of age. Aberrations were measured by painting chromosomes 2 and 8 and cells were examined for clones at 3 months and every 3 months thereafter until 21 months. Clones were identified by comparing the color photographic slides of all abnormal cells from each animal. Determination of clonality was made on the basis of similar breakpoint locations or the presence of other identifying characteristics such as unusual aberrations. To correct the frequency of translocations for the presence of clones, each clone, regardless of how many cells it contained, was counted only once. This reflects the original aberration frequency since each clone originated as only one cell. Among mice exposed to 4 Gy, the mean frequencies of aberrant cell clones ranged from 3-29% of the total number of metaphase cells scored with the highest frequency being 1 year post exposure. 32-70% of reciprocal and 19-92% of non-reciprocal translocations were clonal. A dose response relationship for clones was evident until 21 months when the unexposed animals exhibited a mean frequency of aberrant cell clones >10% of the total number of cells scored. Almost 75% of reciprocal and 95% of non-reciprocal translocations in these unexposed control animals were of clonal origin. Correction for clonal expansion greatly reduced the means and their standard errors at most time points where clonal expansion was prevalent. The biodosimetry was much improved suggesting that correction is beneficial in long-term studies

  3. Radiation induced genetic damage in Aspergillus nidulans

    International Nuclear Information System (INIS)

    Georgiou, J.T.

    1984-01-01

    The mechanism by which ionizing radiation induces genetic damage in haploid and diploid conidia of Aspergillus nidulans was investigated. Although the linear dose-response curves obtained following low LET irradiation implied a 'single-hit' action of radiation, high LET radiations were much more efficient than low LET radiations, which suggests the involvement of a multiple target system. It was found that the RBE values for non-disjunction and mitotic crossing-over were very different. Unlike mitotic crossing-over, the RBE values for non-disjunction were much greater than for cell killing. This suggests that non-disjunction is a particularly sensitive genetical endpoint that is brought about by damage to a small, probably non-DNA target. Radiosensitisers were used to study whether radiation acts at the level of the DNA or some other cellular component. The sensitisation to electrons and/or X-rays by oxygen, and two nitroimidazoles (metronidazole and misonidazole) was examined for radiation induced non-disjunction, mitotic crossing-over, gene conversion, point mutation and cell killing. It was found that these compounds sensitised the cells considerably more to genetic damage than to cell killing. (author)

  4. γ-radiation induces cellular sensitivity and aberrant methylation in human tumor cell lines.

    Science.gov (United States)

    Kumar, Ashok; Rai, Padmalatha S; Upadhya, Raghavendra; Vishwanatha; Prasada, K Shama; Rao, B S Satish; Satyamoorthy, Kapettu

    2011-11-01

    Ionizing radiation induces cellular damage through both direct and indirect mechanisms, which may include effects from epigenetic changes. The purpose of this study was to determine the effect of ionizing radiation on DNA methylation patterns that may be associated with altered gene expression. Sixteen human tumor cell lines originating from various cancers were initially tested for radiation sensitivity by irradiating them with γ-radiation in vitro and subsequently, radiation sensitive and resistant cell lines were treated with different doses of a demethylating agent, 5-Aza-2'-Deoxycytidine (5-aza-dC) and a chromatin modifier, Trichostatin-A (TSA). Survival of these cell lines was measured using 3-(4, 5-Dimethylthiazol- 2-yl)-2, 5-diphenyltetrazolium (MTT) and clonogenic assays. The effect of radiation on global DNA methylation was measured using reverse phase high performance liquid chromatography (RP-HPLC). The transcription response of methylated gene promoters, from cyclin-dependent kinase inhibitor 2A (p16(INK4a)) and ataxia telangiectasia mutated (ATM) genes, to radiation was measured using a luciferase reporter assay. γ-radiation resistant (SiHa and MDAMB453) and sensitive (SaOS2 and WM115) tumor cell lines were examined for the relationship between radiation sensitivity and DNA methylation. Treatment of cells with 5-aza-dC and TSA prior to irradiation enhanced DNA strand breaks, G2/M phase arrest, apoptosis and cell death. Exposure to γ-radiation led to global demethylation in a time-dependent manner in tumor cells in relation to resistance and sensitivity to radiation with concomitant activation of p16(INK4a) and ATM gene promoters. These results provide important information on alterations in DNA methylation as one of the determinants of radiation effects, which may be associated with altered gene expression. Our results may help in delineating the mechanisms of radiation resistance in tumor cells, which can influence diagnosis, prognosis and

  5. The fate of radiation induced giant-nucleated cells of human skin fibroblasts

    Science.gov (United States)

    Almahwasi, A. A.; Jeynes, J. C.; Bradley, D. A.; Regan, P. H.

    2017-11-01

    Radiation-induced giant-nucleated cells (GCs) have been observed to occur within survivors of irradiated cancerous and within healthy cells, both in vivo and in vitro. The expression of such morphological alterations is associated with genomic instability. This study was designed to investigate the fate of GCs induced in a normal human fibroblast cell line (AG1522) after exposure to 0.2, 1 or 2 Gy of X-ray or proton irradiation. The total of 79 individual AG1522 GCs present at 7, 14 or 21 days after each dose point were analysed from fluorescence microscopy images captured over approximately 120 h. The GCs were identified at the beginning of the observation period for each time point post-irradiation and the area of the cell nucleus was measured (μm2) using a cell-recognition MATLAB code. The results demonstrate that the majority of GCs had undergone a prolonged mitotic arrest, which might be an indication of the survival strategy. The live cell microscopy confirms that a giant-nucleated cell formed 14 days after exposure to 0.2 Gy of proton irradiation was divided into two asymmetrical normal-sized cells. These results suggest that a small fraction of GCs can proliferate and form progeny. Some of GCs had disappeared from the microscopy fields. The rate of their loss was decreased as the dose increased but there remains the potential for them to have progeny that could continue to proliferate, ultimately contributing to development of cancer risk. This important method to access delayed effects in normal tissues could act as a potential radioprotective assay for a dose-limiting parameter when applying radiotherapy. These results might have important implications in evaluating risk estimates for patients during radiation therapy treatment.

  6. Inhibition of radiation induced migration of human head and neck squamous cell carcinoma cells by blocking of EGF receptor pathways

    International Nuclear Information System (INIS)

    Pickhard, Anja C; Schlegel, Jürgen; Arnold, Wolfgang; Reiter, Rudolf; Margraf, Johanna; Knopf, Andreas; Stark, Thomas; Piontek, Guido; Beck, Carolin; Boulesteix, Anne-Laure; Scherer, Elias Q; Pigorsch, Steffi

    2011-01-01

    Recently it has been shown that radiation induces migration of glioma cells and facilitates a further spread of tumor cells locally and systemically. The aim of this study was to evaluate whether radiotherapy induces migration in head and neck squamous cell carcinoma (HNSCC). A further aim was to investigate the effects of blocking the epidermal growth factor receptor (EGFR) and its downstream pathways (Raf/MEK/ERK, PI3K/Akt) on tumor cell migration in vitro. Migration of tumor cells was assessed via a wound healing assay and proliferation by a MTT colorimeritric assay using 3 HNSCC cell lines (BHY, CAL-27, HN). The cells were treated with increasing doses of irradiation (2 Gy, 5 Gy, 8 Gy) in the presence or absence of EGF, EGFR-antagonist (AG1478) or inhibitors of the downstream pathways PI3K (LY294002), mTOR (rapamycin) and MEK1 (PD98059). Biochemical activation of EGFR and the downstream markers Akt and ERK were examined by Western blot analysis. In absence of stimulation or inhibition, increasing doses of irradiation induced a dose-dependent enhancement of migrating cells (p < 0.05 for the 3 HNSCC cell lines) and a decrease of cell proliferation (p < 0.05 for the 3 HNSCC cell lines). The inhibition of EGFR or the downstream pathways reduced cell migration significantly (almost all p < 0.05 for the 3 HNSCC cell lines). Stimulation of HNSCC cells with EGF caused a significant increase in migration (p < 0.05 for the 3 HNSCC cell lines). After irradiation alone a pronounced activation of EGFR was observed by Western blot analysis. Our results demonstrate that the EGFR is involved in radiation induced migration of HNSCC cells. Therefore EGFR or the downstream pathways might be a target for the treatment of HNSCC to improve the efficacy of radiotherapy

  7. Effect of a hypoxic cell sensitizer doranidazole on the radiation-induced apoptosis of mouse L5178Y lymphoma cells

    International Nuclear Information System (INIS)

    Aoki, Mizuho; Furusawa, Yoshiya; Shibamoto, Yuta

    2002-01-01

    We investigated the sensitizing effect of the 2-nitroimidazole analogue doranidazole, a new hypoxic radiosensitizer, on radiation-induced apoptosis in L5178Y cells. Apoptosis was assessed by checking DNA ladder formation, the presence of sub-G1 peaks in flow cytometry, and chromation condensation. A radiosensitizing effect of doranidazole was also confirmed by a soft-agar colony assay of surviving cells. In the assay of DNA ladder formation, DNA fragmentation was observed following irradiation under an aerobic or hypoxic condition with or without doranidazole. The proportions of the cells at the sub-G1 peak in a flow cytometric measurement was not very different among the irradiations at 5 Gy under the aerobic condition, 15 Gy under hypoxia, and 10 Gy with 1 mM doranidazole under hypoxia. The fraction of cells with chromatin condensation was found to be significantly increased with doranidazole up to 3 mM when applied under hypoxic irradiation, but did not increase even at 10 mM. The sensitizer enhancement ratio was estimated to be about 1.7 with a concentration of 1 mM. This enhancement ratio was not different from that observed by assaying cell survivals. On the other hand, doranidazole showed no radiosensitizing effect under aerobic conditions with 1 mM. In conclusion, the radiation-induced apoptosis of L5178Y cells was enhanced by doranidazole under hypoxia. (author)

  8. Proliferation, differentiation, and possible radiation-induced chromosome abnormalities in circulating hemopoietic stem cells

    International Nuclear Information System (INIS)

    Amenomori, Tatsuhiko; Honda, Takeo; Matsuo, Tatsuki; Otake, Masanori; Hazama, Ryuji; Tomonaga, Yu; Tomonaga, Masao; Ichimaru, Michito.

    1986-07-01

    The effects of atomic bomb radiation on hemopoietic stem cells were studied cytogenetically and from the aspect of differentiation and proliferation, using single colonies derived from human hemopoietic stem cells. The subjects studied were A-bomb survivors in the high dose exposure group (T65D 100 + rad) with a high incidence (10 % or more) of radiation-induced chromosome abnormalities in their peripheral lymphocytes, and their controls. Examinations were performed on 21 A-bomb survivors (10 males and 11 females) and 11 controls (5 males and 6 females). Colony formation of hemopoietic stem cells (granulocyte/monocyte-colony-forming cells, GM-CFC and burst-forming unit-erythrocytes, BFU-E) was made by the methylcellulose method patterned after the methods of Iscove et al and Ogawa et al using 5 - 10 ml of peripheral blood. Chromosome specimens were prepared from single colonies by the micromethod which we have reported elsewhere. The total number of colonies analyzed in the exposed group was 131 GM-CFC and 75 BFU-E. Chromosome abnormalities were observed in 15 (11.5 %) and 9 (12.0 %) colonies, respectively. In the control group, the total number of colonies analyzed was 61 GM-CFC and 41 BFU-E, but none of the colonies showed chromosome abnormalities. A highly significant difference in chromosome abnormalities was demonstrated by an exact test with a probability of 0.3 % for GM-CFC and 1.7 % for BFU-E. The karyotypes of chromosome abnormalities obtained from the colonies of hemopoietic stem cells in the exposed group were mostly translocations, but deletion and marker chromosomes were also observed. In two individuals, such karyotypic abnormalities as observed in the peripheral lymphocytes were seen also in the hemopoietic precursor cells. This finding suggests that radiation may produce an effect even on relatively undifferentiated hemopoietic stem cells. (author)

  9. Radiation induced damage to the lipid contents of bacteria and cultured mammalian cells

    International Nuclear Information System (INIS)

    Gholipour Khalili, K.

    1993-01-01

    In this study, exponentially growing phase of E. Coli. K12-N167 and cultured mouse leukemic L5178Y were used to study the effect of gamma irradiation on phospholipid contents. Following irradiation, both bacteria and cultured cells were incubated with either 14 C or 32 P labelled precursors for periods of cell division time. Phospholipid composition and their contents were detected in both the bacteria and cultured cells by using liquid scintillation counting and autoradiography methods. In contrast, as radiation dose increased, the Phospholipid contents were decreased in the both bacteria and cultured cells. It was concluded that the changes of phospholipid contents may result to altered activities of phospholipid pathway enzymes damaged by a radiation dose. The results of this investigation would be helpful in control of induced radiation damages in cell killings in radiation workers and radiation treatment of human cancer in the clinics. (author). 35 refs, 3 figs, 4 tabs

  10. Beclin 1 and UVRAG confer protection from radiation-induced DNA damage and maintain centrosome stability in colorectal cancer cells.

    Directory of Open Access Journals (Sweden)

    Jae Myung Park

    Full Text Available Beclin 1 interacts with UV-irradiation-resistance-associated gene (UVRAG to form core complexes that induce autophagy. While cells with defective autophagy are prone to genomic instability that contributes to tumorigenesis, it is unknown whether Beclin1 or UVRAG can regulate the DNA damage/repair response to cancer treatment in established tumor cells. We found that siRNA knockdown of Beclin 1 or UVRAG can increase radiation-induced DNA double strand breaks (DSBs, shown by pATM and γH2Ax, and promote colorectal cancer cell death. Furthermore, knockdown of Beclin 1, UVRAG or ATG5 increased the percentage of irradiated cells with nuclear foci expressing 53BP1, a marker of nonhomologous end joining but not RAD51 (homologous recombination, compared to control siRNA. Beclin 1 siRNA was shown to attenuate UVRAG expression. Cells with a UVRAG deletion mutant defective in Beclin 1 binding showed increased radiation-induced DSBs and cell death compared to cells with ectopic wild-type UVRAG. Knockdown of Beclin 1 or UVRAG, but not ATG5, resulted in a significant increase in centrosome number (γ-tubulin staining in irradiated cells compared to control siRNA. Taken together, these data indicate that Beclin 1 and UVRAG confer protection against radiation-induced DNA DSBs and may maintain centrosome stability in established tumor cells.

  11. Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

    National Research Council Canada - National Science Library

    Lyles, Douglas

    2003-01-01

    .... The novelty in our approach is our ability to enhance the selectivity of killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response...

  12. Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

    National Research Council Canada - National Science Library

    Lyles, Douglas

    2004-01-01

    .... The novelty in our approach is our ability to enhance the selectivity of killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response...

  13. Selective Killing of Prostate Tumor Cells by Cytocidal Viruses

    National Research Council Canada - National Science Library

    Lyles, Douglas S

    2005-01-01

    ...). The novelty in our approach is our ability to enhance the selectivity of VSV-induced killing of tumor cells versus normal cells by manipulating the viral genes that control the antiviral interferon response...

  14. Radiation-induced bystander effects enhanced by elevated sodium chloride through sensitizing cells to bystander factors

    Energy Technology Data Exchange (ETDEWEB)

    Zhu Lingyan; Han Wei; Chen Shaopeng; Zhao Ye; Jiang Erkang; Bao Lingzhi; Pei Bei; Yang Gen; Zhao Guoping; Wang Jun; Xu An [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, P.O. Box 1126, Hefei 230031, Anhui (China); Wu Lijun [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, P.O. Box 1126, Hefei 230031, Anhui (China)], E-mail: ljw@ipp.ac.cn

    2008-09-26

    Radiation-induced bystander effects (RIBE) have been demonstrated to occur widely in various cell lines. However, very little data is available on the genotoxic effects of RIBE combined with other factor(s). We reported previously that with a low dose of {alpha}-particle irradiation, the fraction of {gamma}-H2AX foci-positive cells in non-irradiated bystander cells was significantly increased under elevated NaCl culture conditions. In this study, we further investigated the functional role of NaCl in the enhancement of RIBE using a specially designed co-culture system and micronucleus (MN) test. It was shown that the MN frequency was not increased significantly by elevated NaCl (9.0 g/L) alone or by medium exposure. However, with 1.0 cGy {alpha}-particle irradiation, the induced MN frequency increased significantly in both irradiated and non-irradiated bystander regions. Additional studies showed that elevated NaCl made the non-irradiated bystander cells more vulnerable to bystander factors. Furthermore, it was found that the induced MN frequency in cells both in irradiated and non-irradiated bystander regions was weakened when the hypertonic medium was changed to normotonic medium for 2 h before irradiation. Such observations were quite similar to the co-effect of NaCl and hydrogen peroxide (H{sub 2}O{sub 2}), indicating that elevated NaCl might sensitize non-irradiated cells to bystander factors-induced oxidative stress.

  15. Radiation Induced G2 Chromatic Break and Repairs Kinetics in Human Lymphoblastoid Cells

    International Nuclear Information System (INIS)

    Seong, Jin Sil

    1993-01-01

    In understanding radiosensitivity a new concept of inherent radiosensitivity based on individuality and heterogeneity within a population has recently beer explored. There has been some discussion of possible mechanism underlying differences in radiosensitivity between cells. Ataxia telangiectasia(AT), a rare autosomal recessive genetic disorder, is characterized by hypersensitivity to lonizing radiation and other DNA damaging agents at the cellular level. There have been a lot of efforts to describe the cause of this hypersensitivity to radiation. At the cellular level, chromosome repair kinetics study would be an appropriate approach. The purpose of this study was to better understand radiosensitivity in an approach to investigate kinetics of induction and repair of G2 chromatic breaks using normal, AT heterozygous(ATH), and AT homozygous lymphoblastoid cell lines. In an attempt to estimate initial damage, 9-β-D-arabinosyl-2-fluoroadenine, an inhibitor of DNA synthesis and repair, was used in this study. It was found from this study that radiation induces higher chromatid breaks in AT than in normal and ATH cells. There was no significant differences of initial chromatid breaks between normal and ATH cells. Repair kinetics was the same for all. So the higher level of breaks in AT G2 cells is thought to be a reflection of the increased initial damage. The amount of initial damage correlated well with survival fraction at 2 Gy of cell survival curve following radiation. Therefore, the difference of radiosensitivity in terms of G2 chromosomal sensitivity is thought to result from the difference of initial damage

  16. Radiation-induced polymerization of unsaturated phospholipid mixtures for the synthesis of artificial red cells

    Science.gov (United States)

    Hosoi, F.; Omichi, H.; Akama, K.; Awai, K.; Endo, S.; Nakano, Y.

    1997-08-01

    Radiation induced polymerization of phospholipid containing unsaturated acyl chains was applied to the synthesis of artificial red cells. Vesicles of 1,2-bis-(2,4-octadecadienoyl)-phosphatidylcholine (DODPC) and 1-stearoyl-2-(2,4-octadecadienoyl)-phosphatidylcholine (AODPC) were irradiated by 60Co γ-rays to obtain polymerized bilayer structure of these monomers. It was found that the polymerization of unsaturated groups located at 2-acyl chain of DODPC polymerized faster than those of AODPC. The difference was explained by the packed state of these monomers in the bilayer vesicles. The artificial red cell was obtained by irradiating the mixture of DODPC or AODPC with hemoglobin, cholesterol and palmitic acid sodium salt. The integrity of the irradiated hemoglobin in the vesicle was maintained by keeping the suspended solution at low temperature. On the other hand, oxidation of heme part became remarkable when the vesicle was kept at 37°C. The presence of extra hemoglobin outside the vesicle was found useful to prevent this oxidation.

  17. Caspase-independent cell death mediated by apoptosis-inducing factor (AIF) nuclear translocation is involved in ionizing radiation induced HepG2 cell death

    International Nuclear Information System (INIS)

    Sun, Hengwen; Yang, Shana; Li, Jianhua; Zhang, Yajie; Gao, Dongsheng; Zhao, Shenting

    2016-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The aim of radiotherapy is to eradicate cancer cells with ionizing radiation. Except for the caspase-dependent mechanism, several lines of evidence demonstrated that caspase-independent mechanism is directly involved in the cell death responding to irradiation. For this reason, defining the contribution of caspase-independent molecular mechanisms represents the main goal in radiotherapy. In this study, we focused on the role of apoptosis-inducing factor (AIF), the caspase-independent molecular, in ionizing radiation induced hepatocellular carcinoma cell line (HepG2) cell death. We found that ionizing radiation has no function on AIF expression in HepG2 cells, but could induce AIF release from the mitochondria and translocate into nuclei. Inhibition of AIF could reduce ionizing radiation induced HepG2 cell death. These studies strongly support a direct relationship between AIF nuclear translocation and radiation induced cell death. What's more, AIF nuclear translocation is caspase-independent manner, but not caspase-dependent manner, in this process. These new findings add a further attractive point of investigation to better define the complex interplay between caspase-independent cell death and radiation therapy. - Highlights: • AIF nuclear translocation is involved in ionizing radiation induced hepatocellular carcinoma cell line HepG2 cell death. • AIF mediated cell death induced by ionizing radiation is caspase-independent. • Caspase-independent pathway is involved in ionzing radiation induced HepG2 cell death.

  18. Radiation Induced Apoptosis of Murine Bone Marrow Cells Is Independent of Early Growth Response 1 (EGR1.

    Directory of Open Access Journals (Sweden)

    Karine Z Oben

    Full Text Available An understanding of how each individual 5q chromosome critical deleted region (CDR gene contributes to malignant transformation would foster the development of much needed targeted therapies for the treatment of therapy related myeloid neoplasms (t-MNs. Early Growth Response 1 (EGR1 is a key transcriptional regulator of myeloid differentiation located within the 5q chromosome CDR that has been shown to regulate HSC (hematopoietic stem cell quiescence as well as the master regulator of apoptosis-p53. Since resistance to apoptosis is a hallmark of malignant transformation, we investigated the role of EGR1 in apoptosis of bone marrow cells; a cell population from which myeloid malignancies arise. We evaluated radiation induced apoptosis of Egr1+/+ and Egr1-/- bone marrow cells in vitro and in vivo. EGR1 is not required for radiation induced apoptosis of murine bone marrow cells. Neither p53 mRNA (messenger RNA nor protein expression is regulated by EGR1 in these cells. Radiation induced apoptosis of bone marrow cells by double strand DNA breaks induced p53 activation. These results suggest EGR1 dependent signaling mechanisms do not contribute to aberrant apoptosis of malignant cells in myeloid malignancies.

  19. Reduction of radiation-induced damage to salivary gland by bone marrow derived stem cells

    International Nuclear Information System (INIS)

    Coppes, R.P.; Wierenga, P.K.; Kampinga, H.H.; De Hann, G.

    2003-01-01

    marrow-derived cells home to severely damaged salivary glands after transplantation/mobilisation. Hence, BMSC transplantation could become a promising modality to ameliorate radiation-induced complications in salivary glands after radiotherapy

  20. Age-dependent change in biological characteristics of stem cells in radiation-induced mammary carcinogenesis

    International Nuclear Information System (INIS)

    Shimada, Yoshiya; Nishimura, Mayumi; Kakinuma, Shizuko; Imaoka, Tatsuhiko; Yasukawa-Barnes, Jane; Gould, Michael N.; Clifton, Kelly H.

    2003-01-01

    -dependent susceptibility to radiation-induced breast cancer. (author)

  1. Age-dependent change in biological characteristics of stem cells in radiation-induced mammary carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Yoshiya; Nishimura, Mayumi; Kakinuma, Shizuko; Imaoka, Tatsuhiko [National Institute of Radiological Sciences, Anagawa, Chiba (Japan); Yasukawa-Barnes, Jane; Gould, Michael N.; Clifton, Kelly H. [Univ. of Wisconsin, Department of Human Oncology, Madison, WI (United States)

    2003-07-01

    underlie the age-dependent susceptibility to radiation-induced breast cancer. (author)

  2. JNK inhibition sensitizes tumor cells to radiation-induced premature senescence via Bcl-2/ROS/DDR signaling pathway

    International Nuclear Information System (INIS)

    Lee, Jae Seon; Lee, Je Jung

    2009-01-01

    Premature senescence is considered as a cellular defense mechanism to prevent tumorigenesis. Although recent evidences demonstrate that c-Jun N-terminal kinase (JNK) is involved in the senescence process, the target and exact mechanism of JNK signaling in the regulation of cell proliferation has yet to be defined. In this study, we investigated the role of JNK in premature senescence and demonstrated JNK inhibition sensitized tumor cells to radiation-induced premature senescence

  3. Radiation induced changes in the expression of fibronectin, Pai-1, MMP in rat glomerular epithelial cell

    Energy Technology Data Exchange (ETDEWEB)

    Park, Woo Yoon; Kim, Won Dong; Zheng, Ying; Ha, Tae Sun [Chungbuk National University, Cheongju (Korea, Republic of); Kim, Jae Sung [Seoul National University, Seoul (Korea, Republic of); Cho, Moon June [Chungnam National University, Daejeon (Korea, Republic of)

    2006-03-15

    Renal irradiation can lead to the development of radiation nephropathy, and this is characterized by the accumulation of extracellular matrix and final fibrosis. To determine the possible role of the glomerular epithelial cell, the radiation-induced changes in the expression of its genes associated with the extracellular matrix were analyzed. Rat glomerular epithelial cells (GEpC) were irradiated with a single dose of 0, 2, 5, 10 and 20 Gy with using 6 MV LINAC (Siemens, USA), and the samples were collected 6, 24, 48 and 72 hours post-irradiation, respectively. Northern blotting, western blotting and zymography were used to measure the expression level of fibronectin (Fn), plasminogen activator inhibitor-1 (Pai-1), matrix metalloproteinases-2, 9 (MMP-2, 9), tissue inhibitor of metalloproteinases-2 (TIMP-2), tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Irradiation with a single dose of 10 Gy resulted in a significant increase in Fn mRNA since 24 hours post-irradiation, and a single dose of 5 and 10 Gy significantly increased the Fn immunoreactive protein measured 48 hours post-irradiation. An increase in Pai-mRNA and protein was also observed and especially, a single dose of 10 Gy significantly increased the mRNA measured 24 and 48 hours post-irradiation. The active MMP-2 measured 24 hours post-irradiation slightly increased in a dose dependent manner, but this increase did not reach statistical significance. The levels of MMP-9, TIMP-2, t-PA and u-PA appeared unaltered after irradiation. Irradiation of the glomerular epithelial cells altered the expression of genes associated with the extracellular matrix, implying that the glomerular epithelial cell may be involved in the development of radiation nephropathy.

  4. Radiation induced changes in the expression of fibronectin, Pai-1, MMP in rat glomerular epithelial cell

    International Nuclear Information System (INIS)

    Park, Woo Yoon; Kim, Won Dong; Zheng, Ying; Ha, Tae Sun; Kim, Jae Sung; Cho, Moon June

    2006-01-01

    Renal irradiation can lead to the development of radiation nephropathy, and this is characterized by the accumulation of extracellular matrix and final fibrosis. To determine the possible role of the glomerular epithelial cell, the radiation-induced changes in the expression of its genes associated with the extracellular matrix were analyzed. Rat glomerular epithelial cells (GEpC) were irradiated with a single dose of 0, 2, 5, 10 and 20 Gy with using 6 MV LINAC (Siemens, USA), and the samples were collected 6, 24, 48 and 72 hours post-irradiation, respectively. Northern blotting, western blotting and zymography were used to measure the expression level of fibronectin (Fn), plasminogen activator inhibitor-1 (Pai-1), matrix metalloproteinases-2, 9 (MMP-2, 9), tissue inhibitor of metalloproteinases-2 (TIMP-2), tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Irradiation with a single dose of 10 Gy resulted in a significant increase in Fn mRNA since 24 hours post-irradiation, and a single dose of 5 and 10 Gy significantly increased the Fn immunoreactive protein measured 48 hours post-irradiation. An increase in Pai-mRNA and protein was also observed and especially, a single dose of 10 Gy significantly increased the mRNA measured 24 and 48 hours post-irradiation. The active MMP-2 measured 24 hours post-irradiation slightly increased in a dose dependent manner, but this increase did not reach statistical significance. The levels of MMP-9, TIMP-2, t-PA and u-PA appeared unaltered after irradiation. Irradiation of the glomerular epithelial cells altered the expression of genes associated with the extracellular matrix, implying that the glomerular epithelial cell may be involved in the development of radiation nephropathy

  5. Lack of specificity of chromosome breaks resulting from radiation-induced genomic instability in Chinese hamster cells

    International Nuclear Information System (INIS)

    Trott, K.-R.; Teibe, A.

    1998-01-01

    In V79 Chinese hamster cells, radiation-induced genomic instability results in a persistently increased frequency of micronuclei, dicentric chromosomes and apoptosis and in decreased colony-forming ability. These manifestations of radiation-induced genomic instability may be attributed to an increased rate of chromosome breakage events many generations after irradiation. This chromosomal instability does not seem to be a property which has been inflicted on individual chromosomes at the time of irradiation. Rather, it appears to be secondary to an increased level of non-specific clastogenic factors in the progeny of most if not all irradiated cells. This conclusion is drawn from the observations presented here, that all the chromosomes in surviving V79 cells are involved in the formation of dicentric chromosome aberrations 1 or 2 weeks after irradiation with about equal probability if corrections are made for chromosome length. (orig.)

  6. Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells on the radiation-induced GI syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Shim, Se Hwan; Jang, Won Suk; Lee, Sun Joo; Park, Eun Young; Kim, Youn Joo; Jin, Sung Ho; Park, Sun Hoo; Lee, Seung Sook [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2011-05-15

    The gastrointestinal (GI) tract is one of the most radiosensitive organ systems in the body. Radiation-induced GI injury is described as destruction of crypt cell, decrease in villous height and number, ulceration, and necrosis of intestinal epithelium. Studies show that mesenchymal stem cells (MSCs) treatment may be useful in the repair or regeneration of damaged organs including bone, cartilage, or myocardium. MSCs from umbilical cord blood (UCB) have many advantages because of the immature nature of newborn cells compared to bone marrow derived MSCs. Moreover, UCB-MSCs provide no ethical barriers for basic studies and clinical applications. In this study, we explore the regeneration capability of human UCB-MSCs after radiation-induced GI injury

  7. Influence of the circadian rhythm in cell division on radiation-induced mitotic delay in vivo

    International Nuclear Information System (INIS)

    Rubin, N.A.

    1980-01-01

    All mitotically active normal tissues in mammals investigated to date demonstrate a circadian rhythm in cell division. The murine corneal epithelium is a practical and advantageous tissue model for studying this phenomenon. In animals synchronized to a light-dark (LD) schedule, one sees predictably reproducible occurrences of peaks and troughs in the mitotic index (MI) within each 24-hour (h) period. One of the harmful effects of ionizing radiation on dividing cells is mitotic delay, reported to be a G 2 block in cells approaching mitosis. Affected cells are not killed but are inhibited from entering mitosis and are delayed for a span of time reported to be dose and cell cycle dependent. In the classical description of mitotic delay, MI of irradiated cells begins to drop in relation to the control, which is plotted as a straight line, uniform throughout the experiment. After the damage is repaired, delayed cells can enter mitosis along with other cells in the pool unaffected by the radiation, resulting in a MI higher than control levels. The span of delay and the occurrence of recovery are assumed to be constant for a given dose and tissue under similar experimental conditions. First described in asynchronously-dividing tissue culture cells, this concept is also extrapolated to the in vivo situation

  8. Radiation induced esophageal adenocarcinoma in a woman previously treated for breast cancer and renal cell carcinoma

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    Raissouni Soundouss

    2012-08-01

    Full Text Available Abstract Background Secondary radiation-induced cancers are rare but well-documented as long-term side effects of radiation in large populations of breast cancer survivors. Multiple neoplasms are rare. We report a case of esophageal adenocarcinoma in a patient treated previously for breast cancer and clear cell carcinoma of the kidney. Case presentation A 56 year-old non smoking woman, with no alcohol intake and no familial history of cancer; followed in the National Institute of Oncology of Rabat Morocco since 1999 for breast carcinoma, presented on consultation on January 2011 with dysphagia. Breast cancer was treated with modified radical mastectomy, 6 courses of chemotherapy based on CMF regimen and radiotherapy to breast, inner mammary chain and to pelvis as castration. Less than a year later, a renal right mass was discovered incidentally. Enlarged nephrectomy realized and showed renal cell carcinoma. A local and metastatic breast cancer recurrence occurred in 2007. Patient had 2 lines of chemotherapy and 2 lines of hormonotherapy with Letrozole and Tamoxifen assuring a stable disease. On January 2011, the patient presented dysphagia. Oesogastric endoscopy showed middle esophagus stenosing mass. Biopsy revealed adenocarcinoma. No evidence of metastasis was noticed on computed tomography and breast disease was controlled. Palliative brachytherapy to esophagus was delivered. Patient presented dysphagia due to progressive disease 4 months later. Jejunostomy was proposed but the patient refused any treatment. She died on July 2011. Conclusion We present here a multiple neoplasm in a patient with no known family history of cancers. Esophageal carcinoma is most likely induced by radiation. However the presence of a third malignancy suggests the presence of genetic disorders.

  9. Radiation induced esophageal adenocarcinoma in a woman previously treated for breast cancer and renal cell carcinoma.

    Science.gov (United States)

    Raissouni, Soundouss; Raissouni, Ferdaous; Rais, Ghizlane; Aitelhaj, Meryem; Lkhoyaali, Siham; Latib, Rachida; Mohtaram, Amina; Rais, Fadoua; Mrabti, Hind; Kabbaj, Nawal; Amrani, Naima; Errihani, Hassan

    2012-08-09

    Secondary radiation-induced cancers are rare but well-documented as long-term side effects of radiation in large populations of breast cancer survivors. Multiple neoplasms are rare. We report a case of esophageal adenocarcinoma in a patient treated previously for breast cancer and clear cell carcinoma of the kidney. A 56 year-old non smoking woman, with no alcohol intake and no familial history of cancer; followed in the National Institute of Oncology of Rabat Morocco since 1999 for breast carcinoma, presented on consultation on January 2011 with dysphagia. Breast cancer was treated with modified radical mastectomy, 6 courses of chemotherapy based on CMF regimen and radiotherapy to breast, inner mammary chain and to pelvis as castration. Less than a year later, a renal right mass was discovered incidentally. Enlarged nephrectomy realized and showed renal cell carcinoma. A local and metastatic breast cancer recurrence occurred in 2007. Patient had 2 lines of chemotherapy and 2 lines of hormonotherapy with Letrozole and Tamoxifen assuring a stable disease. On January 2011, the patient presented dysphagia. Oesogastric endoscopy showed middle esophagus stenosing mass. Biopsy revealed adenocarcinoma. No evidence of metastasis was noticed on computed tomography and breast disease was controlled. Palliative brachytherapy to esophagus was delivered. Patient presented dysphagia due to progressive disease 4 months later. Jejunostomy was proposed but the patient refused any treatment. She died on July 2011. We present here a multiple neoplasm in a patient with no known family history of cancers. Esophageal carcinoma is most likely induced by radiation. However the presence of a third malignancy suggests the presence of genetic disorders.

  10. A correlative study on the frequencies of radiation-induced chromosome aberrations in somatic and germ cells of mammals

    International Nuclear Information System (INIS)

    Buul, P.P.W. van

    1976-01-01

    A series of investigations on the correlation between the frequencies of radiation-induced chromosome aberrations in somatic and germ cells of mouse and rhesus monkey is described. In the mouse the induction of reciprocal translocations in bone-marrow cells was compared with that in spermatogonia (as scored in the descending spermatocytes). In the rhesus monkey frequencies of radiation-induced chromosome aberrations in spermatogonia and peripheral blood lymphocytes were studied. Furthermore the effect of multigeneration irradiation (69 generations with 200 rads X-rays) on the sensitivity for translocation induction in spermatogonia of male mice was studied. Frequencies of dicentric chromosomes and chromosomal deletions in cultured peripheral blood lymphocytes of 5 different types of mice were determined following in vitro irradiation with doses of 100 and/or 200 rad X-rays. To obtain more insight into the processes underlying translocation induction in spermatogonia of the mouse, fractionation experiments were conducted

  11. Radiation induced expression of survivin in Ewing sarcoma cell-lines

    International Nuclear Information System (INIS)

    Sheikh-Mounessi, F.; Willich, N.; Greve, B.

    2009-01-01

    Full text: Introduction: Survivin belongs to the Inhibitor of Apoptosis Protein Family (IAP), is a protein of 16.5 kD and active as a homodimer. It is overexpressed in nearly all human tumors and has a vital function in cell division and apoptotic processes. Beside its role as a relevant prognostic and predictive factor it was described to be a molecular target to improve effectiveness of radiotherapy. We investigated the radiation induced survivin expression in Ewing sarcoma cell-lines. Methods: Ewing sarcoma cells were either irradiated with 10 Gy X-ray and harvested at different time points (0, 2, 4, 6, 10 and 24 h) or irradiated with different doses (0, 2, 5 and 10 Gy) and harvested 24 h later. Protein and mRNA expression was analysed by Westernblot or Real-Time PCR. Results: Directly after irradiation with 10 Gy X-ray survivin mRNA expression was increased in relation to the reference GAPDH. Protein expression was increased in a time dependent manner and reached a maximum after 24h. Three of four investigated cell-lines showed a significant dose dependent increase of survivin protein concentration 24h after irradiation. The same three cell-lines showed a LD50 of >30 Gy. The line with the lowest dose dependent survivin induction was investigated to be most radiosensitive (LD50 = 24 Gy). Discussion: Ewing sarcoma is a childhood tumor with relatively poor prognosis. This tumor often shows significant therapeutic resistance to chemo- and/or radiotherapy. It would be of high interest to find new therapeutic approaches for its treatment. We found a remarkable overexpression of survivin in untreated Ewing sarcoma and a time and dose dependent increase of survivin protein concentration after irradiation with X-ray. The cell-line with the lowest survivin induction showed the highest radiosensitivity. In conclusion, our results show that survivin is an inducible radioresistance factor in Ewing sarcoma. This may open new therapeutic options to treat this aggressive

  12. LyGDI expression in HeLa cells increased its sensitivity to radiation-induced apoptosis

    International Nuclear Information System (INIS)

    Zhou Xinwen; Xu Yaxiang

    2006-01-01

    Objective: In order to confirm whether LyGDI has apoptotic signal transduction function and can increase the apoptotic rate of radiation-induced cell death, the lyGDI and mutant D19lyGDI gene, which constructed with the pCDNA3. 1 His A, were transfected into no-endogenous lyGDI HeLa cells. Methods Transient expressions of lyGDI and D19lyGDI in HeLa cells were analyzed by Western blot using anti-mono antibody of LyGDI and Xpress tag. Cell apoptosis was assayed with Annexin V-FITC apoptosis kit. To select stable clone, the transferred HeLa cells had been maintained in G418 medium for 3 weeks, then a cell line, which stably expressed LyGDI and mutant D19lyGDI, was selected. The selected cell line was irradiated with 12 Gy 60 Co y-rays. Caspase-3 activity of the cells was determined by Western blot and cell viability by clone-forming assay after 48 hours post-irradiation culture. Results: Western blot and Annexin V-FITC apoptotic analysis revealed that lyGDI and D19lyGDI transient expressions in HeLa cells induced apoptosis; Caspase-3 activity measurement and clone-forming assay showed that lyGDI increased sensitivity to radiation-induced cell apoptosis. Conclusions: lyGDI performs function in apoptosis signal transduction, its expression in HeLa cells can increase the sensitivity to radiation-induced cell apoptosis. (authors)

  13. Visualizing the effect of tumor microenvironments on radiation-induced cell kinetics in multicellular spheroids consisting of HeLa cells

    International Nuclear Information System (INIS)

    Kaida, Atsushi; Miura, Masahiko

    2013-01-01

    Highlights: •We visualized radiation-induced cell kinetics in spheroids. •HeLa-Fucci cells were used for detection of cell-cycle changes. •Radiation-induced G2 arrest was prolonged in the spheroid. •The inner and outer cell fractions behaved differently. -- Abstract: In this study, we visualized the effect of tumor microenvironments on radiation-induced tumor cell kinetics. For this purpose, we utilized a multicellular spheroid model, with a diameter of ∼500 μm, consisting of HeLa cells expressing the fluorescent ubiquitination-based cell-cycle indicator (Fucci). In live spheroids, a confocal laser scanning microscope allowed us to clearly monitor cell kinetics at depths of up to 60 μm. Surprisingly, a remarkable prolongation of G2 arrest was observed in the outer region of the spheroid relative to monolayer-cultured cells. Scale, an aqueous reagent that renders tissues optically transparent, allowed visualization deeper inside spheroids. About 16 h after irradiation, a red fluorescent cell fraction, presumably a quiescent G0 cell fraction, became distinct from the outer fraction consisting of proliferating cells, most of which exhibited green fluorescence indicative of G2 arrest. Thereafter, the red cell fraction began to emit green fluorescence and remained in prolonged G2 arrest. Thus, for the first time, we visualized the prolongation of radiation-induced G2 arrest in spheroids and the differences in cell kinetics between the outer and inner fractions

  14. Persistence of radiation-induced chromosome aberrations in a long-term cell culture.

    Science.gov (United States)

    Duran, Assumpta; Barquinero, Joan Francesc; Caballín, María Rosa; Ribas, Montserrat; Barrios, Leonardo

    2009-04-01

    The aim of the present study was to evaluate the persistence of chromosome aberrations induced by X rays. FISH painting and mFISH techniques were applied to long-term cultures of irradiated cells. With painting, at 2 Gy the frequency of apparently simple translocations remained almost invariable during all the culture, whereas at 4 Gy a rapid decline was observed between the first and the second samples, followed by a slight decrease until the end of the culture. Apparently simple dicentrics and complex aberrations disappeared after the first sample at 2 and 4 Gy. By mFISH, at 2 Gy the frequency of complete plus one-way translocations remained invariable between the first and last sample, but at 4 Gy a 60% decline was observed. True incomplete simple translocations disappeared at 2 and 4 Gy, indicating that incompleteness could be a factor to consider when the persistence of translocations is analyzed. The analysis by mFISH showed that the frequency of complex aberrations and their complexity increased with dose and tended to disappear in the last sample. Our results indicate that the influence of dose on the decrease in the frequency of simple translocations with time postirradiation cannot be fully explained by the disappearance of true incomplete translocations and complex aberrations. The chromosome involvement was random for radiation-induced exchange aberrations and non-random for total aberrations. Chromosome 7 showed the highest deviations from expected, being less and more involved than expected in the first and last samples, respectively. Some preferential chromosome-chromosome associations were observed, including a coincidence with a cluster from radiogenic chromosome aberrations described in other studies.

  15. Chromosome condensation and radiation-induced G2 arrest studied by the induction of premature chromosome condensation following cell fusion

    International Nuclear Information System (INIS)

    Mitchell, J.B.; Bedford, J.S.

    1978-01-01

    When mitotic and interphase cells are fused together, the chromosomes of the interphase cell sometimes condense prematurely. The phenomenon of premature chromosome condensation (PCC) was utilized in investigating the problem of whether the chromosomes of cells suffering a radiation-induced G 2 delay are capable of condensation. Colcemide-arrested mitotic cells were fused with synchronized G 2 cells, and with irradiated cells suffering a G 2 delay. The frequency of PCC in mitotic X G 2 binucleate cells was determined. This was compared to the PCC frequency in an unirradiated synchronized population rich in G 2 cells after fusion with mitotic cells. Flash-labelling with 3 HTdR and autoradiography allowed S-phase cells to be eliminated. The frequency of G 2 PCCs was not significantly different for the irradiated G 2 -delayed or unirradiated cells. From these results it was concluded that the chromosomes of cells suffering a G 2 arrest are capable of condensation, although the involvement of the condensation process in radiation-induced G 2 delay could not be ruled out. (author)

  16. Radiation-induced apoptosis

    International Nuclear Information System (INIS)

    Ohyama, Harumi

    1995-01-01

    Apoptosis is an active process of gene-directed cellular self-destruction that can be induced in many cell types via numerous physiological and pathological stimuli. We found that interphasedeath of thymocytes is a typical apoptosis showing the characteristic features of apoptosis including cell shrinkage, chromatin condensation and DNA degradation. Moderate dose of radiation induces extensive apoptosis in rapidly proliferating cell population such as the epithelium of intestinal crypt. Recent reports indicate that the ultimate form of radiation-induced mitotic death in several cells is also apoptosis. One of the hallmarks of apoptosis is the enzymatic internucleosomal degradation of chromatin DNA. We identified an endonuclease responsible for the radiation-induced DNA degradation in rat thymocytes. The death-sparing effects of interrupting RNA and protein synthesis suggested a cell genetic program for apoptosis. Apoptosis of thymocytes initiated by DNA damage, such as radiation and radio mimetic substance, absolutely requires the protein of p53 cancer suppresser gene. The cell death induced by glucocorticoid, or aging, has no such requirement. Expression of oncogene bcl-2 rescues cells from the apoptosis. Massive apoptosis in radiosensitive cells induced by higher dose radiation may be fatal. It is suggested that selective apoptotic elimination of cells would play an important role for protection against carcinogenesis and malformation through removal of cells with unrepaired radiation-induced DNA damages. Data to evaluate the significance of apoptosis in the radiation risk are still poor. Further research should be done in order to clarify the roles of the cell death on the acute and late effects of irradiation. (author)

  17. Radiation-induced transformation in oncogene primed C3H/10T1/2 cells; a new system for analysis of multi-step transformation in vitro

    International Nuclear Information System (INIS)

    Drozdoff, V.V.

    1988-01-01

    Several established rodent cell lines, such as C3H/10T1/2 fibroblasts, have been developed to study radiation and chemically-induced malignant transformation. Most experimental evidence has supported the idea that transformation in 10T1/2 cells involved at least two steps but that the apparent frequency of transformation depends on the density of plated cells. A new approach is presented here for studying radiation-induced transformation. An oncogene primed cell system (C3H-myc) was developed by introducing a constitutively active mouse c-myc gene into 10T1/2 cells. A primary goal was to determine if the introduction of an activated oncogene could substitute for one of the required steps in radiation-induced transformation. Results are presented that show that the expression of the exogenous myc gene significantly increased the frequency of radiation-induced transformation in these cells. Subculture experiments performed to analyze the kinetics of transformation in C3H-myc cells and reconstruction experiments allowing the effects of normal cells on radiation-induced transformants to be determined indicated that transformed cells arose very shortly after irradiation. These results support the conclusion that a radiation-induced event can complement the effect of myc in C3H-myc cells and directly result in transformation. This system thus provides an opportunity to isolate early steps in radiation-induced transformation and should facilitate the identification and analysis of these events

  18. Dose-dependency and reversibility of radiation-induced injury in cardiac explant-derived cells of mice

    Science.gov (United States)

    Luo, Lan; Yan, Chen; Urata, Yoshishige; Hasan, Al Shaimaa; Goto, Shinji; Guo, Chang-Ying; Zhang, Shouhua; Li, Tao-Sheng

    2017-01-01

    We evaluated the dose-dependency and reversibility of radiation-induced injury in cardiac explant-derived cells (CDCs), a mixed cell population grown from heart tissues. Adult C57BL/6 mice were exposed to 0, 10, 50 and 250 mGy γ-rays for 7 days and atrial tissues were collected for experiments 24 hours after last exposure. The number of CDCs was significantly decreased by daily exposure to over 250 mGy. Interestingly, daily exposure to over 50 mGy significantly decreased the c-kit expression and telomerase activity, increased 53BP1 foci in the nuclei of CDCs. However, CD90 expression and growth factors production in CDCs were not significantly changed even after daily exposure to 250 mGy. We further evaluated the reversibility of radiation-induced injury in CDCs at 1 week and 3 weeks after a single exposure to 3 Gy γ-rays. The number and growth factors production of CDCs were soon recovered at 1 week. However, the increased expression of CD90 were retained at 1 week, but recovered at 3 weeks. Moreover, the decreased expression of c-kit, impaired telomerase activity, and increased 53BP1 foci were poorly recovered even at 3 weeks. These data may help us to find the most sensitive and reliable bio-parameter(s) for evaluating radiation-induced injury in CDCs. PMID:28098222

  19. Study on bone marrow mesenchymal stem cells in repairing of radiation induced acute liver injury of rats

    International Nuclear Information System (INIS)

    Bao Yongxing; Lou Fan; Zhao Huarong; Zhu Huhu; Ma Yan; Wen Hao

    2010-01-01

    Objective: To investigate the role of mesenchymal stem cells in the repair of radiation induced liver injury. Methods: 12 female SD rats were irradiated with 20 Gy 6 MV X-rays on the right lobe of the liver, to establish the model of radiation induced liver injury. The rats were divided randomly into two groups as invention group and control group, and transplanted with 1 ml male mesenchymal suspension or 1 ml normal saline in 4 hours after radiotherapy. The morphological changes of liver were observed. The existence of sex determining gene Y(SRY) and the level of alpha-smooth muscle actin (a-SMA) were detected. Results: Some injury of right lobe liver in two groups were observed, and the injury degree of right lobe liver in intervention group were lower than that of control group. The amount of SRY positive cells in the right lobe liver of intervention group was higher than that in the left lobe liver (t = 3.77, P <0.05). The positive expression rate of a-SMA in right lobe liver of intervention group was lower than that of control group. Conclusions: Acute radiation induced liver injury could lead BMSCs' homing in order to decrease the degree of liver fibrosis. (authors)

  20. Wnt/β-catenin pathway involvement in ionizing radiation-induced invasion of U87 glioblastoma cells

    International Nuclear Information System (INIS)

    Dong, Zhen; Zhou, Lin; Han, Na; Zhang, Mengxian; Lyu, Xiaojuan

    2015-01-01

    Radiotherapy has been reported to promote the invasion of glioblastoma cells; however, the underlying mechanisms remain unclear. Here, we investigated the role of the Wnt/β-catenin pathway in radiation-induced invasion of glioblastoma cells. U87 cells were irradiated with 3 Gy or sham irradiated in the presence or absence of the Wnt/β-catenin pathway inhibitor XAV 939. Cell invasion was determined by an xCELLigence real-time cell analyser and matrigel invasion assays. The intracellular distribution of β-catenin in U87 cells with or without irradiation was examined by immunofluorescence and Western blotting of nuclear fractions. We next investigated the effect of irradiation on Wnt/β-catenin pathway activity using TOP/FOP flash luciferase assays and quantitative polymerase chain reaction analysis of β-catenin target genes. The expression levels and activities of two target genes, matrix metalloproteinase (MMP)-2 and MMP-9, were examined further by Western blotting and zymography. U87 cell invasiveness was increased significantly by ionizing radiation. Interestingly, ionizing radiation induced nuclear translocation and accumulation of β-catenin. Moreover, we found increased β-catenin/TCF transcriptional activities, followed by up-regulation of downstream genes in the Wnt/β-catenin pathway in irradiated U87 cells. Importantly, inhibition of the Wnt/β-catenin pathway by XAV 939, which promotes degradation of β-catenin, significantly abrogated the pro-invasion effects of irradiation. Mechanistically, XAV 939 suppressed ionizing radiation-triggered up-regulation of MMP-2 and MMP-9, and inhibited the activities of these gelatinases. Our data demonstrate a pivotal role of the Wnt/β-catenin pathway in ionizing radiation-induced invasion of glioblastoma cells, and suggest that targeting β-catenin is a promising therapeutic approach to overcoming glioma radioresistance. (orig.) [de

  1. The amount of DNA damage needed to activate the radiation-induced G2 checkpoint varies between single cells

    International Nuclear Information System (INIS)

    Tkacz-Stachowska, Kinga; Lund-Andersen, Christin; Velissarou, Angeliki; Myklebust, June H.; Stokke, Trond; Syljuåsen, Randi G.

    2011-01-01

    Background and purpose: The radiation-induced G2 checkpoint helps facilitate DNA repair before cell division. However, recent work has revealed that human cells often escape the G2 checkpoint with unrepaired DNA breaks. The purpose was to explore whether G2 checkpoint activation occurs according to a threshold level of DNA damage. Materials and methods: G2 checkpoint activation was assayed at 75–90 min and 24–48 h after X-ray irradiation of BJ diploid fibroblasts and U2OS osteosarcoma cells. Multiparameter flow cytometry with pacific blue barcoding, and flow cytometry-based sorting of phospho-H3 positive cells to microscope slides, were used to examine the DNA damage marker γ-H2AX in individual mitotic cells that had escaped the G2 checkpoint. Results: For all radiation doses and times tested, the number of γ-H2AX foci varied between individual mitotic cells. At 75 min the median levels of γ-H2AX in mitotic cells increased with higher radiation doses. At 24–48 h, following a prolonged G2 checkpoint, cells were more resistant to checkpoint re-activation by a second dose of radiation. Conclusion: Our results suggest that different amounts of DNA damage are needed to activate the G2 checkpoint in individual cells. Such single cell variation in checkpoint activation may potentially contribute to radiation-induced genomic instability.

  2. Enhancement of radiation induced oxidative stress in tumour cells by EGCG

    International Nuclear Information System (INIS)

    Das, U.; Das, T.; Sengupta, A.; Biswas, S.; Dey, S.; Chakraborty, A.

    2017-01-01

    In view of the fact that radiotherapy fails in the later stages of cancer due to the radioresistant tumor cells, it is most important in radiobiology to enhance the oxidative damage of the tumor cells by using a tumor selective cytotoxic agent. The increase in radiosensitivity is important both for optimizing radiation dose for tumors and for designing strategies to improve the therapeutic ratio. Amount and time of treatment of radiation (IR), epigallocatechin gallate (EGCG) and epicatechin (EC) were determined using MTT assay. Biochemical assay, Flow cytometry and immune blots were employed to elucidate the enhanced sensitization of EC and EGCG along with IR in hepatocellular carcinoma cells (HepG2). The effects were more effective in killing the HepG2 cells compared to only irradiation. It was observed that the ROS generation was significantly increased in combination group (IR+EGCG/EC) over the IR group. Lower reduced glutathione content, higher TBARS and decreased catalase activity in combination group provided additive support. Combination treatment caused cell cycle arrest at G2/M phase. Mitochondrial membrane potential was greatly reduced and the percentage of apoptotic population increased in combination group compared to IR alone. Moreover, the higher expression of p53 and activation of caspase 3 in combination group over the IR alone indicated EC and EGCG along with ionizing radiation increase the oxidative stressed condition in HepG2 cell that leads the apoptosis of the cells. The novel use of this combination of radiation and tea polyphenol will remain an effective radiotherapeutic strategy. (author)

  3. Single-hit mechanism of tumour cell killing by radiation.

    Science.gov (United States)

    Chapman, J D

    2003-02-01

    To review the relative importance of the single-hit mechanism of radiation killing for tumour response to 1.8-2.0 Gy day(-1) fractions and to low dose-rate brachytherapy. Tumour cell killing by ionizing radiation is well described by the linear-quadratic equation that contains two independent components distinguished by dose kinetics. Analyses of tumour cell survival curves that contain six or more dose points usually provide good estimates of the alpha- and beta-inactivation coefficients. Superior estimates of tumour cell intrinsic radiosensitivity are obtained when synchronized populations are employed. The characteristics of single-hit inactivation of tumour cells are reviewed and compared with the characteristics of beta-inactivation. Potential molecular targets associated with single-hit inactivation are discussed along with strategies for potentiating cell killing by this mechanism. The single-hit mechanism of tumour cell killing shows no dependence on dose-rate and, consequently, no evidence of sublethal damage repair. It is uniquely potentiated by high linear-energy-transfer radiation, exhibits a smaller oxygen enhancement ratio and exhibits a larger indirect effect by hydroxyl radicals than the beta-mechanism. alpha-inactivation coefficients vary slightly throughout interphase but mitotic cells exhibit extremely high alpha-coefficients in the range of those observed for lymphocytes and some repair-deficient cells. Evidence is accumulating to suggest that chromatin in compacted form could be a radiation-hypersensitive target associated with single-hit radiation killing. Analyses of tumour cell survival curves demonstrate that it is the single-hit mechanism (alpha) that determines the majority of cell killing after doses of 2Gy and that this mechanism is highly variable between tumour cell lines. The characteristics of single-hit inactivation are qualitatively and quantitatively distinct from those of beta-inactivation. Compacted chromatin in tumour cells

  4. Caspase-independent cell death mediated by apoptosis-inducing factor (AIF) nuclear translocation is involved in ionizing radiation induced HepG2 cell death

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Hengwen [Department of Radiation, Cancer Center of Guangdong General Hospital (Guangdong Academy of Medical Science), Guangzhou, 510080, Guangdong (China); Yang, Shana; Li, Jianhua [Department of Physiology, Guangzhou Medical University, Guangzhou, 510182, Guangdong (China); Zhang, Yajie [Department of Pathology, Guangzhou Medical University, Guangzhou, 510182, Guangdong (China); Gao, Dongsheng [Department of Oncology, Guangdong Medical College Affiliated Pengpai Memorial Hospital, Hai Feng, 516400, Gungdong (China); Zhao, Shenting, E-mail: zhaoshenting@126.com [Department of Physiology, Guangzhou Medical University, Guangzhou, 510182, Guangdong (China)

    2016-03-25

    Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The aim of radiotherapy is to eradicate cancer cells with ionizing radiation. Except for the caspase-dependent mechanism, several lines of evidence demonstrated that caspase-independent mechanism is directly involved in the cell death responding to irradiation. For this reason, defining the contribution of caspase-independent molecular mechanisms represents the main goal in radiotherapy. In this study, we focused on the role of apoptosis-inducing factor (AIF), the caspase-independent molecular, in ionizing radiation induced hepatocellular carcinoma cell line (HepG2) cell death. We found that ionizing radiation has no function on AIF expression in HepG2 cells, but could induce AIF release from the mitochondria and translocate into nuclei. Inhibition of AIF could reduce ionizing radiation induced HepG2 cell death. These studies strongly support a direct relationship between AIF nuclear translocation and radiation induced cell death. What's more, AIF nuclear translocation is caspase-independent manner, but not caspase-dependent manner, in this process. These new findings add a further attractive point of investigation to better define the complex interplay between caspase-independent cell death and radiation therapy. - Highlights: • AIF nuclear translocation is involved in ionizing radiation induced hepatocellular carcinoma cell line HepG2 cell death. • AIF mediated cell death induced by ionizing radiation is caspase-independent. • Caspase-independent pathway is involved in ionzing radiation induced HepG2 cell death.

  5. Chemical chaperones reduce ionizing radiation-induced endoplasmic reticulum stress and cell death in IEC-6 cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Eun Sang; Lee, Hae-June; Lee, Yoon-Jin [Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Jeong, Jae-Hoon [Division of Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Kang, Seongman [Division of Life Sciences, Korea University, Seoul 136-701 (Korea, Republic of); Lim, Young-Bin, E-mail: yblim@kirams.re.kr [Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)

    2014-07-25

    Highlights: • UPR activation precedes caspase activation in irradiated IEC-6 cells. • Chemical ER stress inducers radiosensitize IEC-6 cells. • siRNAs that targeted ER stress responses ameliorate IR-induced cell death. • Chemical chaperons prevent cell death in irradiated IEC-6 cells. - Abstract: Radiotherapy, which is one of the most effective approaches to the treatment of various cancers, plays an important role in malignant cell eradication in the pelvic area and abdomen. However, it also generates some degree of intestinal injury. Apoptosis in the intestinal epithelium is the primary pathological factor that initiates radiation-induced intestinal injury, but the mechanism by which ionizing radiation (IR) induces apoptosis in the intestinal epithelium is not clearly understood. Recently, IR has been shown to induce endoplasmic reticulum (ER) stress, thereby activating the unfolded protein response (UPR) signaling pathway in intestinal epithelial cells. However, the consequences of the IR-induced activation of the UPR signaling pathway on radiosensitivity in intestinal epithelial cells remain to be determined. In this study, we investigated the role of ER stress responses in IR-induced intestinal epithelial cell death. We show that chemical ER stress inducers, such as tunicamycin or thapsigargin, enhanced IR-induced caspase 3 activation and DNA fragmentation in intestinal epithelial cells. Knockdown of Xbp1 or Atf6 with small interfering RNA inhibited IR-induced caspase 3 activation. Treatment with chemical chaperones prevented ER stress and subsequent apoptosis in IR-exposed intestinal epithelial cells. Our results suggest a pro-apoptotic role of ER stress in IR-exposed intestinal epithelial cells. Furthermore, inhibiting ER stress may be an effective strategy to prevent IR-induced intestinal injury.

  6. Radiation-induced interphase death observed in human T-cell lymphoma cells established as a nude mouse tumor line

    International Nuclear Information System (INIS)

    Igarashi, T.; Yoshida, S.; Miyamoto, T.

    1990-01-01

    Interphase death of cells occurs physiologically in healthy animal tissues as well as in tissues pathologically injured by radiation or drugs. An active self-destruction process has been found to play a major role in the interphase death of highly radiosensitive cells. However, the mechanism of this radiation-induced interphase death in human lymphoma has not yet been studied in detail. In the present study, we examined a lymphoma derived from a child lymphoblastic lymphoma bearing CD1, CD4, and CD8 antigens and established in nude mice. Low-dose x-irradiation of this lymphoma induced interphase cell death with characteristic morphological and biological changes of an active self-destruction process, i.e., changes in cell surface appearance seen using scanning electron microscopy and nuclear fragmentation accompanied with an increase in free DNA. The process was proved to require protein synthesis. It was concluded that the radiosensitivity of this T-cell lymphoma of common thymic type is mainly due to the occurrence of the active self-destruction process

  7. Levels of p21WAF1/CIP1 do not affect radiation-induced cell death in human breast epithelial cells

    International Nuclear Information System (INIS)

    Kim, Harold E.; Han, Sue J.; Waid, David; Lee, Yong J.; Kim, Hyeong-Reh Choi

    1997-01-01

    Purpose/Objective: Loss of the wild-type p53 activity and/or overexpression of the proto-oncogene bcl-2 are frequently detected in breast cancer and suggested to be related to resistance to chemotherapy and radiation therapy. The long-term goals of this study are to identify the downstream signaling molecules for anti-proliferative and apoptotic activities of p53 and to investigate the interaction of bcl-2 with p53 in human breast epithelial cells. We previously showed that overexpression of bcl-2 downregulates radiation-induced expression of p21 WAF1/CIP1 , a p53 downstream molecule that functions to inhibit cyclin dependent kinases, and suppresses radiation-induced apoptosis in human breast epithelial cell line (MCF10A). In this study, we investigated the role of p21 WAF1/CIP1 in radiation-induced cell death in MCF10A cells. Materials and Methods: To determine whether downregulation of p21 WAF1/CIP1 is required for anti-apoptotic activity of bcl-2, and to investigate the roles of p21 WAF1/CIP1 in cell death following irradiation, we transfected p21 WAF1/CIP1 expression vector into bcl-2 overexpressing MCF10A cells. The effects of p21 WAF1/CIP1 overexpression on cell growth, radiation-induced apoptosis and clonogenic cell survival were analyzed. Results: Overexpression of p21 WAF1/CIP1 resulted in marked growth inhibition, but no effect on dose-dependent radiation-induced cell lethality as determined by clonogenic survival assay. Radiation-induced apoptosis was not detected in bcl-2 overexpressing MCF10A cells independent of levels of p21 WAF1/CIP1 expression. Conclusion: This study suggests that bcl-2 downregulation of p21 WAF1/CIP1 is independent of anti-apoptotic activity of bcl-2 and that levels of p21 WAF1/CIP1 do not affect radiation-induced cell death in human breast epithelial cells

  8. Individual radiosensitivity does not correlate with radiation-induced apoptosis in lymphoblastoid cell lines or CD{sup 3+} lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Wistop, A.; Keller, U.; Grabenbauer, G.G.; Sauer, R.; Distel, L.V.R. [Dept. of Radiation Oncology, Friedrich Alexander Univ. Erlangen-Nuremberg, Erlangen (Germany); Sprung, C.N. [Div. of Research, Peter MacCallum Cancer Centre, East Melbourne, VIC (Australia)

    2005-05-01

    Background and purpose: spontaneous and radiation-induced apoptosis of lymphoblastoid cell lines (LCLs) derived from healthy donors, cancer patients and donors with radiosensitivity syndromes as well as CD{sup 3+} lymphocytes from patients with {>=} grade 3 late toxicity were investigated as a possible marker for the detection of individual radiosensitivity. These investigations are based on the hypothesis that hypersensitive patients have reduced levels of apoptosis after in vitro irradiation as a result of a defect in the signaling pathway. Material and methods: Epstein-Barr virus-(EBV-)transformed LCLs derived from five healthy donors, seven patients with heterozygous or homozygous genotype for ataxia-telangiectasia or Nijmegen breakage syndrome and five patients with {>=} grade 3 late toxicity (RTOG) were investigated. In addition, CD{sup 3+} lymphocytes from 21 healthy individuals and 18 cancer patients including five patients with a proven cellular hypersensitivity to radiation were analyzed. Cells were irradiated in vitro with a dose of 2 and 5 Gy and were incubated for 48 h. Apoptotic rates were measured by the TUNEL assay followed by customized image analysis. Results: four out of seven radiosensitivity syndrome patients were identified to have an increased cellular radiosensitivity as determined by reduced apoptotic rates after irradiation of their respective LCLs. Comparatively, only two of the five hypersensitive cancer patients were clearly identified by reduced apoptotic rates. Spontaneous apoptotic rates were very homogeneous among all 39 samples from controls and patients, while lymphocytes of all cancer patients showed significantly lower radiation-induced rates. Conclusion: only a subgroup of hypersensitive patients may be identified by reduction of radiation-induced apoptotic rate. It is concluded that the hypothesis according to which hypersensitive cells have reduced levels of apoptosis is only conditionally true. The authors suggest that this

  9. Models for radiation-induced tissue degeneration and conceptualization of rehabilitation of irradiated tissue by cell therapy

    International Nuclear Information System (INIS)

    Phulpin, Berengere

    2011-01-01

    Radiation therapy induced acute and late sequelae within healthy tissue included in the irradiated area. In general, lesions are characterized by ischemia, cell apoptosis and fibrosis. In this context, cell therapy using bone marrow mesenchymal stem cells (BMSC) might represent an attractive new therapeutic approach, based partly on their angiogenic ability and their involvement in the natural processes of tissue repair. The first part of this work consisted in the development of experimental mouse model of radio-induced tissue degeneration similar to that occurring after radiotherapy. The aim was to better understand the physiopathological mechanisms of radiation-induced tissue damage and to determine the best treatment strategy. The second part of this work investigated the feasibility of autologous BMSC therapy on the murine model of radiation previously established with emphasis on two pre-requisites: the retention of the injected cells within the target tissue and the evaluation of the graft on bone metabolism. This preclinical investigation in a mouse model constitutes an essential step allowing an evaluation of the benefit of cell therapy for the treatment of radiation-induced tissue injury. Data from these studies could allow the proposal of clinical studies [fr

  10. Attenuation of radiation-induced DNA damage due to paracrine interactions between normal human epithelial and stromal cells

    International Nuclear Information System (INIS)

    Saenko, V.A.; Nakazawa, Yu.; Rogounovitch, T.I.; Suzuki, K.; Mitsutake, N.; Matsuse, M.; Yamashita, S.

    2007-01-01

    Complete text of publication follows. Objective: Developmentally, every tissue accommodates different types of cells, such as epitheliocytes and stromal cells in parenchymal organs. To better understand the complexity of radiation response, it is necessary to evaluate possible cross-talk between different tissue components. This work was set out to investigate reciprocal influence of normal human epithelial cells and fibroblasts on the extent of radiation-induced DNA damage. Methods: Model cultures of primary human thyrocytes (PT), normal diploid fibroblasts (BJ), PT/BJ cell co-culture and conditioned medium transfer were used to examine DNA damage in terms of γ-H2AX foci number per cell or by Comet assay after exposure to different doses of γ-rays. Results: In co-cultures, the kinetics of γ-H2AX foci number change was dose-dependent and similar to that in individual PT and BJ cultures. The number of γ-H2AX foci in co-cultures was significantly lower (∼25%) in both types of cells comparing to individual cultures. Reciprocal conditioned medium transfer to individual counterpart cells prior to irradiation resulted in approximately 35% reduction in the number γ-H2AX foci at 1 Gy and lower doses in both PT and BJ demonstrating the role of paracrine soluble factors. Comet assay corroborated the results of γ-H2AX foci counting in conditioned medium transfer experiments. In contrast to medium conditioned on PT cells, conditioned medium collected from several human thyroid cancer cell lines failed to establish DNA-protected state in BJ fibroblasts. In its turn, medium conditioned on BJ cells did not change the extent of radiation-induced DNA damage in cancer cell lines tested. Conclusion: The results imply the existence of a network of soluble factor-mediated paracrine interactions between normal epithelial and stromal cells that could be a part of natural mechanism by which cells protect DNA from genotoxic stress.

  11. Further studies on the possible relationship between radiation-induced reciprocal translocations and intrinsic radiosensitivity of human tumor cells

    International Nuclear Information System (INIS)

    Virsik-Peuckert, P.; Rave-Fraenk, M.; Schmidberger, H.

    1996-01-01

    Background and purpose. The aim of the present study was to estimate yields of radiation-induced translocations in surviving cells of several human tumor cell lines and in normal diploid human fibroblasts, and to compare these yields with corresponding intrinsic radiosensitivities determined by standard colony-formation assay. Material and methods. The yields of radiation-induced reciprocal translocations were investigated by fluorescence in situ hybridization. Chromosomes no. 1 and no. 4 were 'painted' with fluorescent hybridization probes for whole chromosomes. Translocation yields and cell survival were determined for different doses up to 6 Gy of 200 kV X-rays. Results. We observed a higher frequency of reciprocal translocations in the radiosensitive cells MCF-7 and MDA-MB-436 than in the radioresistant cells CaSki, WiDr, A549 and normal skin fibroblasts. For primary squamous cell carcinoma cells, ZMK-1, an intermediate radiosensitivity and an intermediate translocation yield were observed. The dose-dependence of translocation yields involving chromosomes no. 1 or no. 4 varied in different cell lines: it was linear or linear with a plateau at higher doses. Conclusions. A comparison of the data obtained with chromosomes no. 1 and no. 4 in the investigated cell types, indicates that intrinsic radiosensitivity of different tumor cells observed at the survival level, is correlated with different translocation yields, respectively. This correlation was observed for all cell types investigated, independent of the number of copies of the painted chromosome per cell or the radiation dose. However, for low doses (under 1 Gy), the yields of translocations determined for the individual chromosomes seem to be too low for a discrimination between radioresistant or radiosensitive cells

  12. Protein Kinase CK2 Regulates Cytoskeletal Reorganization during Ionizing Radiation-Induced Senescence of Human Mesenchymal Stem Cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Daojing; Jang, Deok-Jin

    2009-08-21

    Human mesenchymal stem cells (hMSC) are critical for tissue regeneration. How hMSC respond to genotoxic stresses and potentially contribute to aging and cancer remain underexplored. We demonstrated that ionizing radiation induced cellular senescence of hMSC over a period of 10 days, showing a critical transition between day 3 and day 6. This was confirmed by senescence-associated beta-galactosidase (SA-{beta}-gal) staining, protein expression profiles of key cell cycle regulators (retinoblastoma (Rb) protein, p53, p21{sup waf1/Cip1}, and p16{sup INK4A}), and senescence-associated secretory phenotypes (SASPs) (IL-8, IL-12, GRO, and MDC). We observed dramatic cytoskeletal reorganization of hMSC through reduction of myosin-10, redistribution of myosin-9, and secretion of profilin-1. Using a SILAC-based phosphoproteomics method, we detected significant reduction of myosin-9 phosphorylation at Ser1943, coinciding with its redistribution. Importantly, through treatment with cell permeable inhibitors (4,5,6,7-tetrabromo-1H-benzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT)), and gene knockdown using RNA interference, we identified CK2, a kinase responsible for myosin-9 phosphorylation at Ser1943, as a key factor contributing to the radiation-induced senescence of hMSC. We showed that individual knockdown of CK2 catalytic subunits CK2{alpha} and CK2{alpha}{prime} induced hMSC senescence. However, only knockdown of CK2{alpha} resulted in morphological phenotypes resembling those of radiation-induced senescence. These results suggest that CK2{alpha} and CK2{alpha}{prime} play differential roles in hMSC senescence progression, and their relative expression might represent a novel regulatory mechanism for CK2 activity.

  13. Radiation-induced apoptosis and cell cycle checkpoints in human colorectal tumour cell lines

    International Nuclear Information System (INIS)

    Playle, L.C.

    2001-03-01

    The p53 tumour suppressor gene is mutated in 75% of colorectal carcinomas and is critical for DNA damage-induced G1 cell cycle arrest. Data presented in this thesis demonstrate that after treatment with Ionizing Radiation (IR), colorectal tumour cell lines with mutant p53 are unable to arrest at G1 and undergo cell cycle arrest at G2. The staurosporine derivative, UCN-01, was shown to abrogate the IR-induced G2 checkpoint in colorectal tumour cell lines. Furthermore, in some cell lines, abrogation of the G2 checkpoint was associated with radiosensitisation. Data presented in this study demonstrate that 2 out of 5 cell lines with mutant p53 were sensitised to IR by UCN-01. In order to determine whether radiosensitisation correlated with lack of functional p53, transfected derivatives of an adenoma-derived cell line were studied, in which endogenous wild type p53 was disrupted by expression of a dominant negative p53 mutant protein (and with a vector control). In both these cell lines UCN-01 abrogated the G2 arrest however this was not associated with radiosensitisation, indicating that radiosensitisation is a cell type-specific phenomenon. Although 2 colorectal carcinoma cell lines, with mutant p53, were sensitised to IR by UCN-01, the mechanisms of p53-independent IR-induced apoptosis in the colon are essentially unknown. The mitogen-activated protein kinase (MAPK) pathways (that is the JNK, p38 and ERK pathways) have been implicated in apoptosis in a range of cell systems and in IR-induced apoptosis in some cell types. Data presented in this study show that, although the MAPKs can be activated by the known activator anisomycin, there is no evidence of a role for MAPKs in IR-induced apoptosis in colorectal tumour cell lines, regardless of p53 status. In summary, some colorectal tumour cell lines with mutant p53 can be sensitised to IR-induced cell death by G2 checkpoint abrogation and this may be an important treatment strategy, however mechanisms of IR-induced p53

  14. Radiation-induced cell disintegrations in cultured rat hepatoma cells JTC 2

    International Nuclear Information System (INIS)

    Sakka, Masatoshi

    1979-01-01

    Disintegration of hepatoma cells of rat were recorded by time lapse cinemicrography for more than 5 days and about 1000 pedigrees were analyzed. Five generations were followed up in control and 2 or 3 generations in irradiated cells. Cells were attached on vessel wall spreading themselves in intermitotic phase while they stood up from the wall in mitotic phase taking a roun form. When a cell disintegrates in interphase the disintegration is called D sub( s) and one in mitotic period D sub( r). The frequency of D sub( s)S' is about 3 times as much as D sub( r)S'. An age of a disintegrated cell in generation 1 and 2 was measured as the previous mitosis was age 0. Generation times of the comparable generations of surviving sister branches of the same pedigrees were used as controls. Most disintegration took place at the same age with surviving sisters indicating a determined, not at random, age of cell death. A cell in an initial state flowed to any one of the following states with or without irradiation; surviving, disintegrated, end cell or escaping out of observation field. A single exposure of 400 to 900 R induced a typical reproductive death but effective extinction of clones was observed only in small pedigrees. Temporary hypothermia and hyperthermia immediately after exposure had no remarkable lethal effects on several early generations. (author)

  15. Radiation-induced Epstein-Barr virus reactivation in gastric cancer cells with latent EBV infection.

    Science.gov (United States)

    Nandakumar, Athira; Uwatoko, Futoshi; Yamamoto, Megumi; Tomita, Kazuo; Majima, Hideyuki J; Akiba, Suminori; Koriyama, Chihaya

    2017-07-01

    Epstein-Barr virus, a ubiquitous human herpes virus with oncogenic activity, can be found in 6%-16% of gastric carcinomas worldwide. In Epstein-Barr virus-associated gastric carcinoma, only a few latent genes of the virus are expressed. Ionizing irradiation was shown to induce lytic Epstein-Barr virus infection in lymphoblastoid cell lines with latent Epstein-Barr virus infection. In this study, we examined the effect of ionizing radiation on the Epstein-Barr virus reactivation in a gastric epithelial cancer cell line (SNU-719, an Epstein-Barr virus-associated gastric carcinoma cell line). Irradiation with X-ray (dose = 5 and 10 Gy; dose rate = 0.5398 Gy/min) killed approximately 25% and 50% of cultured SNU-719 cells, respectively, in 48 h. Ionizing radiation increased the messenger RNA expression of immediate early Epstein-Barr virus lytic genes (BZLF1 and BRLF1), determined by real-time reverse transcription polymerase chain reaction, in a dose-dependent manner at 48 h and, to a slightly lesser extent, at 72 h after irradiation. Similar findings were observed for other Epstein-Barr virus lytic genes (BMRF1, BLLF1, and BcLF1). After radiation, the expression of transforming growth factor beta 1 messenger RNA increased and reached a peak in 12-24 h, and the high-level expression of the Epstein-Barr virus immediate early genes can convert latent Epstein-Barr virus infection into the lytic form and result in the release of infectious Epstein-Barr virus. To conclude, Ionizing radiation activates lytic Epstein-Barr virus gene expression in the SNU-719 cell line mainly through nuclear factor kappaB activation. We made a brief review of literature to explore underlying mechanism involved in transforming growth factor beta-induced Epstein-Barr virus reactivation. A possible involvement of nuclear factor kappaB was hypothesized.

  16. Mechanisms of Ionizing Radiation-Induced Cell Death in Primary Lung Cells

    Science.gov (United States)

    2013-03-05

    lose their capacity to replicate after a certain number       10 of passages. This finite number was termed the “ Hayflick limit ” and cells...Upstream and downstream of mTOR. Genes & development 18:1926-45 78. Hayflick L. 1965. The Limited in Vitro Lifetime of Human Diploid Cell Strains...can lead to death. During the course of radiotherapy, the use of IR for the treatment of thoracic cancers is limited by IR-induced cell death to the

  17. Alpha radiation-induced alterations of the proliferation kinetics, chromatin structure and gene expression in mammalian cells

    International Nuclear Information System (INIS)

    Hieber, L.

    1983-01-01

    Exponentially growing mammalian cells were exposed to 3.4 MeV alpha particles. The chromatin of cells arrested in G2 by alpha irradiation was severely damaged, though all cells were still capable to condensate their chromatin after fusion with mitotic cells. In addition to the common types of aberrations (breaks, gaps, dicentrics and exchanges) cells were found possessing one or more chromosomes with long stretches of undercondensed chromatin. Repair of these lesions was indicated by site specific unscheduled DNA synthesis and by the observation that condensation of these regions improved during G2 arrest. Furthermore, during G2 arrest the synthesis of two cellular proteins was stimulated. This was studied by two-dimensional gel electrophoresis of 35 S-methionine labeled cellular proteins. All these findings provided evidence that radiation-induced G2 arrest is caused by chromatin damage, which prevents regular chromosome condensation for mitosis. (orig./MG) [de

  18. Middle infrared radiation induces G2/M cell cycle arrest in A549 lung cancer cells.

    Science.gov (United States)

    Chang, Hsin-Yi; Shih, Meng-Her; Huang, Hsuan-Cheng; Tsai, Shang-Ru; Juan, Hsueh-Fen; Lee, Si-Chen

    2013-01-01

    There were studies investigating the effects of broadband infrared radiation (IR) on cancer cell, while the influences of middle-infrared radiation (MIR) are still unknown. In this study, a MIR emitter with emission wavelength band in the 3-5 µm region was developed to irradiate A549 lung adenocarcinoma cells. It was found that MIR exposure inhibited cell proliferation and induced morphological changes by altering the cellular distribution of cytoskeletal components. Using quantitative PCR, we found that MIR promoted the expression levels of ATM (ataxia telangiectasia mutated), ATR (ataxia-telangiectasia and Rad3-related and Rad3-related), TP53 (tumor protein p53), p21 (CDKN1A, cyclin-dependent kinase inhibitor 1A) and GADD45 (growth arrest and DNA-damage inducible), but decreased the expression levels of cyclin B coding genes, CCNB1 and CCNB2, as well as CDK1 (Cyclin-dependent kinase 1). The reduction of protein expression levels of CDC25C, cyclin B1 and the phosphorylation of CDK1 at Thr-161 altogether suggest G(2)/M arrest occurred in A549 cells by MIR. DNA repair foci formation of DNA double-strand breaks (DSB) marker γ-H2AX and sensor 53BP1 was induced by MIR treatment, it implies the MIR induced G(2)/M cell cycle arrest resulted from DSB. This study illustrates a potential role for the use of MIR in lung cancer therapy by initiating DSB and blocking cell cycle progression.

  19. The role of the sympathetic nervous system in radiation-induced apoptosis in jejunal crypt cells of spontaneously hypertensive rats

    International Nuclear Information System (INIS)

    Matsuu, Mutsumi; Shichijo; Kazuko; Nakamura, Yasuko; Ikeda, Yuji; Naito, Shinji; Ito, Masahiro; Okaichi, Kumio; Sekine, Ichiro

    2000-01-01

    To evaluate the effect of the sympathetic nervous system on radiation-induced apoptosis in jejunal crypt cells, apoptosis levels were compared in spontaneously hypertensive rats (SHR), animals which are a genetic hyperfunction model of the sympathetic nervous system, and normotensive Wistar-Kyoto rats (WKY). SHR and WKY were exposed to whole body X-ray irradiation at doses from 0.5 to 2 Gy. The apoptotic index in jejunal crypt cells was significantly greater in SHR than in WKY at each time point after irradiation and at each dose. WKY and SHR were treated with reserpine to induce sympathetic dysfunction, and were subsequently exposed to irradiation. Reserpine administration to SHR or WKY resulted in a significant suppression of apoptosis. p53 accumulation was detected in the jejunum in both WKY and SHR after irradiation by Western blotting analysis. There were no significant differences in the levels of p53 accumulation in irradiated intestine between WKY and SHR. These findings suggested that hyperfunction of the sympathetic nervous system is involved in the mechanism of high susceptibility to radiation-induced apoptosis of the jejunal crypt cells. (author)

  20. The prevention of radiation-induced DNA damage and apoptosis in human intestinal epithelial cells by salvianic acid A

    Directory of Open Access Journals (Sweden)

    Yanjun Zhang

    2014-07-01

    Full Text Available The topic of radiation always provokes public debate, and the uses of radiation for therapeutic and other purposes have always been associated with some anxiety. Salvia miltiorrhiza Bunge has been widely used for the treatment of various diseases including cerebrovascular diseases, coronary artery diseases, and myocardial infarction. Salvianolic acid A (SAA d (+-(3,4-dihydroxyphenyl lactic acid is the principal effective, watersoluble constituent of Salvia miltiorrhiza Bunge. In our present study, radiation-induced DNA damage and apoptosis in human intestinal epithelial cells (HIEC in the presence and absence of SAA were examined. We investigated the effects of SAA on ROS formation and the activity of enzymatic antioxidants (SOD, the lipid peroxidative index and the levels of non-enzymatic antioxidant (GSH. Finally, we investigated whether the reduction of radiation-induced cell death caused by SAA might be related to mitochondria-dependent apoptosis. Present findings indicate that SAA is a promising radioprotective agent with a strong antioxidant activity. SAA exerted its protective action on the proliferative activity of HIEC cells as evidenced by decreased cytotoxicity after exposure to γ-radiation. It is possible that SAA achieved its radioprotective action, at least in part, by enhancing DNA repair and the activity of antioxidant enzymes, by scavenging ROS and by inhibiting the mitochondria-dependent apoptotic pathway.

  1. The role of stem cells in the prevention and treatment of radiation-induced xerostomia in patients with head and neck cancer.

    Science.gov (United States)

    Nevens, Daan; Nuyts, Sandra

    2016-06-01

    Xerostomia is an important complication following radiotherapy (RT) for head and neck cancer. Current treatment approaches are insufficient and can only temporarily relieve symptoms. New insights into the physiopathology of radiation-induced xerostomia might help us in this regard. This review discusses the current knowledge of salivary gland stem cells in radiation-induced xerostomia and their value in the prevention and treatment of this complication. Salivary gland stem cell transplantation, bone marrow-derived cell mobilization, molecular regulation of parotid stem cells, stem cell sparing RT, and adaptive RT are promising techniques that are discussed in this study. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  2. [gammadelta T cells stimulated by zoledronate kill osteosarcoma cells].

    Science.gov (United States)

    Jiang, Hui; Xu, Qiang; Yang, Chao; Cao, Zhen-Guo; Li, Zhao-Xu; Ye, Zhao-Ming

    2010-12-01

    To investigate the cytotoxicity of human γδT cells from PBMCs stimulated by zoledronate against osteosarcoma cell line HOS in vitro and in vivo and evaluate the relavent pathways. The peripheral blood mononuclear cells (PBMCs)of healthy donors were stimulated by single dose zoledronate and cultured in the present of IL-2 for two weeks, analysising the percentage of γδT cells on a FACSCalibur cytometer.Study the cytotoxicity of γδT cells against the osteosarcoma line HOS using LDH release assay kit. Pre-treatment of γδT cells with anti-human γδTCR antibody, anti-human NKG2D antibody and concanamycin A to bolck the relavent pathways for evaluating the mechenisms of its cytotoxicity. In vivo, BALB/c mice were inoculated subcutaneously osteosarcoma cell HOS for developing hypodermal tumors. And they were randomized into two groups: unteated group, γδT cell therapy group. Tumor volume and weight of the two groups were compared. After two weeks of culture, γδT cells from zoledronate-stimulated PBMCs could reach (95±3)%. When the E:T as 6:1, 12:1, 25:1, 50:1, the percentage of osteosarcoma cell HOS killed by γδT cells was 26.8%, 31.5%, 37.8%, 40.9%, respectively.When anti-huma γδTCR antibody, anti-human NKG2D antibody and concanamycin A blocked the relavent pathways, the percentage was 32.3%, 4.7%, 16.7% ( E:T as 25:1), respectively. In vivo, the tumor inhibition rate of the group of γδT cell therapy was 42.78%. γδT cells derived from PBMCs stimulated by zoledronate can acquired pure γδT cells. And they show strong cytoxicity against osteosarcoma cell line HOS in vitro and in vivo.

  3. Lovastatin enhances in vitro radiation-induced apoptosis of rat B-cell lymphoma cells

    International Nuclear Information System (INIS)

    Rozados, V.R.; Hinrichsen, L.I.; Scharovsky, O.G.; Rosario Univ., Rosario; McDonnel, J.

    2005-01-01

    Our previous demonstration of an antimetastatic effect of lovastatin, both in rat sarcoma and lymphoma tumor-models, as well as the fact that lovastatin and radiation are able to stop the cell cycle in different phases, suggested the feasibility of a combined treatment. We studied the effect of the in vitro combined treatment of a B-cell rat lymphoma (L-TACB) with lovastatin and irradiation. The results herein obtained provide new information about the role of statins as radiosensitizers. The antitumor effect of the combined treatment was higher than that elicited by either treatment alone. This effect could be a consequence, at least in part, of an enhanced apoptosis

  4. Study of interaction among silicon, lithium, oxygen and radiation-induced defects for radiation-hardened solar cells

    Science.gov (United States)

    Berman, P. A.

    1973-01-01

    In order to improve reliability and the useful lifetime of solar cell arrays for space use, a program was undertaken to develop radiation-hardened lithium-doped silicon solar cells. These cells were shown to be significantly more resistant to degradation by ionized particles than the presently used n-p nonlithium-doped silicon solar cells. The results of various analyses performed to develop a more complete understanding of the physics of the interaction among lithium, silicon, oxygen, and radiation-induced defects are presented. A discussion is given of those portions of the previous model of radiation damage annealing which were found to be in error and those portions which were upheld by these extensive investigations.

  5. Comparison of radiation-induced DNA-protein cross-links formed in oxic, hypoxic, and glutathione depleted cells

    International Nuclear Information System (INIS)

    Xue, L.; Friedman, L.R.; Chiu, S.; Ramakrishnan, N.; Oleinick, N.L.

    1987-01-01

    Treatment of cells with L-buthionine sulfoximine (BSO) inhibits the synthesis of glutathione (GSH). Subsequent metabolism depletes the cells of GSH. GSH-depletion sensitizes both oxic and hypoxic cells to the lethal effects of ionizing radiation. DNA-protein cross-links (DPC) are formed preferentially between DNA sequences active in transcription and a subset of proteins of the nuclear matrix. Thus, DPC may be an indicator lesion of damage in sensitive regions of the genome. The interrelationships between GSH level, oxic vs. hypoxic status, and the yield of DPC have been studied in terms of number of lesions and repair rate in Chinese hamster V79 and in human lung carcinoma A549 cells. The data suggest that elevated background levels of DPC are indicative of a reduced repair capacity, and greater radiation-induced yields of DPC in hypoxia may also be indicative of a compromised repair mechanism

  6. Enhanced micronucleus formation in the descendants of {gamma}-ray-irradiated tobacco cells: Evidence for radiation-induced genomic instability in plant cells

    Energy Technology Data Exchange (ETDEWEB)

    Yokota, Yuichiro, E-mail: yokota.yuichiro@jaea.go.jp [Life Science and Biotechnology Division, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 1233 Watanuki-machi, Takasaki, Gunma 370-1292 (Japan); Funayama, Tomoo; Hase, Yoshihiro [Life Science and Biotechnology Division, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 1233 Watanuki-machi, Takasaki, Gunma 370-1292 (Japan); Hamada, Nobuyuki [Radiation Safety Research Center, Nuclear Technology Research Laboratory, Central Research Institute of Electric Power Industry, 2-11-1 Iwado-kita, Komae, Tokyo 201-8511 (Japan); Kobayashi, Yasuhiko; Tanaka, Atsushi; Narumi, Issay [Life Science and Biotechnology Division, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 1233 Watanuki-machi, Takasaki, Gunma 370-1292 (Japan)

    2010-09-10

    Ionizing radiation-induced genomic instability has been documented in various end points such as chromosomal aberrations and mutations, which arises in the descendants of irradiated mammalian or yeast cells many generations after the initial insult. This study aimed at addressing radiation-induced genomic instability in higher plant tobacco cells. We thus investigated micronucleus (MN) formation and cell proliferation in tobacco cells irradiated with {gamma}-rays and their descendants. In {gamma}-irradiated cells, cell cycle was arrested at G{sub 2}/M phase at around 24 h post-irradiation but released afterward. In contrast, MN frequency peaked at 48 h post-irradiation. Almost half of 40 Gy-irradiated cells had MN at 48 h post-irradiation, but proliferated as actively as sham-irradiated cells up to 120 h post-irradiation. Moreover, the descendants that have undergone at least 22 generations after irradiation still showed a two-fold MN frequency compared to sham-irradiated cells. This is the direct evidence for radiation-induced genomic instability in tobacco cells.

  7. Lack of spontaneous and radiation-induced chromosome breakage at interstitial telomeric sites in murine scid cells.

    Science.gov (United States)

    Wong, H-P; Mozdarani, H; Finnegan, C; McIlrath, J; Bryant, P E; Slijepcevic, P

    2004-01-01

    Interstitial telomeric sites (ITSs) in chromosomes from DNA repair-proficient mammalian cells are sensitive to both spontaneous and radiation-induced chromosome breakage. Exact mechanisms of this chromosome breakage sensitivity are not known. To investigate factors that predispose ITSs to chromosome breakage we used murine scid cells. These cells lack functional DNA-PKcs, an enzyme involved in the repair of DNA double-strand breaks. Interestingly, our results revealed lack of both spontaneous and radiation-induced chromosome breakage at ITSs found in scid chromosomes. Therefore, it is possible that increased sensitivity of ITSs to chromosome breakage is associated with the functional DNA double-strand break repair machinery. To investigate if this is the case we used scid cells in which DNA-PKcs deficiency was corrected. Our results revealed complete disappearance of ITSs in scid cells with functional DNA-PKcs, presumably through chromosome breakage at ITSs, but their unchanged frequency in positive and negative control cells. Therefore, our results indicate that the functional DNA double-strand break machinery is required for elevated sensitivity of ITSs to chromosome breakage. Interestingly, we observed significant differences in mitotic chromosome condensation between scid cells and their counterparts with restored DNA-PKcs activity suggesting that lack of functional DNA-PKcs may cause a defect in chromatin organization. Increased condensation of mitotic chromosomes in the scid background was also confirmed in vivo. Therefore, our results indicate a previously unanticipated role of DNA-PKcs in chromatin organisation, which could contribute to the lack of ITS sensitivity to chromosome breakage in murine scid cells. Copyright 2003 S. Karger AG, Basel

  8. Denaturation of membrane proteins and hyperthermic cell killing

    NARCIS (Netherlands)

    Burgman, Paulus Wilhelmus Johannes Jozef

    1993-01-01

    Summarizing: heat induced denaturation of membrane proteins is probably related to hyperthermic cell killing. Induced resistance of heat sensitive proteins seems to be involved in the development of thermotolerance. Although many questions remain still to be answered, it appears that HSP72, when

  9. Radiofrequency radiation-induced calcium-ion-efflux enhancement from human and other neuroblastoma cells in culture: [Final technical report

    International Nuclear Information System (INIS)

    Dutta, S.K.; Ghosh, B.; Blackman, C.F.

    1988-01-01

    In order to test the generality of radiofrequency-radiation-induced change in alternation of 45 Ca/sup 2/plus// efflux from avian and feline brain tissues, human neuroblastoma cells were exposed to electromagnetic radiation at 147 MHz, amplitude modulated (AM) at 16 Hz, at specific absorption rates (SAR) of 0.1, 0.05, 0.01, 0.005, 0.001, and 0.0005 Wkg. Significant 45 Ca/sup 2/plus// efflux was obtained at SAR values of 0.05 and 0.005 Wkg. Enchanced efflux at 0.05 Wkg peaked at the 13-to-16 Hz and at the 57.5-to-60 Hz modulation ranges. A Chinese hamster-mouse hybrid neuroblastoma was also shown to exhibit enchanced radiation-induced 45 Ca/sup 2/plus// efflux at an SAR of 0.05 Wkg, using 147 MHz, AM at 16 hz. These results confirm that amplitude-modulated radiofrequency radiation can induce response in cells of nervous tissue origin from widely different animal species including humans. The results are also consistent with reports of similar findings in avian and feline brain tissue reported by others and indicate the general nature of the phenomenon. 9 refs., 3 tabs

  10. Radiation-induced perturbation of cell-to-cell signalling and communication

    International Nuclear Information System (INIS)

    Mariotti, L.; Facoetti, A.; Bertolotti, A.; Ranza, E.; Alloni, D.; Ottolenghi, A.

    2011-01-01

    The investigation of the bystander phenomena (i.e. the induction of damage in cells not directly traversed by radiation) is strictly related to the study of the mechanisms of intercellular communication and of the perturbative effects of radiation. A new possible way to try to solve the bystander puzzle is through a 'systems radiation biology' approach with the total integration of experimental and theoretical activities. In particular, this contribution will focus on: (1) 'ad hoc' experiments designed to quantify key parameters involved in intercellular signalling (focusing, as a pilot study, on release, decay and internalization of interleukin-6 molecules, their modulation by radiation, and possible differences between in vivo/in vitro behaviour); (2) the implementation and the development of two different modelling approaches: a stochastic model (based on a Monte Carlo code) that takes account of the local mechanisms of release and internalization of signalling molecules (e.g. cytokines) and an analytical model where signal molecules are treated as a population and their temporal behaviour is described by differential equations. This approach provided instruments to investigate the complex phenomena of signal transmission and the role of cell communication to guarantee (maintain) the robustness of the in vitro experimental systems against the effects of perturbations. (authors)

  11. Wortmannin efficiently suppresses the recovery from radiation-induced damage in pimonidazole-unlabeled quiescent tumor cell population

    International Nuclear Information System (INIS)

    Masunaga, Shin-ichiro; Suzuki, Minoru; Kondo, Natsuko; Narabayashi, Masaru; Ono, Koji; Sakurai, Yoshinori; Tanaka, Hiroki; Maruhashi, Akira

    2013-01-01

    Labeling of proliferating (P) cells in mice bearing EL4 tumors was achieved by continuous administration of 5-bromo-2'-deoxyuridine (BrdU). Tumors were irradiated with γ-rays at 1 h after pimonidazole administration followed by caffeine or wortmannin treatment. Twenty-four hours later, assessment of the responses of quiescent (Q) and total (=P+Q) cell populations were based on the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of the pimonidazole-unlabeled tumor cell fractions was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. The pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q cells than total cells. However, a significantly greater decrease in radio-sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using an assay performed 24 hours after irradiation, was more clearly observed in Q cells than total cells. In both the pimonidazole-unlabeled and the whole cell fractions, wortmannin efficiently suppressed the reduction in sensitivity due to delayed assay. Wortmannin combined with γ-ray irradiation is useful for suppressing the recovery from radiation-induced damage especially in the pimonidazole-unlabeled cell fraction within the total and Q tumor cell populations. (author)

  12. X-ray radiation induced bystander effects of human glioblastoma T98G cells under hypoxia condition

    International Nuclear Information System (INIS)

    Zhang Jianghong; Jin Yizun; Shao Chunlin; Prise, K.M.

    2008-01-01

    Non-irradiated bystander human glioblastoma T98G cells were co-cultured (CC) with irradiated cells or treated with conditioned medium (CM) from irradiated cells under hypoxic condition, then micronucleus (MN) of both irradiated cells and bystander cells were measured for the investigation of radiation induced bystander effect and its mechanism. It has been found that the MN yield (Y MN ) of non-irradiated bystander T98G cells is obviously enhanced after the cell co-culture, or CM treatment, but this increment is diminished by free radical scavenger, dimethyl sulfoxide (DMSO). When hypoxic or normoxic T98G cells are treated with CM obtained from irradiated cells under either hypoxic or normoxic condition, the biggest bystander response has been observed in the group of hypoxic by- stander cells treated with CM from irradiated normoxic cells. However, all of these increments of bystander Y MN could be eliminated by aminoguanidine, an iNOS inhibitor. Therefore, under hypoxic condition, free radicals, especially reactive oxygen species and nitric oxide, are involved in the bystander response induced by irradiated T98G cells. (authors)

  13. Radiation-induced changes in the cell membrane of cultured human endothelial cells

    International Nuclear Information System (INIS)

    Vegt, G.B.; Wassenaar, A.M.; Kawilarang-de Haas, E.W.; Schuette, P.Pv.; van der Linden, M.; Di Bon-de Ruijter, M.; Boon, A.

    1985-01-01

    We investigated the effect of irradiation on the kinetic characteristics of amino acid and glucose transport, and the effect on the activity of the cell membrane-bound enzyme 5'-nucleotidase and on the receptor-mediated stimulation of cyclic adenosine monophosphate synthesis by prostaglandin E1. Irradiation inhibited the sodium-dependent amino acid transport by a reduced binding of the amino acid to the transport unit. The transport of glucose, which appeared to be a sodium-independent process, was temporarily stimulated by increased maximal velocity of the transport. No effect was found on the binding to the transport unit. Irradiation increased the 5'-nucleotidase activity and decreased the prostaglandin E1-stimulated cyclic adenosine monophosphate synthesis 48 h after exposure to 20 Gy. It is concluded that irradiation decreases sodium-dependent transport by impairment of the transport unit, does not impair a sodium-independent process, and has opposite effects on membrane-bound enzyme activity and a receptor-mediated process

  14. Dosimetry analysis on radiation-induced acute esophagitis after three-dimensional conformal radiotherapy for non-small cell lung cancer

    International Nuclear Information System (INIS)

    ZZhu Shuchai; Cui Yanli; Li Juan; Liu Zhikun; Shen Wenbin; Su Jingwei; Wang Yuxiang

    2010-01-01

    Objective: To analyze the related factors with radiation-induced esophagitis after threedimensional conformal radiotherapy for non-small cell lung cancer (NSCLC), in order to explore the predictors for optimizing the treatment planning of NSCLC. Methods: From Aug 2000 to Dec 2004, 104 NSCLC patients received radiotherapy and were eligible for this study, 45 cases squamous cell carcinoma, 20 cases adenocarcinoma, 33 cases carrying with cancer cells by test and 6 case with no definitive pathologic feature.46 patients were treated with three dimensional conformal radiotherapy (3DCRT), the other 58 patients conventional radiotherapy (CRT) before later-course 3DCRT. All the patients received the prescribed dose between 60-78 Gy and the median dose 66 Gy. The correlation of the variables were evaluated by Spearman relationship analysis. The morbidity of radiation-induced esophagitis was analyzed by X 2 test. The multivariate effect on radiation-induced esophagitis was statistically processed by Logistic regression model. Results: In 104 patients, the morbidity of radiation- induced esophagitis was 46.2%, including 32 cases at grade 1, 15 cases at grade 2, 1 case at grade 3. Univariate analysis showed the maximal and mean dose of esophagus, the volume of esophagus irradiated, the values of V 40 , V 45 , V 50 , V 55 , V 60 , LETT 45 , LETT 50 , LETT 55 , LETT 60 for the esophagus were correlated with radiation-induced esophagitis. Logistic regression model showed that the maximum dose received by the esophagus was the independent factor of ≥ 2 grade radiation-induced esophagitis. Conclusions: The maxmal dose of esophagus received might be the important factor of radiation-induced esophagitis. (authors)

  15. Radiation-induced DNA damage and repair in radiosensitive and radioresistant human tumour cells measured by field inversion gel electrophoresis

    International Nuclear Information System (INIS)

    Smeets, M.F.M.A.; Mooren, E.H.M.; Begg, A.C.

    1993-01-01

    Radiation-induced DNA damage induction and repair was measured in two human squamous carcinoma cell lines with differing radiosensitivities. Experiments were carried out with field inversion gel electrophoresis (FIGE), adapted to measure DNA double strand break (DSB) induction and repair in unlabelled cells. The sensitivity of the method was increased by introducing a hybridization membrane into the agarose gel. Damaged DNA accumulated on one spot on the membrane resulting in high local concentrations. This DNA was quantified using radioactively-labelled total human DNA as a probe. Radiosensitivity differences at physiological temperatures could not be explained by differences in either induction or repair of DNA damage as measured by pulsed field gel electrophoresis. (author)

  16. Scientific projection paper for mutagenesis, transformation and cell killing

    International Nuclear Information System (INIS)

    Todd, P.

    1980-01-01

    Our knowledge about mutagenesis, transformation, and cell killing by ionizing radiation consists of large bodies of data, which are potentially useful in terms of application to human risk assessment and to the constructive use of radiation, as in cancer treatment. The three end-points discussed above are united by at least five significant concepts in radiation research strategy: (1) The inter-relationships among the important end-points, mutation, carcinogenesis, and cell killing. Research on one is meaningful only in the context of information about the other two. (2) The interaction of radiations with other agents in producing these end-points. (3) The mechanisms of action of other environmental mutagenic, carcinogenic, and cytotoxic agents. (4) The use of repair deficient human mutant cells. (5) The study of radiation damage mechanisms. There is no better way to extrapolate laboratory data to the clinical and public worlds than to understand the underlying biological mechanisms that produced the data

  17. The protective effect of fermented milk kefir on radiation-induced apoptosis in colonic crypt cells of rats

    International Nuclear Information System (INIS)

    Matsuu, Mutsumi; Shichijo, Kazuko; Okaichi, Kumio

    2003-01-01

    To evaluate the effect of fermented milk kefir on X-ray-induced apoptosis in the colon of rats, we examined the apoptotic index, the mean number of apoptotic cells detected by H and E staining per crypt in the colon, in control rats and kefir-pretreated rats drinking kefir for 12 days before irradiation. Apoptotic cells were confirmed by TUNEL staining, and active caspase-3 expression was studied by immunohistochemistry. The cell position of apoptotic cells and active caspase-3 positive cells were examined. The apoptotic index of kefir-treated rats was significantly (p<0.05) decreased 2 h after 1 Gy irradiation in comparison with control rats at crypt cell positions 1-3, 5-7, 13, and 15. Active caspase-3 expression in the kefir-treated rats was also significantly (p<0.05) reduced in comparison with control rats 2 h after 1 Gy irradiation at crypt cell positions 1-4, 13, and 15. This study indicated that kefir protects colonic crypt cells against radiation-induced apoptosis, which was most pronounced in the stem cell region of the crypt. The antiapoptotic effect of fermented milk kefir was due to the inhibition of caspase-3 activation. (author)

  18. Ionizing radiation induces PI3K-dependent JNK activation for amplifying mitochondrial dysfunction in human cervical cancer cells

    International Nuclear Information System (INIS)

    Kim, Min Jung; Choi, Soon Young; Bae, Sang Woo; Kang, Chang Mo; Lee, Yun Sil; Lee, Su Jae

    2005-01-01

    Ionizing radiation is one of the most commonly used treatments for a wide variety of tumors. Exposure of cells to ionizing radiation results in the simultaneous activation or down regulation of multiple signaling pathways, which play critical role in controlling cell death and cell survival after irradiation in a cell type specific manner. The molecular mechanism by which apoptotic cell death occurs in response to ionizing radiation has been widely explored but not precisely deciphered. Therefore an improved understanding of the mechanisms involved in radiation-induced apoptosis may ultimately provide novel strategies of intervention in specific signal transduction pathways to favorably alter the therapeutic ratio in the treatment of human malignancies. The aim of our investigation was to elucidate molecular mechanisms of the mitochondrial dysfunction mediated apoptotic cell death triggered by ionizing radiation in human cervical cancer cells. We demonstrated that ionizing radiation utilizes PI3K-JNK signaling pathway for amplifying mitochondrial dysfunction and susequent apoptotic cell death: We showed that PI3K-dependent JNK activation leads to transcriptional upregulation of Fas and the phosphorylation/inactivation of Bcl-2, resulting in mitochondrial dysfunction-mediated apoptotic cell death in response to ionizing radiation

  19. Cell cycle age dependence for radiation-induced G2 arrest: evidence for time-dependent repair

    International Nuclear Information System (INIS)

    Rowley, R.

    1985-01-01

    Exponentially growing eucaryotic cells, irradiated in interphase, are delayed in progression to mitosis chiefly by arrest in G 2 . The sensitivity of Chinese hamster ovary cells to G 2 arrest induction by X rays increases through the cell cycle, up to the X-ray transition point (TP) in G 2 . This age response can be explained by cell cycle age-dependent changes in susceptibility of the target(s) for G 2 arrest and/or by changes in capability for postirradiation recovery from G 2 arrest damage. Discrimination between sensitivity changes and repair phenomena is possible only if the level of G 2 arrest-causing damage sustained by a cell at the time of irradiation and the level ultimately expressed as arrest can be determined. The ability of caffeine to ameliorate radiation-induced G 2 arrest, while inhibiting repair of G 2 arrest-causing damage makes such an analysis possible. In the presence of caffeine, progression of irradiated cells was relatively unperturbed, but on caffeine removal, G 2 arrest was expressed. The duration of G 2 arrest was independent of the length of the prior caffeine exposure. This finding indicates that the target for G 2 arrest induction is present throughout the cell cycle and that the level of G 2 arrest damage incurred is initially constant for all cell cycle phases. The data are consistent with the existence of a time-dependent recovery mechanism to explain the age dependence for radiation induction of G 2 arrest

  20. The different radiation response and radiation-induced bystander effects in colorectal carcinoma cells differing in p53 status.

    Science.gov (United States)

    Widel, Maria; Lalik, Anna; Krzywon, Aleksandra; Poleszczuk, Jan; Fujarewicz, Krzysztof; Rzeszowska-Wolny, Joanna

    2015-08-01

    Radiation-induced bystander effect, appearing as different biological changes in cells that are not directly exposed to ionizing radiation but are under the influence of molecular signals secreted by irradiated neighbors, have recently attracted considerable interest due to their possible implication for radiotherapy. However, various cells present diverse radiosensitivity and bystander responses that depend, inter alia, on genetic status including TP53, the gene controlling the cell cycle, DNA repair and apoptosis. Here we compared the ionizing radiation and bystander responses of human colorectal carcinoma HCT116 cells with wild type or knockout TP53 using a transwell co-culture system. The viability of exposed to X-rays (0-8 Gy) and bystander cells of both lines showed a roughly comparable decline with increasing dose. The frequency of micronuclei was also comparable at lower doses but at higher increased considerably, especially in bystander TP53-/- cells. Moreover, the TP53-/- cells showed a significantly elevated frequency of apoptosis, while TP53+/+ counterparts expressed high level of senescence. The cross-matched experiments where irradiated cells of one line were co-cultured with non-irradiated cells of opposite line show that both cell lines were also able to induce bystander effects in their counterparts, however different endpoints revealed with different strength. Potential mediators of bystander effects, IL-6 and IL-8, were also generated differently in both lines. The knockout cells secreted IL-6 at lower doses whereas wild type cells only at higher doses. Secretion of IL-8 by TP53-/- control cells was many times lower than that by TP53+/+ but increased significantly after irradiation. Transcription of the NFκBIA was induced in irradiated TP53+/+ mainly, but in bystanders a higher level was observed in TP53-/- cells, suggesting that TP53 is required for induction of NFκB pathway after irradiation but another mechanism of activation must operate in

  1. Study on the protective effect of MgSO4 on the radiation-induced neural stem cell injury

    International Nuclear Information System (INIS)

    Liu Ping; Tu Yu

    2010-01-01

    Objective: To explore the neuroprotective effect of magnesium sulfate on radiation induced neural stem cell injury. Methods: Brain tissue was obtained from new-born sprague-dawley rats within 24 hours, and the cerebral hemisphere was dissociated to culture the neural stem cells. After being identified by immunofluorescence method, the neural stem cells were randomly divided into 3 groups as blank control group, experimental control group and experimental group. The neural stem cells of experimental control group and experimental group were irradiated with 2 or 4 Gy of gamma rays. The proliferation and the cell cycle of neural stem cells were detected at different time-points ranging from 24 h,48 h, 72 h after irradiation with CCK-8 and FCM. Results: Compared with the blank control group, the proliferation rate of experimental control group was significantly reduced (t=5.33-8.44, P<0.05 ), and the G 1 phase arrest of experimental control group was significantly enhanced (t=30.60-71.22, P<0.05).Compared with the experimental control group, the proliferation of experimental group significantly increased excluding that of 24 h (t=2.45-4.71, P<0.05), the apoptosis rate of experimental group significantly decreased (t=6.73-41.12, P<0.05), which was closer to the blank control group.Conclusion: Magnesium sulfate can alleviate the injury of proliferation and decrease the cell apoptosis in the early stage after irradiation. (authors)

  2. Properties of murine leukemia viruses produced by leukemic cells established from NIH Swiss mice with radiation-induced leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Okumoto, Masaaki; Nishikawa, Ryosuke; Takamori, Yasuhiko; Iwai, Yoshiaki; Iwai, Mineko [Radiation Center of Osaka Prefecture, Sakai (Japan); Imai, Shunsuke; Morimoto, Junji; Tsubura, Yoshihiko

    1984-06-01

    Three leukemic cell lines, designated NIH-RL1, NIH-RL2 and NFS-RL1, were established from spleen and thymuses of NIH Swiss and NFS mice with radiation-induced leukemia. The culture fluids of these cell lines contained RNA-dependent DNA polymerase (RDDP) activities associated with particles of buoyant density of 1.15-1.17 (g/cm/sup 3/). The divalent cation reqirement of these enzymes was characteristic for that of murine leukemia viruses. In competition radioimmunoassay, a major core protein, p30, was detected in culture fluid of each leukemic cell line. Competition curves of viral p30 produced by these cell lines revealed that these viruses were very similar to those of xenotropic viruses of NZB mice. These viruses were undetectable both by XC plaque assay using SC-1 cells as an indicator cell, and by mink S/sup +/L/sup -/ focus induction assay. These viruses also lacked productive infectivity to mink lung cells (CCL-64), and were nononcogenic in syngeneic mice when the viruses were intrathymically inoculated.

  3. Polymer electrolyte membranes for fuel cells by radiation induced grafting with electron beam irradiation: state-of-the-art

    International Nuclear Information System (INIS)

    Nasef, M.M.; Nasef, M.M.

    2010-01-01

    Polymer electrolyte membranes have generated considerable interest in various fields of industrial interest due to their wide spread applications in fuel cells, batteries, electrolyzers sensors and actuators. Such diversity in applications implies a strong demand to architect the membranes towards particular properties for specific applications. Radiation induced grafting of vinyl and acrylic monomers into polymeric films, is an appealing method for producing various polymer electrolyte membranes. This method has the advantages of simplicity, controllability over the composition leading to tailored membrane properties and absence of shaping problem as preparation starts with substrate in a film form. It also has the flexibility of using various types of radiation sources such as gamma-rays and electron beam. Of all, electron beam (EB) accelerator is an advantageous source of high energy radiation that can initiate grafting reactions required for preparation of the membranes particularly when pilot scale production and commercial applications are sought. The grafting penetration can be varied from surface to bulk of membranes depending on the acceleration energy. This lecture reviews the-state of- the-art in the use of EB irradiation in preparation of composite and grafted polymer electrolyte membranes for fuel cell applications by radiation induced grafting with simultaneous irradiation and preirradiation methods. The use of simultaneous EB irradiation method was found to simplify the process and reduce the reaction time as well as the monomer consumption whereas the use of preirradiation method in a single-step route provides a shorter route to prepare polymer electrolyte membranes with improved properties and reduced cost in addition of setting basis for designing a continuous line to produce these membranes with dedicated EB facilities

  4. An Investigation of the Effects of Raw Garlic on Radiation-induced Bystander Effects in MCF7 Cells

    Directory of Open Access Journals (Sweden)

    Shokouhozaman Soleymanifard

    2014-11-01

    Full Text Available Introduction Radiation-induced bystander effect (RIBE is a phenomenon in which radiation signals are transmitted from irradiated cells to non-irradiated ones, inducing radiation effects in these cells. RIBE plays an effective role in radiation response at environmentally relevant low doses and in radiotherapy, given its impact on adjacent normal tissues or those far from the irradiated tumor. Reactive oxygen species contribute to RIBE induction. Therefore, the present study was conducted to investigate the possible inhibitory effects of garlic, as an antioxidant-containing plant, on RIBE. Materials and Methods MCF7 cells, treated with raw garlic extracts, were irradiated by 60Co gamma rays, and their culture medium was transferred to non-irradiated autologous bystander cells. Percentage cell viability and micronucleus formation in both irradiated and bystander cells were examined and compared with corresponding cell groups, not treated with garlic. Results Treatment with garlic extract reduced the number of micronucleus-containing cells in both irradiated and bystander cells. However, it only increased the percentage cell viability in bystander cells, not the irradiated ones. Conclusion RIBE was effectively suppressed by raw garlic extracts. Inhibitory effects of raw garlic may be of particular importance for exposure to environmentally relevant low doses, where RIBE dominates direct radiation effects. They are also partially important for addressing the limited therapeutic gain of radiotherapy, as they may only increase the percentage cell viability of bystander cells, not the directly irradiated tumor cells. However, more comprehensive in-vivo research regarding garlic treatment duration is required to support the obtained results.

  5. Double suicide genes selectively kill human umbilical vein endothelial cells

    Directory of Open Access Journals (Sweden)

    Liu Lunxu

    2011-02-01

    Full Text Available Abstract Background To construct a recombinant adenovirus containing CDglyTK double suicide genes and evaluate the killing effect of the double suicide genes driven by kinase domain insert containing receptor (KDR promoter on human umbilical vein endothelial cells. Methods Human KDR promoter, Escherichia coli (E. coli cytosine deaminase (CD gene and the herpes simplex virus-thymidine kinase (TK gene were cloned using polymerase chain reaction (PCR. Plasmid pKDR-CDglyTK was constructed with the KDR promoter and CDglyTK genes. A recombinant adenoviral plasmid AdKDR-CDglyTK was then constructed and transfected into 293 packaging cells to grow and harvest adenoviruses. KDR-expressing human umbilical vein endothelial cells (ECV304 and KDR-negative liver cancer cell line (HepG2 were infected with the recombinant adenoviruses at different multiplicity of infection (MOI. The infection rate was measured by green fluorescent protein (GFP expression. The infected cells were cultured in culture media containing different concentrations of prodrugs ganciclovir (GCV and/or 5-fluorocytosine (5-FC. The killing effects were measured using two different methods, i.e. annexin V-FITC staining and terminal transferase-mediated dUTP nick end-labeling (TUNEL staining. Results Recombinant adenoviruses AdKDR-CDglyTK were successfully constructed and they infected ECV304 and HepG2 cells efficiently. The infection rate was dependent on MOI of recombinant adenoviruses. ECV304 cells infected with AdKDR-CDglyTK were highly sensitive to GCV and 5-FC. The cell survival rate was dependent on both the concentration of the prodrugs and the MOI of recombinant adenoviruses. In contrast, there were no killing effects in the HepG2 cells. The combination of two prodrugs was much more effective in killing ECV304 cells than GCV or 5-FC alone. The growth of transgenic ECV304 cells was suppressed in the presence of prodrugs. Conclusion AdKDR-CDglyTK/double prodrog system may be a useful

  6. Low Concentration of Exogenous Carbon Monoxide Modulates Radiation-Induced Bystander Effect in Mammalian Cell Cluster Model

    Directory of Open Access Journals (Sweden)

    Wenqing Wu

    2016-12-01

    Full Text Available During radiotherapy procedures, radiation-induced bystander effect (RIBE can potentially lead to genetic hazards to normal tissues surrounding the targeted regions. Previous studies showed that RIBE intensities in cell cluster models were much higher than those in monolayer cultured cell models. On the other hand, low-concentration carbon monoxide (CO was previously shown to exert biological functions via binding to the heme domain of proteins and then modulating various signaling pathways. In relation, our previous studies showed that exogenous CO generated by the CO releasing molecule, tricarbonyldichlororuthenium (CORM-2, at a relatively low concentration (20 µM, effectively attenuated the formation of RIBE-induced DNA double-strand breaks (DSB and micronucleus (MN. In the present work, we further investigated the capability of a low concentration of exogenous CO (CORM-2 of attenuating or inhibiting RIBE in a mixed-cell cluster model. Our results showed that CO (CORM-2 with a low concentration of 30 µM could effectively suppress RIBE-induced DSB (p53 binding protein 1, p53BP1, MN formation and cell proliferation in bystander cells but not irradiated cells via modulating the inducible nitric oxide synthase (iNOS andcyclooxygenase-2 (COX-2. The results can help mitigate RIBE-induced hazards during radiotherapy procedures.

  7. Radiation-induced esophagitis in local advanced non-small cell lung cancer after three-dimensional conformal radiotherapy

    International Nuclear Information System (INIS)

    Tian Dandan; Wang Yuxiang; Qiu Rong; Zhu Shuchai; Tian Xiuming; Qiao Xueying

    2014-01-01

    Objective: To explore radiation-induced esophagitis and its related factors in the patients with local advanced non-small cell lung cancer (NSCLC) which were treated with three-dimensional conformal radiation therapy (3D-CRT). Methods: From January 2001 to December 2008, 203 patients who suffered from stage Ⅲ NSCLC were achieved, including 163 males and 40 females, with a median age of 63 years old, while 79 cases were in stage Ⅲ_a and 124 in stage Ⅲ_b. The equivalent median dose of tumor was 62 Gy(range of 50-78 Gy). Among them, 74 cases were administered with radiotherapy alone, 45 with sequential radiotherapy and chemotherapy, 87 cases with concurrent radiochemotherapy. Radiation esophagitis was evaluated with RTOG standard. The dosimetric parameters was estimated from dose volume histogrma (DVH). The clinical and dosimetric parameters of radiation esophagitis were evaluated by spearman correlatived univariate and Logistic multivariable analysis.Results After radiotherapy, out of 203 patients, 87 had acute radiation esophagitis(RE), 47 in grade 1, 37 in grade 2, and 3 in grade 3 RE. According to spearman correlatived analysis, the correlatived factors included ages, chemotherapy, GTV, PTV, the mean doses of PTV and lung, the max and mean dose of esophagus, V_4_0, V_4_5, V_5_0, V_5_5, V_6_0, length of esophagus (total circumference) treated with 45 Gy (LETT_4_5), and LETT_5_0 (r = -0.162-0.235, P 0.05). There were 21 factors, such as gender, age, smoking, clinical stage, site of tumor, chemotherapy, GTV, PTV, mean dose of PTV and lung, max and mean dose of esophagus, V_4_0-V_6_0 of esophagus, LETT_4_5_-_6_0, incorporated into multivariable analysis, only chemotherapy and V_4_5 of esophagus were independent predicted factors(Wald = 4.626, 9.882, P < 0.05). Conclusions: In local advanced NSCLC after 3D-CRT, chemotherapy(especially concurrent radiochemotherapy) could increase radiation-induced esophagitis. The parameter of DVH could also be used to predict

  8. Wnt/β-catenin pathway involvement in ionizing radiation-induced invasion of U87 glioblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Zhen [Huazhong University of Science and Technology, Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Wuhan (China); Zhou, Lin [Huazhong University of Science and Technology, Department of Histoembryology, Tongji Medical College, Wuhan (China); Han, Na; Zhang, Mengxian [Huazhong University of Science and Technology, Department of Oncology, Tongji Hospital, Tongji Medical College, Wuhan (China); Lyu, Xiaojuan [Huazhong University of Science and Technology, Department of Oncology, The Central Hospital of Wuhan, Tongji Medical College, Wuhan (China)

    2015-08-15

    Radiotherapy has been reported to promote the invasion of glioblastoma cells; however, the underlying mechanisms remain unclear. Here, we investigated the role of the Wnt/β-catenin pathway in radiation-induced invasion of glioblastoma cells. U87 cells were irradiated with 3 Gy or sham irradiated in the presence or absence of the Wnt/β-catenin pathway inhibitor XAV 939. Cell invasion was determined by an xCELLigence real-time cell analyser and matrigel invasion assays. The intracellular distribution of β-catenin in U87 cells with or without irradiation was examined by immunofluorescence and Western blotting of nuclear fractions. We next investigated the effect of irradiation on Wnt/β-catenin pathway activity using TOP/FOP flash luciferase assays and quantitative polymerase chain reaction analysis of β-catenin target genes. The expression levels and activities of two target genes, matrix metalloproteinase (MMP)-2 and MMP-9, were examined further by Western blotting and zymography. U87 cell invasiveness was increased significantly by ionizing radiation. Interestingly, ionizing radiation induced nuclear translocation and accumulation of β-catenin. Moreover, we found increased β-catenin/TCF transcriptional activities, followed by up-regulation of downstream genes in the Wnt/β-catenin pathway in irradiated U87 cells. Importantly, inhibition of the Wnt/β-catenin pathway by XAV 939, which promotes degradation of β-catenin, significantly abrogated the pro-invasion effects of irradiation. Mechanistically, XAV 939 suppressed ionizing radiation-triggered up-regulation of MMP-2 and MMP-9, and inhibited the activities of these gelatinases. Our data demonstrate a pivotal role of the Wnt/β-catenin pathway in ionizing radiation-induced invasion of glioblastoma cells, and suggest that targeting β-catenin is a promising therapeutic approach to overcoming glioma radioresistance. (orig.) [German] Studien haben gezeigt, dass eine Strahlentherapie die Invasivitaet von

  9. Differential modulation of a radiation-induced bystander effect in glioblastoma cells by pifithrin-alpha and wortmannin

    Energy Technology Data Exchange (ETDEWEB)

    Shao Chunlin, E-mail: clshao@shmu.edu.c [Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032 (China); Zhang Jianghong [Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032 (China); Prise, Kevin M. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Lisburn Road, Belfast BT9 7AB (United Kingdom)

    2010-03-15

    The implication of radiation-induced bystander effect (RIBE) for both radiation protection and radiotherapy has attracted significant attention, but a key question is how to modulate the RIBE. The present study found that, when a fraction of glioblastoma cells in T98G population were individually targeted with precise helium particles through their nucleus, micronucleus (MN) were induced and its yield increased non-linearly with radiation dose. After co-culturing with irradiated cells, additional MN could be induced in the non-irradiated bystander cells and its yield was independent of irradiation dose, giving direct evidence of a RIBE. Further results showed that the RIBE could be eliminated by pifithrin-alpha (p53 inhibitor) but enhanced by wortmannin (PI3K inhibitor). Moreover, it was found that nitric oxide (NO) contributed to this RIBE, and the levels of NO of both irradiated cells and bystander cells could be extensively diminished by pifithrin-alpha but insignificantly reduced by wortmannin. Our results indicate that RIBE can be modulated by p53 and PI3K through a NO-dependent and NO-independent pathway, respectively.

  10. Platelet-derived growth factor (PDGF)-signaling mediates radiation-induced apoptosis in human prostate cancer cells with loss of p53 function

    International Nuclear Information System (INIS)

    Kim, Harold E.; Han, Sue J.; Kasza, Thomas; Han, Richard; Choi, Hyeong-Seon; Palmer, Kenneth C.; Kim, Hyeong-Reh C.

    1997-01-01

    Platelet-derived growth factor (PDGF) signals a diversity of cellular responses in vitro, including cell proliferation, survival, transformation, and chemotaxis. PDGF functions as a 'competence factor' to induce a set of early response genes expressed in G 1 including p21 WAF1/CIP1 , a functional mediator of the tumor suppressor gene p53 in G 1 /S checkpoint. For PDGF-stimulated cells to progress beyond G 1 and transit the cell cycle completely, progression factors in serum such as insulin and IGF-1 are required. We have recently shown a novel role of PDGF in inducing apoptosis in growth-arrested murine fibroblasts. The PDGF-induced apoptosis is rescued by insulin, suggesting that G 1 /S checkpoint is a critical determinant for PDGF-induced apoptosis. Because recent studies suggest that radiation-induced signal transduction pathways interact with growth factor-mediated signaling pathways, we have investigated whether activation of the PDGF-signaling facilitates the radiation-induced apoptosis in the absence of functional p53. For this study we have used the 125-IL cell line, a mutant p53-containing, highly metastatic, and hormone-unresponsive human prostate carcinoma cell line. PDGF signaling is constitutively activated by transfection with a p28 v-sis expression vector, which was previously shown to activate PDGF α- and β- receptors. Although the basal level of p21 WAF1/CIP1 expression and radiation-induced apoptosis were not detectable in control 125-IL cells as would be predicted in mutant p53-containing cells, activation of PDGF-signaling induced expression of p21 WAF1/CIP1 and radiation-induced apoptosis. Our study suggests that the level of 'competence' growth factors including PDGF may be one of the critical determinants for radiation-induced apoptosis, especially in cells with loss of p53 function at the site of radiotherapy in vivo

  11. First-in-man mesenchymal stem cells for radiation-induced xerostomia (MESRIX): study protocol for a randomized controlled trial.

    Science.gov (United States)

    Grønhøj, Christian; Jensen, David H; Glovinski, Peter V; Jensen, Siri Beier; Bardow, Allan; Oliveri, Roberto S; Specht, Lena; Thomsen, Carsten; Darkner, Sune; Kiss, Katalin; Fischer-Nielsen, Anne; von Buchwald, Christian

    2017-03-07

    Salivary gland hypofunction and xerostomia are major complications following radiotherapy for head and neck cancer and may lead to debilitating oral disorders and impaired quality of life. Currently, only symptomatic treatment is available. However, mesenchymal stem cell (MSC) therapy has shown promising results in preclinical studies. Objectives are to assess safety and efficacy in a first-in-man trial on adipose-derived MSC therapy (ASC) for radiation-induced xerostomia. This is a single-center, phase I/II, randomized, placebo-controlled, double-blinded clinical trial. A total of 30 patients are randomized in a 1:1 ratio to receive ultrasound-guided, administered ASC or placebo to the submandibular glands. The primary outcome is change in unstimulated whole salivary flow rate. The secondary outcomes are safety, efficacy, change in quality of life, qualitative and quantitative measurements of saliva, as well as submandibular gland size, vascularization, fibrosis, and secretory tissue evaluation based on contrast-induced magnetic resonance imaging (MRI) and core-needle samples. The assessments are performed at baseline (1 month prior to treatment) and 1 and 4 months following investigational intervention. The trial is the first attempt to evaluate the safety and efficacy of adipose-derived MSCs (ASCs) in patients with radiation-induced xerostomia. The results may provide evidence for the effectiveness of ASC in patients with salivary gland hypofunction and xerostomia and deliver valuable information for the design of subsequent trials. EudraCT, Identifier: 2014-004349-29. Registered on 1 April 2015. ClinicalTrials.gov, Identifier: NCT02513238 . First received on 2 July 2015. The trial is prospectively registered.

  12. Rate-limiting events in hyperthermic cell killing

    International Nuclear Information System (INIS)

    Landry, J.; Marceau, N.

    1978-01-01

    The inactivation rate of HeLa cells for temperatures ranging from 41 to 55 0 C and treatment durations varying from 2 to 300 min was analyzed in thermodynamic terms by considering the dependence of cell free energy (ΔG + ) on temperature. Within this temperature range the loss of proliferative capacity exhibits a complex temperature dependence which is characterized by entropy and enthalpy values that gradually decrease as temperature increases. This complex process of heat-induced cell killing was postulated to be the result of a series of reactions, each of them being alternatively rate limiting within a certain temperature range. From this kinetic scheme a mathematical model was derived and, in the case of HeLa cells, the use of a least-squares search parameter procedure (as applied to the derived survival regression function) demonstrated that three such sequential reactions were sufficient to explain all experimental data points obtained within the 41 to 55 0 C range. The proposed model was also shown to be adequate for explaining survival data of HeLa cells exposed to nanosecond heat pulses of infrared laser energy. Considerations of thermodynamic properties of known biochemical reactions suggest plausible rate-limiting events in hyperthermic cell killing

  13. Effect of pulsed electron beam on cell killing

    International Nuclear Information System (INIS)

    Acharya, Santhosh; Joseph, Praveen; Sanjeev, Ganesh; Narayana, Y.; Bhat, N.N.

    2009-01-01

    The extent of repairable and irreparable damage in a living cell produced by ionizing radiation depends on the quality of the radiation. In the case of sparsely ionizing radiation, the dose rate and the pattern of energy deposition of the radiation are the important physical factors which can affect the amount of damage in living cells. In the present study, radio-sensitive and radioresistive bacteria cells were exposed to 8 MeV pulsed electron beam and the efficiency of cell-killing was investigated to evaluate the Do, the mean lethal dose. The dose to the cell was delivered in micro-second pulses at an instantaneous dose rate of 2.6 x 10 5 Gy s -1 . Fricke dosimeter was used to measure the absorbed dose of electron beam. The results were compared with those of gamma rays. The survival curve of radio-resistive Deinococcus-radiodurans (DR) is found to be sigmoidal and the survival response for radio-sensitive Escherichia-coli (E-coli) is found to be exponential without any shoulder. Comparison of Do values indicate that irradiation with pulsed electron beam resulted in more cell-killing than was observed for gamma irradiation. (author)

  14. Bystander Host Cell Killing Effects of Clostridium perfringens Enterotoxin

    Directory of Open Access Journals (Sweden)

    Archana Shrestha

    2016-12-01

    Full Text Available Clostridium perfringens enterotoxin (CPE binds to claudin receptors, e.g., claudin-4, and then forms a pore that triggers cell death. Pure cultures of host cells that do not express claudin receptors, e.g., fibroblasts, are unaffected by pathophysiologically relevant CPE concentrations in vitro. However, both CPE-insensitive and CPE-sensitive host cells are present in vivo. Therefore, this study tested whether CPE treatment might affect fibroblasts when cocultured with CPE-sensitive claudin-4 fibroblast transfectants or Caco-2 cells. Under these conditions, immunofluorescence microscopy detected increased death of fibroblasts. This cytotoxic effect involved release of a toxic factor from the dying CPE-sensitive cells, since it could be reproduced using culture supernatants from CPE-treated sensitive cells. Supernatants from CPE-treated sensitive cells, particularly Caco-2 cells, were found to contain high levels of membrane vesicles, often containing a CPE species. However, most cytotoxic activity remained in those supernatants even after membrane vesicle depletion, and CPE was not detected in fibroblasts treated with supernatants from CPE-treated sensitive cells. Instead, characterization studies suggest that a major cytotoxic factor present in supernatants from CPE-treated sensitive cells may be a 10- to 30-kDa host serine protease or require the action of that host serine protease. Induction of caspase-3-mediated apoptosis was found to be important for triggering release of the cytotoxic factor(s from CPE-treated sensitive host cells. Furthermore, the cytotoxic factor(s in these supernatants was shown to induce a caspase-3-mediated killing of fibroblasts. This bystander killing effect due to release of cytotoxic factors from CPE-treated sensitive cells could contribute to CPE-mediated disease.

  15. Radiation-induced changes in glomerular and tubular cell kinetics and morphology following irradiation of a single kidney in the pig

    International Nuclear Information System (INIS)

    Robbins, Mike E. C.; Bonsib, Stephen M.; Ikeda, Andrea; Soranson, Julie A.; Wilson, George D.; Rezvani, Mohi; Golding, Stephen J.; Whitehouse, Elizabeth; Hopewell, John W.

    1995-01-01

    Purpose: Radiation-induced changes in glomerular and tubular cell kinetics and morphology following irradiation of a single pig kidney were assessed. Methods and Materials: The right kidney of 13 adult female Large White pigs was irradiated with a single dose of 9.8 Gy γ rays. Animals were serially killed between 2 and 24 weeks postirradiation (PI); 1 h prior to postmortem each pig received 500 mg bromodeoxyuridine (BrdUrd). At postmortem, both kidneys were removed and tissue taken to prepare cell suspensions. The labeling index (LI) of these suspensions was measured using flow cytometry; in vivo BrdUrd incorporation in glomerular and tubular cells was determined immunohistochemically. The kidneys were also assessed histologically. Results: Irradiation of the right kidney alone resulted in a significant increase in renal cell LI in both the irradiated and the contralateral unirradiated kidney within 2 weeks of irradiation; peak values of 1.57 ± 0.32% and 1.04 ± 0.13%, respectively, were seen 4 weeks PI, significantly greater p < 0.001) than the preirradiation value of 0.18 ± 0.01%. The LI values then declined with time, but remained greater than those seen prior to irradiation. A similar pattern of response was determined from counts of labeled glomerular and tubular cells identified immunohistochemically. The increase in labeled glomerular cells was seen 2 weeks PI, whereas that for the tubular cells did not occur until 4 weeks PI. The irradiated kidney exhibited diffuse, progressive glomerular alterations. In contrast, tubular damage was focal; the irradiated kidney also exhibited a prominent vasculopathy, involving arteriolar and peripheral interlobular artery thickening. The contralateral unirradiated kidney appeared unchanged. Conclusion: These findings confirm the hypothesis that the morphologic and kinetic responses observed after irradiation of a single kidney are similar to those observed after irradiation of both kidneys. Renal irradiation results in

  16. Use of Human Cadaveric Mesenchymal Stem Cells for Cell Therapy of a Chronic Radiation-Induced Skin Lesion: A Case Report

    International Nuclear Information System (INIS)

    Portas, M.; Coppola, A.; Mansilla, E.; Drago, H.; Dubner, D.; Radl, A.; Di Giorgio, M.

    2016-01-01

    Acute and late radiation-induced injury on skin and subcutaneous tissues are associated with substantial morbidity in radiation therapy, interventional procedures and also are of concern in the context of nuclear or radiological accidents. Pathogenesis is initiated by depletion of acutely responding epithelial tissues and damage to vascular endothelial micro-vessels. Efforts for medical management of severe radiation-induced lesions have been made. Nevertheless, the development of strategies to promote wound healing, including stem cell therapy, is required. From 1997 to 2014, over 248 patients were referred to the Radio-pathology Committee of Hospital de Quemados del Gobierno de la Ciudad de Buenos Aires (Burns Hospital) for the diagnosis and therapy of radiation-induced localized lesions. As part of the strategies for the management of severe cases, there is an ongoing research and development protocol on 'Translational Clinical Trial phases I/II to evaluate the safety and efficacy of adult mesenchymal stem cells from bone marrow for the treatment of large burns and radiological lesions'. The object of this work was to describe the actions carried out by the Radio-pathology Committee of the Burns Hospital in a chronic case with more than 30 years of evolution without positive response to conventional treatments. The approach involved the evaluation of the tissular compromise of the lesion, the prognosis and the personalized treatment, including regenerative therapy. (authors)

  17. Use of Human Cadaveric Mesenchymal Stem Cells for Cell Therapy of a Chronic Radiation-Induced Skin Lesion: A Case Report.

    Science.gov (United States)

    Portas, M; Mansilla, E; Drago, H; Dubner, D; Radl, A; Coppola, A; Di Giorgio, M

    2016-09-01

    Acute and late radiation-induced injury on skin and subcutaneous tissues are associated with substantial morbidity in radiation therapy, interventional procedures and also are of concern in the context of nuclear or radiological accidents. Pathogenesis is initiated by depletion of acutely responding epithelial tissues and damage to vascular endothelial microvessels. Efforts for medical management of severe radiation-induced lesions have been made. Nevertheless, the development of strategies to promote wound healing, including stem cell therapy, is required. From 1997 to 2014, over 248 patients were referred to the Radiopathology Committee of Hospital de Quemados del Gobierno de la Ciudad de Buenos Aires (Burns Hospital) for the diagnosis and therapy of radiation-induced localized lesions. As part of the strategies for the management of severe cases, there is an ongoing research and development protocol on 'Translational Clinical Trial phases I/II to evaluate the safety and efficacy of adult mesenchymal stem cells from bone marrow for the treatment of large burns and radiological lesions'. The object of this work was to describe the actions carried out by the Radiopathology Committee of the Burns Hospital in a chronic case with more than 30 years of evolution without positive response to conventional treatments. The approach involved the evaluation of the tissular compromise of the lesion, the prognosis and the personalized treatment, including regenerative therapy. © World Health Organisation 2016. All rights reserved. The World Health Organization has granted Oxford University Press permission for the reproduction of this article.

  18. Cell kinetics of hypoxic cells in a murine tumour in vivo: flow cytometric determination of the radiation-induced blockage of cell cycle progression

    International Nuclear Information System (INIS)

    Rutgers, D.H.; Niessen, D.P.P.; Linden, P.M. van der

    1987-01-01

    Cells from the small cell population of viable cells in the large necrotic centre of murine M8013 tumours were investigated with respect to their cell kinetics. Flow cytometry (FCM) of this part of subcutaneously transplanted tumours revealed the presence of tumour cells with G1,S and G2 + M phase DNA-contents. These severely hypoxic cells could have stopped cell cycle progression due to the nutritional deprivation, irrespective of their position within the cell cycle. Labelling methods, used to disclose the cell kinetics of this cell population, are hampered by the absence of a transport system in these large necrotic areas. Therefore FCM was used to monitor radiation induced changes in the cell cycle distribution. From this investigation it was concluded that hypoxic cells in the necrotic centre of the M8013 tumour progress through the cell cycle. As well as a cell population with a cell cycle time (Tsub(c)) of approximately 84 hr, a subpopulation with a Tsub(c) of approximately 21 hr occurred. (author)

  19. AMRI-59 has a role of radiosensitizer via enhancement of γ-ionizing radiation-induced apoptotic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Wan Gi; Cho, Jeong Hyun; Kim, Ju Yeon; Hwang, Sang Gu; Um, Hong Duck; Park, Jong Kuk [KAERI, Daejeon (Korea, Republic of)

    2016-05-15

    Recent in vitro studies have suggested that may increase the invasiveness of some cancer cells (e.g., glioma, hepatocellular carcinoma, and pancreatic cancer cells) by stimulating several intracellular signaling pathways and in vivo studies have found that radiotherapy of primary tumor sites may promote metastasis. Thus, in addition to having therapeutic effects, IR might promote the malignant traits of surviving cancer cells. The existing efforts to develop radiosensitizing agents have focused on overcoming radioresistance and reducing damage to normal tissues. Recently, concepts of personalized- or precision medicine are developed due to advancement of mega data technique, which provide new targets to develop new anti-cancer drugs. In this study, we sought to identify the radiosensitizer effect of AMRI-59 in vitro and in vivo., which is recently developed specific inhibitor of peroxiredoxin (Prx) I. AMRI-59 enhanced radiation-induced cell death and its mean calculated dose enhancement ratio was 1.26. We also found combination of AMRI-59 and IR In a xenograft assay, the combined PHCM and radiation group showed 14.3 days of growth delay versus the control in terms of tumor growth. The enhancement factor of this combined treatment was determined to be 2.03.

  20. The different radiation response and radiation-induced bystander effects in colorectal carcinoma cells differing in p53 status

    Energy Technology Data Exchange (ETDEWEB)

    Widel, Maria, E-mail: maria.widel@polsl.pl [Biosystems Group, Institute of Automatic Control, Silesian University of Technology, 16 Akademicka Street, 44-100 Gliwice (Poland); Lalik, Anna; Krzywon, Aleksandra [Biosystems Group, Institute of Automatic Control, Silesian University of Technology, 16 Akademicka Street, 44-100 Gliwice (Poland); Poleszczuk, Jan [College of Inter-faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, 93 Zwirki i Wigury Street, 02-089 Warsaw (Poland); Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida (United States); Fujarewicz, Krzysztof; Rzeszowska-Wolny, Joanna [Biosystems Group, Institute of Automatic Control, Silesian University of Technology, 16 Akademicka Street, 44-100 Gliwice (Poland)

    2015-08-15

    Highlights: • We tested radiation response and bystander effect on HCT116p53+/+ and p53−/− cells. • The p53+/+ cells developed premature senescence in exposed and bystander neighbors. • Directly exposed and bystander p53−/− cells died profoundly through apoptosis. • Interleukins 6 and 8 were differently generated by both cell lines. • NFκB path was activated mainly in p53+/+ hit cells, in p53 −/− in bystanders only. - Abstract: Radiation-induced bystander effect, appearing as different biological changes in cells that are not directly exposed to ionizing radiation but are under the influence of molecular signals secreted by irradiated neighbors, have recently attracted considerable interest due to their possible implication for radiotherapy. However, various cells present diverse radiosensitivity and bystander responses that depend, inter alia, on genetic status including TP53, the gene controlling the cell cycle, DNA repair and apoptosis. Here we compared the ionizing radiation and bystander responses of human colorectal carcinoma HCT116 cells with wild type or knockout TP53 using a transwell co-culture system. The viability of exposed to X-rays (0–8 Gy) and bystander cells of both lines showed a roughly comparable decline with increasing dose. The frequency of micronuclei was also comparable at lower doses but at higher increased considerably, especially in bystander TP53-/- cells. Moreover, the TP53-/- cells showed a significantly elevated frequency of apoptosis, while TP53+/+ counterparts expressed high level of senescence. The cross-matched experiments where irradiated cells of one line were co-cultured with non-irradiated cells of opposite line show that both cell lines were also able to induce bystander effects in their counterparts, however different endpoints revealed with different strength. Potential mediators of bystander effects, IL-6 and IL-8, were also generated differently in both lines. The knockout cells secreted IL-6 at

  1. The different radiation response and radiation-induced bystander effects in colorectal carcinoma cells differing in p53 status

    International Nuclear Information System (INIS)

    Widel, Maria; Lalik, Anna; Krzywon, Aleksandra; Poleszczuk, Jan; Fujarewicz, Krzysztof; Rzeszowska-Wolny, Joanna

    2015-01-01

    Highlights: • We tested radiation response and bystander effect on HCT116p53+/+ and p53−/− cells. • The p53+/+ cells developed premature senescence in exposed and bystander neighbors. • Directly exposed and bystander p53−/− cells died profoundly through apoptosis. • Interleukins 6 and 8 were differently generated by both cell lines. • NFκB path was activated mainly in p53+/+ hit cells, in p53 −/− in bystanders only. - Abstract: Radiation-induced bystander effect, appearing as different biological changes in cells that are not directly exposed to ionizing radiation but are under the influence of molecular signals secreted by irradiated neighbors, have recently attracted considerable interest due to their possible implication for radiotherapy. However, various cells present diverse radiosensitivity and bystander responses that depend, inter alia, on genetic status including TP53, the gene controlling the cell cycle, DNA repair and apoptosis. Here we compared the ionizing radiation and bystander responses of human colorectal carcinoma HCT116 cells with wild type or knockout TP53 using a transwell co-culture system. The viability of exposed to X-rays (0–8 Gy) and bystander cells of both lines showed a roughly comparable decline with increasing dose. The frequency of micronuclei was also comparable at lower doses but at higher increased considerably, especially in bystander TP53-/- cells. Moreover, the TP53-/- cells showed a significantly elevated frequency of apoptosis, while TP53+/+ counterparts expressed high level of senescence. The cross-matched experiments where irradiated cells of one line were co-cultured with non-irradiated cells of opposite line show that both cell lines were also able to induce bystander effects in their counterparts, however different endpoints revealed with different strength. Potential mediators of bystander effects, IL-6 and IL-8, were also generated differently in both lines. The knockout cells secreted IL-6 at

  2. Radiation induced reproductive death as a function of mammalian cell ploidy

    International Nuclear Information System (INIS)

    Philbrick, D.A.

    1976-09-01

    Mammalian cells containing different multiples of the diploid chromosome set were created through drug induction and cell fusion. In all cell strains used the chromosome number was determined from metaphase spreads, as well as from DNA content and cell size. The survival of cells as a function of radiation dose was determined for cell lines with differing chromosome complements at 37 0 C, 4 0 C, in hypertonic media, while frozen, and with increasing levels of incorporated IUdR. Survival of frozen diploid and hypotetraploid Chinese hamster cells was determined following varying numbers of decays of incorporated 3 HTdR and 125 IUdR. The percent of reproductively viable cells following irradiation is a function of the cell ploidy, i.e., the number of haploid sets of chromosomes contained in the cell genome. At 37 0 C and in hypertonic media, the Chinese hamster cells of progressively higher ploidies are increasingly sensitive to irradiation. As the number of chromosomes per unit cell volume increases the radiosensitivity increases. Both trends suggest interaction between chromosomes as an important cause of cell death

  3. Radiation induced reproductive death as a function of mammalian cell ploidy

    Energy Technology Data Exchange (ETDEWEB)

    Philbrick, D.A.

    1976-09-01

    Mammalian cells containing different multiples of the diploid chromosome set were created through drug induction and cell fusion. In all cell strains used the chromosome number was determined from metaphase spreads, as well as from DNA content and cell size. The survival of cells as a function of radiation dose was determined for cell lines with differing chromosome complements at 37/sup 0/C, 4/sup 0/C, in hypertonic media, while frozen, and with increasing levels of incorporated IUdR. Survival of frozen diploid and hypotetraploid Chinese hamster cells was determined following varying numbers of decays of incorporated /sup 3/HTdR and /sup 125/IUdR. The percent of reproductively viable cells following irradiation is a function of the cell ploidy, i.e., the number of haploid sets of chromosomes contained in the cell genome. At 37/sup 0/C and in hypertonic media, the Chinese hamster cells of progressively higher ploidies are increasingly sensitive to irradiation. As the number of chromosomes per unit cell volume increases the radiosensitivity increases. Both trends suggest interaction between chromosomes as an important cause of cell death.

  4. Evaluation of radiation-induced genotoxicity on human melanoma cells (SK-MEL-37) by flow cytometry

    International Nuclear Information System (INIS)

    Bonfim, Leticia; Carvalho, Luma Ramirez de; Vieira, Daniel Perez

    2017-01-01

    Micronucleus assay is a test used to evaluate genotoxic damage in cells, which can be caused by various factors, like ionizing radiation. Interactions between radiation energies and DNA can cause breakage, leading to use chromosomal mutations or loss of genetic material, important events that could be induced in solid tumors to mitigate its expansion within human body. Melanoma has been described as a tumor with increased radio resistance. This work evaluated micronuclei percentages (%MN) in human melanoma cells (SK-MEL-37), irradiated by gamma radiation, with doses between 0 and 16Gy. Cell suspensions were irradiated in PBS by a "6"0Co source in doses between 0 and 16Gy, and incubated by 48h. Then cell membranes were lysed in the presence of SYTOX Green and EMA dyes, preserving nuclear membranes. Using this method, EMA-stained nuclei could be discriminated as those derived from dead cells, and SYTOX nuclei and micronuclei could be quantified. Micronuclei percentages were found to be proportional to dose, (R2 = 0.997). Only the highest dose (16Gy) could induce statistically significant increase of MN (p<0.0001), although cultures irradiated by 4, 8 and 16Gy showed significant increase of dead cell fractions. Calculation of the nuclei-to-beads ratio showed that 8 and 16Gy could reduce melanoma cell proliferation. Results showed that although cell death and loss of proliferative capacity could be observed on cultures irradiated at lower doses, genotoxic damage could be induced only on a higher dose. Resistance to radiation-induced genotoxicity could explain a relatively high radio resistance of melanoma tumors. (author)

  5. Evaluation of radiation-induced genotoxicity on human melanoma cells (SK-MEL-37) by flow cytometry

    Energy Technology Data Exchange (ETDEWEB)

    Bonfim, Leticia; Carvalho, Luma Ramirez de; Vieira, Daniel Perez, E-mail: leticia.bonfim@ipen.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2017-11-01

    Micronucleus assay is a test used to evaluate genotoxic damage in cells, which can be caused by various factors, like ionizing radiation. Interactions between radiation energies and DNA can cause breakage, leading to use chromosomal mutations or loss of genetic material, important events that could be induced in solid tumors to mitigate its expansion within human body. Melanoma has been described as a tumor with increased radio resistance. This work evaluated micronuclei percentages (%MN) in human melanoma cells (SK-MEL-37), irradiated by gamma radiation, with doses between 0 and 16Gy. Cell suspensions were irradiated in PBS by a {sup 60}Co source in doses between 0 and 16Gy, and incubated by 48h. Then cell membranes were lysed in the presence of SYTOX Green and EMA dyes, preserving nuclear membranes. Using this method, EMA-stained nuclei could be discriminated as those derived from dead cells, and SYTOX nuclei and micronuclei could be quantified. Micronuclei percentages were found to be proportional to dose, (R2 = 0.997). Only the highest dose (16Gy) could induce statistically significant increase of MN (p<0.0001), although cultures irradiated by 4, 8 and 16Gy showed significant increase of dead cell fractions. Calculation of the nuclei-to-beads ratio showed that 8 and 16Gy could reduce melanoma cell proliferation. Results showed that although cell death and loss of proliferative capacity could be observed on cultures irradiated at lower doses, genotoxic damage could be induced only on a higher dose. Resistance to radiation-induced genotoxicity could explain a relatively high radio resistance of melanoma tumors. (author)

  6. Recovery from radiation-induced damage in primary cultures of human epithelial thyroid cells

    International Nuclear Information System (INIS)

    Miller, R.C.; Hiraoka, Toshio; Enno, Masumi; Takeichi, Nobuo.

    1985-01-01

    Human thyroid epithelial tissues from 23 individuals were obtained from surgical tissue, and cultured in vitro. Dose response survival curves showed thyroid cells, when compared to mammary epithelial and skin fibroblast cells of human origin, to be only slightly more radiosensitive to X-rays. Cell survival curves from the cell strains showed wide variability in radiation sensitivity. Of the 23 cell strains tested, 21 strains displayed significant shoulders (nonzero quasi-threshold (D q ) values and extrapolation number (n) values greater than 1) at low dose exposures. The ability of human cells to recover from radiation damage was further studied by dose fractionation. Two cell strains were given a total X-ray dose of 304 cGy in two equal fractions separated by varying time intervals. Maximal cell survival was observed when the time interval exceeded two hours. When the two cell strains were exposed to 152 cGy of X-rays followed four hours later by second graded doses, cell survival was enhanced as compared to survival after single dose exposures. However, no benefit of dose splitting was observed when cells were exposed to low second doses. These results support previous studies showing that human cells are capable of repair but require relatively large doses to elicit a repair response. (author)

  7. Recovery from radiation-induced damage in primary cultures of human epithelial thyroid cells

    International Nuclear Information System (INIS)

    Miller, R.C.; Hiraoka, Toshio; Enno, Masumi; Takeichi, Nobuo.

    1985-09-01

    Human thyroid epithelial tissue from 23 individuals was obtained from surgical tissue, and cultured in vitro. Dose-response survival curves showed thyroid cells, when compared to mammary epithelial and skin fibroblast cells of human origin, to be only slightly more radiosensitive to X rays. Cell survival curves from the cell strains showed wide variability in radiation sensitivity. Of the 23 cell strains tested, 21 strains displayed significant shoulders (nonzero quasi-threshold (Dsub(q)) values and extrapolation number (n) values greater than 1)* at low dose exposures. The ability of human cells to recover from radiation damage was further studied by dose fractionation. Two cell strains were given a total X-ray dose of 304 cGy in two equal fractions separated by varying time intervals. Maximal cell survival was observed when the time interval exceeded two hours. When the two cell strains were exposed to 152 cGy of X rays followed four hours later by second graded doses, cell survival was enhanced as compared to survival after single dose exposures. However, no benefit of dose splitting was observed when cells were exposed to low second doses. These results support previous studies showing that human cells are capable of repair but require relatively large doses to elicit a repair response. (author)

  8. Radiation induced formation of giant cells in Saccharomyces uvarum. Pt. 4. Macromolecular synthesis and protein patterns

    Energy Technology Data Exchange (ETDEWEB)

    Rink, H; Baumstark-Khan, C; Partke, H J

    1986-08-01

    X-irradiated (1.0 kGy) yeast cells (Saccharomyces uvarum, ATCC 9080), grown in liquid medium stop their mitotic activities and form giant cells by development of several buds which do not separate from mother cells. Depending on the time in culture, wet and dry weights per cell, protein- RNA- and DNA- contents per cell as well as incorporation rates of /sup 14/C-leucine per cell and per hour and patterns (isoelectric focusing) of water soluble proteins were studied. Weights per cell, RNA and protein contents per cell and /sup 14/C-leucine incorporation rates increase markedly in giant cells, whereas DNA content per cell is only duplicated. Protein patterns in isoelectric focusing show one interesting difference. In samples from giant cells one protein band (IP=6.63) decreases after 8 h in culture and later on disappears completely. This finding is not due to primary damage in X-irradiated DNA but seems to be related to the control of cell cycle events.

  9. DNA-repair, cell killing and normal tissue damage

    International Nuclear Information System (INIS)

    Dahm-Daphi, J.; Dikomey, E.; Brammer, I.

    1998-01-01

    Background: Side effects of radiotherapy in normal tissue is determined by a variety of factors of which cellular and genetic contributions are described here. Material and methods: Review. Results: Normal tissue damage after irradiation is largely due to loss of cellular proliferative capacity. This can be due to mitotic cell death, apoptosis, or terminal differentiation. Dead or differentiated cells release cytokines which additionally modulate the tissue response. DNA damage, in particular non-reparable or misrepaired double-strand breaks are considered the basic lesion leading to G1-arrest and ultimately to cell inactivation. Conclusion: Evidence for genetic bases of normal tissue response, cell killing and DNA-repair capacity is presented. However, a direct link of all 3 endpoints has not yet been proved directly. (orig.) [de

  10. The effect of caffeine and adenine on radiation induced suppression of DNA synthesis, and cell survival

    International Nuclear Information System (INIS)

    Wilcoxson, L.T.; Griffiths, T.D.

    1984-01-01

    Exposure of cultured mammalian cells to ionizing radiation or UV light results in a transient decrease in the rate of DNA synthesis. This depression in synthetic rate may be attenuated or deferred via a post-irradiation treatment with caffeine or adenine. It has been suggested that this attenuation may increase the fixation of damage and, therefore, increase radiation sensitivity. However, it has been previously reported that, for V79 cells treated with caffeine or adenine, no correlation exists between the extent of depression and cell survival. The present investigation expands upon these findings by examining the effect of caffeine or adenine post-irradiation treatment on two cell lines with normal UV sensitivity, mouse 3T3 and CHO AA8 cells, and one UV sensitive cell line, CHO UV5 cells. Both caffeine and adenine have been found to reduce, or delay, the suppression in DNA synthesis in all three cell lines. Surprisingly, caffeine appeared to induced even the UV5 cells to recover DNA synthetic ability. The amount of reduction in suppression of DNA synthesis, however, varies between the different cell lines and no consistent relationship with cell survival has emerged

  11. Radiation-induced inhibition of human endothelial cells replicating in culture

    International Nuclear Information System (INIS)

    DeGowin, R.L.; Lewis, L.J.; Mason, R.E.; Borke, M.K.; Hoak, J.C.

    1976-01-01

    The radiosensitivity of some tumors may depend upon the sensitivity of their microvasculature to radiation. Heretofore, the dose-response of human endothelial cells replicating in tissue culture has not been published. In studies reported here, we exposed flasks containing 4 to 7 x 10 4 genetically identical human endothelial cells to doses of x irradiation from 125 to 1000 rad. During the phase of logarithmic growth, cell counts were compared to those of an unirradiated control to construct a dose--response curve. Similar studies were performed with normal fibroblasts. We found that 160 rad suppressed endothelial cell replication by 37 percent. Although recovery was evident with doses of 500 rad, no net increase in cell number occurred in 3 weeks in flasks of endothelial cells that received 750 or 1000 rad. Fibroblasts were slightly less sensitive under these conditions. To our knowledge, this is the first report of a radiation dose--response curve for human endothelial cells replicating in culture

  12. Protective Role of R-spondin1, an Intestinal Stem Cell Growth Factor, against Radiation-Induced Gastrointestinal Syndrome in Mice

    OpenAIRE

    Bhanja, Payel; Saha, Subhrajit; Kabarriti, Rafi; Liu, Laibin; Roy-Chowdhury, Namita; Roy-Chowdhury, Jayanta; Sellers, Rani S.; Alfieri, Alan A.; Guha, Chandan

    2009-01-01

    Background Radiation-induced gastrointestinal syndrome (RIGS) results from a combination of direct cytocidal effects on intestinal crypt and endothelial cells and subsequent loss of the mucosal barrier, resulting in electrolyte imbalance, diarrhea, weight loss, infection and mortality. Because R-spondin1 (Rspo1) acts as a mitogenic factor for intestinal stem cells, we hypothesized that systemic administration of Rspo1 would amplify the intestinal crypt cells and accelerate the regeneration of...

  13. Protective effect of atorvastatin on radiation-induced vascular endothelial cell injury in vitro

    International Nuclear Information System (INIS)

    Ran Xinze; Zong Zhaowen; Liu Dengqun; Su Yongping; Zheng Huaien; Ran Xi; Xiang Guiming

    2010-01-01

    Vascular endothelial cells are very sensitive to ionizing radiation, and it is important to develop effective prevent agents and measures in radiation exposure protection. In the present study, the protective effects of atorvastatin on irradiated human umbilical vein endothelial cells (HUVEC) and the possible mechanisms were explored. Cultured HUVEC were treated by atorvastatin at a final concentration of 10 μmol/ml for 10 minutes, and then irradiated at a dose of 2 Gy or 25 Gy. Twenty-four hours after irradiation, apoptosis of HUVEC was monitored by flow cytometry, and the expression of thrombomodulin (TM) and protein C activation in HUVEC was respectively assessed by flow cytometry and spectrophotometry. After treatment with atorvastatin for 24 h, the rate of cell apoptosis decreased by 6% and 16% in cells irradiated with 2 Gy and 25 Gy, respectively. TM expression increased by 77%, 59%, and 61% in untreated cells, 2 Gy irradiation-treated cells, and 25 Gy irradiation-treated cells, respectively. The protein C levels in 2 Gy and 25 Gy irradiation-treated cells were reduced by 23% and 34% when compared with untreated cells, but up-regulated by 79% and 76% when compared with cells which were irradiated and treated with atorvastatin. In conclusion, these data indicate that atorvastatin exerts protective effects on irradiated HUVEC by reducing apoptosis by up-regulating TM expression and enhancing protein C activation in irradiated HUVEC. (author)

  14. Protective effect of atorvastatin on radiation-induced vascular endothelial cell injury in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Xinze, Ran; Zhaowen, Zong; Dengqun, Liu; Yongping, Su; Huaien, Zheng [College of Preventive Medicine, Third Military Medical Univ., Chongqing (China); Xi, Ran; Guiming, Xiang [Xinqiao Hospital, Third Military Medical Univ., Chongqing (China)

    2010-09-15

    Vascular endothelial cells are very sensitive to ionizing radiation, and it is important to develop effective prevent agents and measures in radiation exposure protection. In the present study, the protective effects of atorvastatin on irradiated human umbilical vein endothelial cells (HUVEC) and the possible mechanisms were explored. Cultured HUVEC were treated by atorvastatin at a final concentration of 10 {mu}mol/ml for 10 minutes, and then irradiated at a dose of 2 Gy or 25 Gy. Twenty-four hours after irradiation, apoptosis of HUVEC was monitored by flow cytometry, and the expression of thrombomodulin (TM) and protein C activation in HUVEC was respectively assessed by flow cytometry and spectrophotometry. After treatment with atorvastatin for 24 h, the rate of cell apoptosis decreased by 6% and 16% in cells irradiated with 2 Gy and 25 Gy, respectively. TM expression increased by 77%, 59%, and 61% in untreated cells, 2 Gy irradiation-treated cells, and 25 Gy irradiation-treated cells, respectively. The protein C levels in 2 Gy and 25 Gy irradiation-treated cells were reduced by 23% and 34% when compared with untreated cells, but up-regulated by 79% and 76% when compared with cells which were irradiated and treated with atorvastatin. In conclusion, these data indicate that atorvastatin exerts protective effects on irradiated HUVEC by reducing apoptosis by up-regulating TM expression and enhancing protein C activation in irradiated HUVEC. (author)

  15. Radioadaptive response. Efficient repair of radiation-induced DNA damage in adapted cells

    International Nuclear Information System (INIS)

    Ikushima, Takaji; Aritomi, Hisako; Morisita, Jun

    1996-01-01

    To verify the hypothesis that the induction of a novel, efficient repair mechanism for chromosomal DNA breaks may be involved in the radioadaptive response, the repair kinetics of DNA damage has been studied in cultured Chinese hamster V79 cells with single-cell gel electrophoresis. The cells were adapted by priming exposure with 5 cGy of γ-rays and 4-h incubation at 37C. There were no indication of any difference in the initial yields of DNA double-strand breaks induced by challenging doses from non-adapted cells and from adapted cells. The rejoining of DNA double-strand breaks was monitored over 120 min after the adapted cells were challenged with 5 or 1.5 Gy, doses at the same level to those used in the cytogenetical adaptive response. The rate of DNA damage repair in adapted cells was higher than that in non-adapted cells, and the residual damage was less in adapted cells than in non-adapted cells. These results indicate that the radioadaptive response may result from the induction of a novel, efficient DNA repair mechanism which leads to less residual damage, but not from the induction of protective functions that reduce the initial DNA damage

  16. Study on immobilized yeast cells with hydrophilic polymer carrier by radiation-induced copolymerization

    International Nuclear Information System (INIS)

    Li Zhengkui; Zhang Bosen

    1993-01-01

    Various kinds of monomers 2-hydroxyethyl methacrylate (HEMA), 2-hydroxyethyl acrylate (HEA), hydroxypropyl methacrylate (HPMA) and methoxy polyethylene glycol methylacrylate (M-23G) are copolymerized by radiation technique at low temperature (-78 degree C) and several kinds of copolymer carriers were obtained. Yeast cells are immobilized through adhesion and multiplication of yeast cells themselves on these carriers. The ethanol productivity of immobilized yeast cells with these carriers was related to the monomer composition and water content of copolymer carriers and the optimum monomer composition was 20%:10% in poly (HEA-M23G). In this case, the ethanol productivity of immobilized yeast cells was 26 mg/(ml · h), which was 4 times as high as that of free cells. Effect of adding crosslinking reagent (4G) in lower monomer composition of poly(HEA-M23G) on the ethanol productivity of immobilized cells was better than that in higher one in this work

  17. Radiation-induced apoptosis of neural precursors cell cultures: early modulation of the response mediated by reactive oxygen and nitrogen species (ROS/RNS)

    Energy Technology Data Exchange (ETDEWEB)

    Gisone, P.; Dubner, D.; Robello, E.; Michelin, S.; Perez, M. R.

    2004-07-01

    Apoptosis, the typical mode of radiation-induced cell death in developing Central Nervous System (CNS), is closely related with the oxidative status. Enhanced radiation-induced generation of ROS/RNS has been observed after exposures to low radiation doses leading to cellular amplification of signal transduction and further molecular and cellular radiation-responses. Moreover Nitric oxide (NO) and hydroxyl radical are implicated in dopaminergic neurotoxicity in different parading. This study is an attempt to address the participation of radiation-induced free radicals production, the contribution of endogenous NO generation, and the excitonic pathway, in the radiation-induced apoptosis of neural cortical precursors. Cortical cells obtained from at 17 gestational day (gd) were irradiated with doses from 0,2 Gy to 2 Gy at a dose-rate of 0.3 Gy/m. A significant decrease of Luminol-dependent Chemiluminescence was evident 30 m after irradiation reaching basal levels at 120 m follow for a tendency to increasing values Incubations with Superoxide Dismatuse (SOD) decreased significantly the chemiluminescence in irradiated samples NO content estimated by measuring the stable products NO{sub 2} and NO{sub 3} released to the culture medium in the same period, has shown a time-dependent accumulation from 1 h post-irradiation. the apoptosis, determined 24 h post-irradiation by flow cytometry, morphology and DNA fragmentation revealed a dose-effect relationship with significant differences from 0.4 Gy. The samples pre-treated with 10 mM of N-acetyl cysteine (NAC) a precursor of intracellular GSH synthesis, shown a significant decrease of the apoptosis. Apoptosis was significantly increased in irradiated cells after inhibition of nitric oxide synthase (NOS) byL-NAME. We conclude that ROS/RNS play a pivotal role in the early signaling pathways leading to a radiation-induced cell death. (Author) 40 refs.

  18. Radiation-induced apoptosis of neural precursors cell cultures: early modulation of the response mediated by reactive oxygen and nitrogen species (ROS/RNS)

    International Nuclear Information System (INIS)

    Gisone, P.; Dubner, D.; Robello, E.; Michelin, S.; Perez, M. R.

    2004-01-01

    Apoptosis, the typical mode of radiation-induced cell death in developing Central Nervous System (CNS), is closely related with the oxidative status. Enhanced radiation-induced generation of ROS/RNS has been observed after exposures to low radiation doses leading to cellular amplification of signal transduction and further molecular and cellular radiation-responses. Moreover Nitric oxide (NO) and hydroxyl radical are implicated in dopaminergic neurotoxicity in different parading. This study is an attempt to address the participation of radiation-induced free radicals production, the contribution of endogenous NO generation, and the excitonic pathway, in the radiation-induced apoptosis of neural cortical precursors. Cortical cells obtained from at 17 gestational day (gd) were irradiated with doses from 0,2 Gy to 2 Gy at a dose-rate of 0.3 Gy/m. A significant decrease of Luminol-dependent Chemiluminescence was evident 30 m after irradiation reaching basal levels at 120 m follow for a tendency to increasing values Incubations with Superoxide Dismatuse (SOD) decreased significantly the chemiluminescence in irradiated samples NO content estimated by measuring the stable products NO 2 and NO 3 released to the culture medium in the same period, has shown a time-dependent accumulation from 1 h post-irradiation. the apoptosis, determined 24 h post-irradiation by flow cytometry, morphology and DNA fragmentation revealed a dose-effect relationship with significant differences from 0.4 Gy. The samples pre-treated with 10 mM of N-acetyl cysteine (NAC) a precursor of intracellular GSH synthesis, shown a significant decrease of the apoptosis. Apoptosis was significantly increased in irradiated cells after inhibition of nitric oxide synthase (NOS) byL-NAME. We conclude that ROS/RNS play a pivotal role in the early signaling pathways leading to a radiation-induced cell death. (Author) 40 refs

  19. X-radiation-induced transformation in a C3H mouse embryo-derived cell line

    International Nuclear Information System (INIS)

    Terzaghi, M.; Little, J.B.

    1976-01-01

    Reproducible x-ray-induced oncogenic transformation has been demonstrated in an established cell line of mouse embryo fibroblasts. Cells derived from transformed foci formed malignant tumors when injected into syngeneic hosts. An exponential increase in the number of transformants per viable cell occurred with doses of up to 400 rads of x-radiation. The transformation frequency in exponentially growing cultures remained constant at 2.3 x 10 -3 following doses of 400 to 1500 rads. There was little change in survival following x-ray doses up to 300 rads. Doses greater than 300 rads were associated with an exponential decline in survival; the D 0 for the survival curve was 175 rads. Transformation frequency varied with changes in the number of viable cells seeded per dish. There was about a 10-fold decline in the transformation frequency when the number of cells was increased from 400 to 1000 viable cells/100-mm Petri dish. Below this density range there was little change in transformation frequency. The presence of lethally preirradiated cells was not associated with an enhancement of transformation in irradiated cells or with the induction of transformation in unirradiated cell cultures. Amphotericin B (Fungizone) inhibited the appearance of transformants when added to the culture medium within 2 to 3 weeks after initiation of the experiment

  20. Melanoma stem cells in experimental melanoma are killed by radioimmunotherapy

    International Nuclear Information System (INIS)

    Jandl, Thomas; Revskaya, Ekaterina; Jiang, Zewei; Harris, Matthew; Dorokhova, Olena; Tsukrov, Dina; Casadevall, Arturo; Dadachova, Ekaterina

    2013-01-01

    Introduction: In spite of recently approved B-RAF inhibitors and immunomodulating antibodies, metastatic melanoma has poor prognosis and novel treatments are needed. Melanoma stem cells (MSC) have been implicated in the resistance of this tumor to chemotherapy. Recently we demonstrated in a Phase I clinical trial in patients with metastatic melanoma that radioimmunotherapy (RIT) with 188-Rhenium( 188 Re)-6D2 antibody to melanin was a safe and effective modality. Here we investigated the interaction of MSC with RIT as a possible mechanism for RIT efficacy. Methods: Mice bearing A2058 melanoma xenografts were treated with either 1.5 mCi 188 Re-6D2 antibody, saline, unlabeled 6D2 antibody or 188 Re-labeled non-specific IgM. Results: On Day 28 post-treatment the tumor size in the RIT group was 4-times less than in controls (P < 0.001). The tumors were analyzed by immunohistochemistry and FACS for two MSC markers — chemoresistance mediator ABCB5 and H3K4 demethylase JARID1B. There were no significant differences between RIT and control groups in percentage of ABCB5 or JARID1B-positive cells in the tumor population. Our results demonstrate that unlike chemotherapy, which kills tumor cells but leaves behind MSC leading to recurrence, RIT kills MSC at the same rate as the rest of tumor cells. Conclusions: These results have two main implications for melanoma treatment and possibly other cancers. First, the susceptibility of ABCB5 + and JARID1B + cells to RIT in melanoma might be indicative of their susceptibility to antibody-targeted radiation in other cancers where they are present as well. Second, specifically targeting cancer stem cells with radiolabeled antibodies to ABCB5 or JARID1B might help to completely eradicate cancer stem cells in various cancers

  1. Enhancement of Temozolomide and radiation induced damage in malignant glioma cell lines by 2-deoxy-D-glucose

    International Nuclear Information System (INIS)

    Kumari, Kalyani; Shyam, Sai; Chandrasekhar Sagar, B.K.; Jagath Lal, G.; Kalia, Vijay Kumar

    2014-01-01

    Malignant Gliomas are the most common and aggressive CNS tumors. The current standard treatment includes surgery, followed by Temozolomide (TMZ)-Radiotherapy. It leads to increased survival as compared to radiotherapy alone. However hematological toxicities are also increased by the combination treatments. Therefore, it is important to carry out further preclinical studies, to develop more effective treatment for these tumors. 2-deoxy-D-Glucose (2-DG), an inhibitor of glycolytic energy metabolism, has been shown earlier to differentially inhibit growth and survival of tumor cells in vitro. It also increases tumor regression in experimental models; and has been used in a few clinical studies as radiosensitizer. In the present study, effects of combining 2-DG with TMZ on radiation induced damage were studied in established malignant glioma cell lines (U251MG and U87MG); and primary cultures derived from malignant glioma biopsies. Exponentially growing cells were exposed to drugs and radiation. Drugs were removed 4 hours later and cultures were processed further for different assays of damage. Effects on proliferation response, viability and total cellular damage (TCD; micronuclei + apoptosis) were studied after post-treatment growth for 1, 2, 4 or 6 days. Our results showed that combination of 2-DG with TMZ ± Radiation significantly inhibited tumor cell proliferation up to 6 days, at low drug concentrations in primary as well as in established cell lines. The TCD at 24 and 48 hours after Gamma irradiation was also significantly increased by the combination of drugs as compared to individual treatments. Experiments to study proliferation kinetics by flow cytometry and cell survival are in progress. These studies suggest that 2-DG significantly enhances the cytotoxic effect of TMZ + radiation without increasing toxic side effects. Therefore, combining 2-DG with TMZ+ radiation therapy could be a potential strategy to improve the therapeutic outcome for Malignant

  2. Progressive behavioral changes during the maturation of rats with early radiation-induced hypoplasia of fascia dentata granule cells

    International Nuclear Information System (INIS)

    Mickley, G.A.; Ferguson, J.L.; Mulvihill, M.A.; Nemeth, T.J.

    1989-01-01

    Localized exposure of the neonatal rat brain to X-rays produces neuronal hypoplasia specific to the granule cell layer of the hippocampal dentate gyrus. This brain damage causes locomotor hyperactivity, slowed acquisition of passive avoidance tasks and long bouts of spontaneous turning (without reversals) in a bowl apparatus. Here we report how these behavioral deficits change as a function of subject aging and behavioral test replications. Portions of the neonatal rat cerebral hemispheres were X-irradiated in order to selectively damage the granule cells of the dentate gyrus. The brains of experimental animals received a fractionated dose of X rays (13 Gy total) over postnatal days 1 to 16 and control animals were sham-irradiated. Rats between the ages of 71-462 days were tested 3 separate times on each of the following 3 behavioral tests: (1) spontaneous locomotion, (2) passive avoidance acquisition, and (3) spontaneous circling in a large plastic hemisphere. Rats with radiation-induced damage to the fascia dentata exhibited long bouts of slow turns without reversals. Once they began, irradiated subjects perseverated in turning to an extent significantly greater than sham-irradiated control subjects. This irradiation effect was significant during all test series. Moreover, in time, spontaneous perseverative turning was significantly potentiated in rats with hippocampal damage but increased only slightly in controls. Early radiation exposure produced locomotor hyperactivity in young rats. While activity levels of controls remained fairly stable throughout the course of the experiment, the hyperactivity of the irradiated animals decreased significantly as they matured

  3. Genetic modification to induce CXCR2 overexpression in mesenchymal stem cells enhances treatment benefits in radiation-induced oral mucositis.

    Science.gov (United States)

    Shen, Zongshan; Wang, Jiancheng; Huang, Qiting; Shi, Yue; Wei, Zhewei; Zhang, Xiaoran; Qiu, Yuan; Zhang, Min; Wang, Yi; Qin, Wei; Huang, Shuheng; Huang, Yinong; Liu, Xin; Xia, Kai; Zhang, Xinchun; Lin, Zhengmei

    2018-02-14

    Radiation-induced oral mucositis affects patient quality of life and reduces tolerance to cancer therapy. Unfortunately, traditional treatments are insufficient for the treatment of mucositis and might elicit severe side effects. Due to their immunomodulatory and anti-inflammatory properties, the transplantation of mesenchymal stem cells (MSCs) is a potential therapeutic strategy for mucositis. However, systemically infused MSCs rarely reach inflamed sites, impacting their clinical efficacy. Previous studies have demonstrated that chemokine axes play an important role in MSC targeting. By systematically evaluating the expression patterns of chemokines in radiation/chemical-induced oral mucositis, we found that CXCL2 was highly expressed, whereas cultured MSCs negligibly express the CXCL2 receptor CXCR2. Thus, we explored the potential therapeutic benefits of the transplantation of CXCR 2 -overexpressing MSCs (MSCs CXCR2 ) for mucositis treatment. Indeed, MSCs CXCR2 exhibited enhanced targeting ability to the inflamed mucosa in radiation/chemical-induced oral mucositis mouse models. Furthermore, we found that MSC CXCR2 transplantation accelerated ulcer healing by suppressing the production of pro-inflammatory chemokines and radiogenic reactive oxygen species (ROS). Altogether, these findings indicate that CXCR2 overexpression in MSCs accelerates ulcer healing, providing new insights into cell-based therapy for radiation/chemical-induced oral mucositis.

  4. Significant Suppression of CT Radiation-Induced DNA Damage in Normal Human Cells by the PrC-210 Radioprotector.

    Science.gov (United States)

    Jermusek, Frank; Benedict, Chelsea; Dreischmeier, Emma; Brand, Michael; Uder, Michael; Jeffery, Justin J; Ranallo, Frank N; Fahl, William E

    2018-05-21

    While computed tomography (CT) is now commonly used and considered to be clinically valuable, significant DNA double-strand breaks (γ-H2AX foci) in white blood cells from adult and pediatric CT patients have been frequently reported. In this study to determine whether γ-H2AX foci and X-ray-induced naked DNA damage are suppressed by administration of the PrC-210 radioprotector, human blood samples were irradiated in a CT scanner at 50-150 mGy with or without PrC-210, and γ-H2AX foci were scored. X-ray-induced naked DNA damage was also studied, and the DNA protective efficacy of PrC-210 was compared against 12 other common "antioxidants." PrC-210 reduced CT radiation-induced γ-H2AX foci in white blood cells to near background ( P 95% DNA damage. A systemic PrC-210 dose known to confer 100% survival in irradiated mice had no discernible effect on micro-CT image signal-to-noise ratio and CT image integrity. PrC-210 suppressed DNA damage to background or near background in each of these assay systems, thus supporting its development as a radioprotector for humans in multiple radiation exposure settings.

  5. Effect of caffeine on radiation-induced apoptosis in TK6 cells

    International Nuclear Information System (INIS)

    Zhen, W.; Vaughan, A.T.M.

    1995-01-01

    Apoptosis has been measured in cells of the human TK6 lymphoblastoid cell line by recording the release of endonuclease-digested DNA from affected cells using flow cytometry. In asynchronously dividing cells, DNA degradation characteristic of apoptosis was first seen 12 h after irradiation as a defined DNA fluorescent peak of sub-G 1 -phase content, reaching a maximum of 30-50% of the population by 24-72 h. Treating cells with 2 mM caffeine either before or up to 3 h after irradiation eliminated the degradation of DNA entirely. In addition, the percentage of cells in which apoptosis could be detected microscopically decreased from 62.4 ± 0.95% to 16.7 ± 1.5% 72 h after caffeine treatment. Delaying caffeine treatment for 12 h after irradiation reduced DNA degradation by approximately 50% compared to cells receiving radiation alone. DNA degradation induced by serum deprivation was unaffected by caffeine treatment. These data support the contention that irradiation of TK6 cells produces a long-lived cellular signal which triggers apoptosis. Apoptosis produced by serum deprivation does not operate through the same pathway. 36 refs., 5 figs

  6. Effect of caffeine on radiation-induced apoptosis in TK6 cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhen, W.; Vaughan, A.T.M. [Loyola Univ. Chicago, Maywood, IL (United States)

    1995-02-01

    Apoptosis has been measured in cells of the human TK6 lymphoblastoid cell line by recording the release of endonuclease-digested DNA from affected cells using flow cytometry. In asynchronously dividing cells, DNA degradation characteristic of apoptosis was first seen 12 h after irradiation as a defined DNA fluorescent peak of sub-G{sub 1}-phase content, reaching a maximum of 30-50% of the population by 24-72 h. Treating cells with 2 mM caffeine either before or up to 3 h after irradiation eliminated the degradation of DNA entirely. In addition, the percentage of cells in which apoptosis could be detected microscopically decreased from 62.4 {+-} 0.95% to 16.7 {+-} 1.5% 72 h after caffeine treatment. Delaying caffeine treatment for 12 h after irradiation reduced DNA degradation by approximately 50% compared to cells receiving radiation alone. DNA degradation induced by serum deprivation was unaffected by caffeine treatment. These data support the contention that irradiation of TK6 cells produces a long-lived cellular signal which triggers apoptosis. Apoptosis produced by serum deprivation does not operate through the same pathway. 36 refs., 5 figs.

  7. Radiation-induced irreparable heritable changes in cells promoting their tumoral transformation

    International Nuclear Information System (INIS)

    Kuzin, A.M.; Vagabova, M.Eh.; Yurov, S.S.

    1988-01-01

    In experiments with model plant tumors (Kalanchoe-ti plasmid Agrobat. tumefaciens C-58D) it was shown that exposure of the recepient plant to low-level γ-radiation of Gy induced changes in cells that were not repaired over two months promoting tumoral transformations in them. Those changes were shown to persist in the offspring of the exposed somatic cells

  8. Pretreatment of low dose radiation reduces radiation-induced apoptosis in mouse lymphoma (EL4) cells.

    Science.gov (United States)

    Kim, J H; Hyun, S J; Yoon, M Y; Ji, Y H; Cho, C K; Yoo, S Y

    1997-06-01

    Induction of an adaptive response to ionizing radiation in mouse lymphoma (EL4) cells was studied by using cell survival fraction and apoptotic nucleosomal DNA fragmentation as biological end points. Cells in early log phase were pre-exposed to low dose of gamma-rays (0.01 Gy) 4 or 20 hrs prior to high dose gamma-ray (4, 8 and 12 Gy for cell survival fraction analysis; 8 Gy for DNA fragmentation analysis) irradiation. Then cell survival fractions and the extent of DNA fragmentation were measured. Significant adaptive response, increase in cell survival fraction and decrease in the extent of DNA fragmentation were induced when low and high dose gamma-ray irradiation time interval was 4 hr. Addition of protein or RNA synthesis inhibitor, cycloheximide or 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole (DRFB), respectively during adaptation period, the period from low dose gamma-ray irradiation to high dose gamma-ray irradiation, was able to inhibit the induction of adaptive response, which is the reduction of the extent DNA fragmentation in irradiated EL4 cells. These data suggest that the induction of adaptive response to ionizing radiation in EL4 cells required both protein and RNA synthesis.

  9. Transformation of bone marrow stem-cells and radiation-induced myeloid leukemia in mice

    International Nuclear Information System (INIS)

    Hirashima, K.; Bessho, M.; Hayata, I.; Nara, N.; Kawase, Y.; Ohtani, M.

    1982-01-01

    After a single whole-body X-irradiation of 300R to male RFM/MsNrs strain mice, the occurrence of myeloid leukemia initiated since four months and ceased at eleven months after irradiation. The cumulative incidence reached 24.5%. A time course study on the kinetics of pluripotential stem-cells (CFU-S) and granuloid committed stem-cells (CFU-C) in the marrow after 300R was also performed. The repopulation of CFU-S was accomplished within one month whereas that of CFU-C needed 210 days after irradiation. The incidence of leukemia was very rare after the complete repopulation of CFU-C. Simultaneously, collected spleen cells from the irradiated mice without overt leukemia were transplanted into 300-600R irradiated recipients of another sex. Three months thereafter, recipients were sacrificed to detect leukemic changes and the origin of leukemic cells by chromosome analysis. The results revealed that leukemic cell transformation of donor cells began 18 days after irradiation and on an average, 37.1% of the irradiated mice carried potentially leukemic cells for seven months after exposure, whereas none of the unirradiated mice carried leukemic cells at 7 months after irradiation. To investigate host factor(s) contributing to the proliferation of leukemic cells, the suppression of cellular immunity after 300R was measured by GVH mortality assay. However, the recovery of cellular immunity was observed until three months after irradiation and the role of cellular immunity to proliferation of leukemic cells after three months was negligible. (author)

  10. Ionizing Radiation-Induced DNA Damage and Its Repair in Human Cells

    Energy Technology Data Exchange (ETDEWEB)

    Dizdaroglu, Miral

    1999-05-12

    DNA damage in mammalian chromatin in vitro and in cultured mammalian cells including human cells was studied. In the first phase of these studies, a cell culture laboratory was established. Necessary equipment including an incubator, a sterile laminar flow hood and several centrifuges was purchased. We have successfully grown several cell lines such as murine hybridoma cells, V79 cells and human K562 leukemia cells. This was followed by the establishment of a methodology for the isolation of chromatin from cells. This was a very important step, because a routine and successful isolation of chromatin was a prerequisite for the success of the further studies in this project, the aim of which was the measurement of DNA darnage in mammalian chromatin in vitro and in cultured cells. Chromatin isolation was accomplished using a slightly modified procedure of the one described by Mee & Adelstein (1981). For identification and quantitation of DNA damage in cells, analysis of chromatin was preferred over the analysis of "naked DNA" for the following reasons: i. DNA may not be extracted efficiently from nucleoprotein in exposed cells, due to formation of DNA-protein cross-links, ii. the extractability of DNA is well known to decrease with increasing doses of radiation, iii. portions of DNA may not be extracted due to fragmentation, iv. unextracted DNA may contain a significant portion of damaged DNA bases and DNA-protein cross-links. The technique of gas chromatography/mass spectrometry (GC/MS), which was used in the present project, permits the identification and quantitation of modified DNA bases in chromatin in the presence of proteins without the necessity of first isolating DNA from chromatin. This has been demonstrated previously by the results from our laboratory and by the results obtained during the course of the present project. The quality of isolated chromatin was tested by measurement of its content of DNA, proteins, and RNA, by analysis of its protein

  11. Ionizing Radiation-Induced DNA Damage and Its Repair in Human Cells

    International Nuclear Information System (INIS)

    Dizdaroglu, Miral

    1999-01-01

    DNA damage in mammalian chromatin in vitro and in cultured mammalian cells including human cells was studied. In the first phase of these studies, a cell culture laboratory was established. Necessary equipment including an incubator, a sterile laminar flow hood and several centrifuges was purchased. We have successfully grown several cell lines such as murine hybridoma cells, V79 cells and human K562 leukemia cells. This was followed by the establishment of a methodology for the isolation of chromatin from cells. This was a very important step, because a routine and successful isolation of chromatin was a prerequisite for the success of the further studies in this project, the aim of which was the measurement of DNA darnage in mammalian chromatin in vitro and in cultured cells. Chromatin isolation was accomplished using a slightly modified procedure of the one described by Mee ampersand Adelstein (1981). For identification and quantitation of DNA damage in cells, analysis of chromatin was preferred over the analysis of ''naked DNA'' for the following reasons: i. DNA may not be extracted efficiently from nucleoprotein in exposed cells, due to formation of DNA-protein cross-links, ii. the extractability of DNA is well known to decrease with increasing doses of radiation, iii. portions of DNA may not be extracted due to fragmentation, iv. unextracted DNA may contain a significant portion of damaged DNA bases and DNA-protein cross-links. The technique of gas chromatography/mass spectrometry (GC/MS), which was used in the present project, permits the identification and quantitation of modified DNA bases in chromatin in the presence of proteins without the necessity of first isolating DNA from chromatin. This has been demonstrated previously by the results from our laboratory and by the results obtained during the course of the present project. The quality of isolated chromatin was tested by measurement of its content of DNA, proteins, and RNA, by analysis of its protein

  12. The mechanism of radiation-induced interphase death of lymphoid cells: A new hypothesis

    International Nuclear Information System (INIS)

    Eidus, L.K.; Korystov, Yu.N.; Dobrovinskaja, O.R.; Shaposhnikova, V.V.

    1990-01-01

    The interphase death of irradiated rat thymocytes depends on their concentration during postirradiation incubation. The kinetics of pycnosis and cell death determined with the trypan blue exclusion test in the samples with the highest cell concentration (1-2 x 10(7) cells/ml) is consistent with the data available in the literature, whereas the samples with the lowest concentration (2 x 10(5) cells/ml) undergo almost no pycnosis and death after irradiation with doses up to 50 Gy. On the basis of these results, we suggest a new mechanism of interphase death involving an interaction between irradiated thymocytes and the fraction of thymus cells possessing cytocidal activity. The observed correlation between the cytocidal activity and interphase death of thymocytes from animals of different ages favors our mechanism. It was found that the inhibitors which prevent the conjugation of killer cells and their targets do not influence interphase death, while the substances which block the secretion of cytotoxic factors or their action on the target membrane do protect from interphase death. Thus we suggest that the irradiation activates the killer cells to secrete some cytotoxic factors which induce pycnosis and interphase death of thymocytes

  13. Protective immunity to UV radiation-induced skin tumours induced by skin grafts and epidermal cells

    International Nuclear Information System (INIS)

    Ronald Sluyter; Kylie S Yuen; Gary M Halliday

    2001-01-01

    There is little evidence that cutaneous dendritic cells (DC), including epidermal Langerhans cells (LC), can induce immunity to UV radiation (UVR)-induced skin tumours. Here, it is shown that cells within skin can induce protective antitumour immunity against a UVR-induced fibrosarcoma. Transplantation of the skin overlying subcutaneous tumours onto naive recipients could induce protective antitumour immunity, probably because the grafting stimulated the tumour Ag-loaded DC to migrate to local lymph nodes. This suggests that cutaneous APC can present tumour Ag to induce protective antitumour immunity. Previously, it has been shown that immunization of mice with MHC class II+ epidermal cells (EC) pulsed with tumour extracts could induce delayed-type hypersensitivity against tumour cells. Here, this same immunization protocol could induce protective immunity against a minimum tumorigenic dose of UVR-induced fibrosarcoma cells, but not higher doses. Epidermal cells obtained from semiallogeneic donors and pulsed with tumour extract could also induce protective immunity. However, presentation of BSA Ag from the culture medium was found to contribute to this result using semiallogeneic EC. The results suggest that LC overlying skin tumours may be able to induce protective immunity to UVR-induced tumours if stimulated to migrate from the skin. Copyright (2001) Australasian Society of Immunology Inc

  14. Radiation-Induced Bystander Effects in A549 Cells Exposed to 6 MV X-rays.

    Science.gov (United States)

    Yang, Shuning; Xu, Jing; Shao, Weixian; Geng, Chong; Li, Jia; Guo, Feng; Miao, Hui; Shen, Wenbin; Ye, Tao; Liu, Yazhou; Xu, Haiting; Zhang, Xuguang

    2015-07-01

    The aim of the study is to explore the bystander effects in A549 cells that have been exposed to 6MV X-ray. Control group, irradiated group, irradiated conditioned medium (ICM)-received group, and fresh medium group were designed in this study. A549 cells in the logarithmic growth phase were irradiated with 6MV X-ray at 0, 0.5, 1, 1.5, and 2. In ICM-received group, post-irradiation A549 cells were cultured for 3 h and were transferred into non-irradiated A549 cells for further cultivation. Clone forming test was applied to detect the survival fraction of cells. Annexin V-FITC/PI double-staining assay was used to detect the apoptosis of A549 cells 24, 48, 72, and 96 h after 2-Gy 6MV X-ray irradiation, and the curves of apoptosis were drawn. The changes in the cell cycles 4, 48, 72, and 96 h after 2-Gy 6MV X-ray irradiation were detected using PI staining flow cytometry. With the increase of irradiation dose, the survival fraction of A549 cells after the application of 0.5 Gy irradiation was decreasing continuously. In comparison to the control group, the apoptosis rate of the ICM-received group was increased in a time-dependent pattern, with the highest apoptosis rate observed at 72 h (p X-ray irradiation can induce bystander effect on A549 cells, which reaches a peak at 72 h.

  15. Isolation and identification of gene mediating radiation-induced apoptosis in human leukemia U937 cells

    International Nuclear Information System (INIS)

    Tong Xin; Luo Ying; Dong Yan; Sun Zhixian

    1998-01-01

    Objective: Increasing evidences suggest that Caspase family proteases play an important role in the effector mechanism of apoptotic cell death. Radiation (IR) can induce apoptosis in tumor cells, so it is very important to isolate and identify the member of the Caspase family proteases involved in IR-induced apoptosis, and this would contribute to the understanding of the mechanism responsible for apoptosis execution. Methods: A PCR approach to isolate genes for IR-induced apoptosis was developed. The approach used degenerated oligonucleotide encoding the highly conserved peptides that were present in all known Caspases. Results: Protease inhibitors special for Caspases could block the apoptotic cell death caused by IR, and Caspase-3 was isolated from irradiated human leukemia U937 cells. Conclusion: Caspases involve in IR-induced apoptosis, and Caspase-3 is the pivotal element of IR-induced apoptosis

  16. Effect of Trace Elements in Alcohol Beverages on the Type of Radiation-induced Cell Death

    International Nuclear Information System (INIS)

    Sohn, Jong Gi

    2010-01-01

    Developments of radioprotective agents are important issues for minimizing the troubles and the effective treatments in radiotherapy. But few agents are useful in clinical and practical fields. It was shown that trace elements in alcohol beverages might have radioprotective effect. In this study, the types of cell death of lymphocytes according to the commercial alcohol beverage was investigated. Normal healthy volunteers ingested distilled water, beer or soju containing 8.15 mg·dl -1 ethyl ahcohol, respectively. After 2 hours, their blood were sampled with their consents. Fraction of lymphocytes was isolated by density gradient method with Histopaque-1077 (Sigma) and irradiated with dose from 0.5 to 5 Gy. After 60 hour incubation, the cells were harvested and analysed by flow cytometry. Cell viability was decreased by dose dependent manner. Cell viability of beer group was reduced about 15% compared with control group. Apoptosis in soju group was reduced about 20% compared with control group. Apoptosis of beer and control groups are similar. Necrosis of soju group significantly increased about 35% compared with control group. Early apoptosis of beer group was increased compared with control group. Early apoptosis of soju group was decreased about 25% compared with control group. Late apoptosis of beer and control group was increased by dose dependent manner. Late apoptosis of soju group was increased about 20-30% compared with control group. Late apoptosis of soju was increased and the radioprotective effect of soju was minimal because late apoptosis induced the cell necrosis. In case of soju trace elements, total cell apoptosis was decreased about 20% and early cell apoptosis was remarkably low. In this case, mitotic cells death may be dominant mechanism. Therefore, trace elements in soju may not be effective radioprotective agents

  17. Radiation-induced DNA damage in halogenated pyrimidine incorporated cells and its correlation with radiosensitivity

    International Nuclear Information System (INIS)

    Watanabe, R.; Nikjoo, H.

    2003-01-01

    Cells with DNA containing 5-halogenated pyrimidines in place of thymidine show significant reductions of slope (Do) and shoulder (Dq) of their radiation survival curves. Similar radiosensitization has also been observed in the yield of DNA strand breaks. The purpose of this study is to obtain an insight into the mechanism of cell lethality by examining the relationship between the spectrum of DNA damage and the cell survival. In this study we estimated the enhancement of strand breaks due to incorporation of halogenated pyrimidine, the complexity of DNA damage and the probability of the initial DNA damage leading to cell inactivation. Monte Carlo track structure methods were used to model and simulate the induction of strand breakage by X-rays. The increase of DNA strand break was estimated by assuming the excess strand break was caused by the highly reactive uracil radicals at the halouracil substituted sites. The assumption of the enhancement mechanism of strand breaks was examined and verified by comparison with experimental data for induction of SSB and DSB. The calculated DNA damage spectrum shows the increase in complexity of strand breaks is due to incorporation of halogenated pyrimidines. The increase in the yield of DSB and cell lethality show similar trend at various degrees of halogenated pyrimidine substitution. We asked the question whether this agreement supports the hypothesis that DSB is responsible for cell lethality? The estimated number of lethal damage from the cell survival using a linear-quadratic model is much less than the initial yield of DSB. This work examines the correlation of cell lethality as a function of frequencies of complex form of double strand breaks

  18. Protective effect of atorvastatin on radiation-induced endothelial cell injury

    Energy Technology Data Exchange (ETDEWEB)

    Xinze, Ran; Huaien, Zheng; Fengchao, Wang; Xi, Ran; Aiping, Wang; Jing, Han; Yanqi, Zhang; Jun, Chen [Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, College of Preventive Medicine, Third Military Medical University, Chongqing (China)

    2009-04-15

    Objective: To explore the protective effect of atorvastatin on irradiated endothelium and the thrombomodulin (TM) expression. Methods: Cultured human coronary artery endothelial cells (HCAEC) and human umbilical vein endothelial cells (HUVEC) were treated by atorvastatin at the final concentration of 10 {mu}mol/ml for 10 min, and then irradiated with 2 and 25 Gy. Cell cycles status and TM expression were quantitatively measured by flow cytometry 24 hours after irradiation. Protein C activation in endothelial cells was also assessod. Results: After administration with atorvastatin for 24 h, the TM expression increased by 77%, 59% and 61% in normal control group, 2 Gy group and 25 Gy group, respectively (t=27.395, 26.420, 58.065; P=0.000). The protein C levels decreased by 23% and 34% compared with the normal group post-irradiation to 2 and 25 Gy, but increased by 79% and 76% compared with the irradiated control group after administration with atorvastatin. The rates of cell apoptosis decreased by 6% and 16% in 2 Gy and 25 Gy groups, respectively after administration with atorvastatin for 24 h (t=4.178, 17.863; P=0.000). Conclusions: Atorva statin can protect endothelia cell from irradiation-induced apeptosis by increasing TM expression and protein C activation. (authors)

  19. Protective effect of atorvastatin on radiation-induced endothelial cell injury

    International Nuclear Information System (INIS)

    Ran Xinze; Zheng Huaien; Wang Fengchao; Ran Xi; Wang Aiping; Han Jing; Zhang Yanqi; Chen Jun

    2009-01-01

    Objective: To explore the protective effect of atorvastatin on irradiated endothelium and the thrombomodulin (TM) expression. Methods: Cultured human coronary artery endothelial cells (HCAEC) and human umbilical vein endothelial cells (HUVEC) were treated by atorvastatin at the final concentration of 10 μmol/ml for 10 min, and then irradiated with 2 and 25 Gy. Cell cycles status and TM expression were quantitatively measured by flow cytometry 24 hours after irradiation. Protein C activation in endothelial cells was also assessod. Results: After administration with atorvastatin for 24 h, the TM expression increased by 77%, 59% and 61% in normal control group, 2 Gy group and 25 Gy group, respectively (t=27.395, 26.420, 58.065; P=0.000). The protein C levels decreased by 23% and 34% compared with the normal group post-irradiation to 2 and 25 Gy, but increased by 79% and 76% compared with the irradiated control group after administration with atorvastatin. The rates of cell apoptosis decreased by 6% and 16% in 2 Gy and 25 Gy groups, respectively after administration with atorvastatin for 24 h (t=4.178, 17.863; P=0.000). Conclusions: Atorva statin can protect endothelia cell from irradiation-induced apeptosis by increasing TM expression and protein C activation. (authors)

  20. Adaptive response to ionizing radiation induced by low doses of gamma rays in human cell lines

    International Nuclear Information System (INIS)

    Seong, Jinsil; Chang, Ok Suh; Gwi, Eon Kim

    1995-01-01

    Purpose: The aim of this study was to investigate whether the adaptive response could be induced in human lymphoblastoid cell lines and human tumor cell lines. The time necessary for the expression of the adaptive response was also investigated. Materials and Methods: Three lymphoblastoid cell lines from ataxia telangiectasia (AT) homozygote (GM 1526), AT heterozygote (GM 3382), and normal individual (3402p) and two hepatoma cell lines, Hep G2 and Hep 3B, were used in this study. Experiments were carried out by delivering 0.01 Gy followed by 0.5 Gy of gamma radiation to the exponentially growing cells. The time necessary for the expression of the adaptive response was determined by varying the time interval between the two doses from 1 to 72 h. In some experiments, 3-aminobenzamide, a potent inhibitor of poly (ADP-ribose) polymerase, was added immediately after the 0.5 Gy exposure. The cultures were fixed 30 min (for the G 2 chromatid) and 6 h (for the S chromatid) after the 0.5 Gy exposure. Metaphase chromosome assay was carried out to score chromatid breaks as an end point. Results: A prior exposure to 0.01 Gy of gamma rays significantly reduced the number of chromatid breaks induced by subsequent higher doses (0.5 Gy) in all the tested cell lines. The magnitude of the adaptive response was similar among the cell lines despite their different radiosensitivities. In the G 2 chromatids, the adaptive response was observed both at short-time intervals, as early as 1 h, and at long-time intervals. In the S chromatids, however, the adaptive response was shown only at long-time intervals. When 3-aminobenzamide was added after the 0.5 Gy, the adaptive responses were abolished in all the experimental groups. Conclusion: The adaptive response was observed in human lymphoblastoid cell lines and hepatoma cell lines. The magnitude of the adaptive response did not seem to be related to the radiosensitivity of the cells. The elimination of the adaptive response with 3

  1. SU-G-TeP3-10: Radiation Induces Prompt Live-Cell Metabolic Fluxes

    Energy Technology Data Exchange (ETDEWEB)

    Campos, D [University of Wisconsin Madison, Madison, WI (United States); Peeters, W; Bussink, J [Radboud University Medical Center, Nijmegen, GA (United States); Nickel, K [University of Wisconsin - Madison, Madison, Wisconsin (United States); Burkel, B; Kimple, R; Kogel, A van der; Eliceiri, K [University of Wisconsin - Madison, Madison, WI (United States); Kissick, M [University of Wisconsin, Madison, WI (United States)

    2016-06-15

    Purpose: To compare metabolic dynamics and HIF-1α expression following radiation between a cancerous cell line (UM-SCC-22B) and a normal, immortalized cell line, NOK (Normal Oral Keratinocyte). HIF-1 is a key factor in metabolism and radiosensitivity. A better understanding of how radiation affects the interplay of metabolism and HIF-1 might give a better understanding of the mechanisms responsible for radiosensitivity. Methods: Changes in cellular metabolism in response to radiation are tracked by fluorescence lifetime of NADH. Expression of HIF-1α was measured by immunofluorescence for both cell lines with and without irradiation. Radiation response is also monitored with additional treatment of a HIF-1α inhibitor (chrysin) as well as a radical scavenger (glutathione). Changes in oxygen consumption and respiratory capacity are also monitored using the Seahorse XF analyzer. Results: An increase in HIF-1α was found to be in response to radiation for the cancer cell line, but not the normal cell line. Radiation was found to shift metabolism toward glycolytic pathways in cancer cells as measured by oxygen consumption and respiratory capacity. Radiation response was found to be muted by addition of glutathione to cell media. HIF-1α inhibition similarly muted radiation response in cancer. Conclusion: The HIF-1 protein complex is a key regulator cellular metabolism through the regulation of glycolysis and glucose transport enzymes. Moreover, HIF-1 has shown radio-protective effects in tumor vascular endothelia, and has been implicated in metastatic aggression. Monitoring interplay between metabolism and the HIF-1 protein complex can give a more fundamental understanding of radiotherapy response.

  2. SU-G-TeP3-10: Radiation Induces Prompt Live-Cell Metabolic Fluxes

    International Nuclear Information System (INIS)

    Campos, D; Peeters, W; Bussink, J; Nickel, K; Burkel, B; Kimple, R; Kogel, A van der; Eliceiri, K; Kissick, M

    2016-01-01

    Purpose: To compare metabolic dynamics and HIF-1α expression following radiation between a cancerous cell line (UM-SCC-22B) and a normal, immortalized cell line, NOK (Normal Oral Keratinocyte). HIF-1 is a key factor in metabolism and radiosensitivity. A better understanding of how radiation affects the interplay of metabolism and HIF-1 might give a better understanding of the mechanisms responsible for radiosensitivity. Methods: Changes in cellular metabolism in response to radiation are tracked by fluorescence lifetime of NADH. Expression of HIF-1α was measured by immunofluorescence for both cell lines with and without irradiation. Radiation response is also monitored with additional treatment of a HIF-1α inhibitor (chrysin) as well as a radical scavenger (glutathione). Changes in oxygen consumption and respiratory capacity are also monitored using the Seahorse XF analyzer. Results: An increase in HIF-1α was found to be in response to radiation for the cancer cell line, but not the normal cell line. Radiation was found to shift metabolism toward glycolytic pathways in cancer cells as measured by oxygen consumption and respiratory capacity. Radiation response was found to be muted by addition of glutathione to cell media. HIF-1α inhibition similarly muted radiation response in cancer. Conclusion: The HIF-1 protein complex is a key regulator cellular metabolism through the regulation of glycolysis and glucose transport enzymes. Moreover, HIF-1 has shown radio-protective effects in tumor vascular endothelia, and has been implicated in metastatic aggression. Monitoring interplay between metabolism and the HIF-1 protein complex can give a more fundamental understanding of radiotherapy response.

  3. Processing of radiation-induced clustered DNA damage generates DSB in mammalian cells

    International Nuclear Information System (INIS)

    Gulston, M.K.; De Lara, C.M.; Davis, E.L.; Jenner, T.J.; O'Neill, P.

    2003-01-01

    Full text: Clustered DNA damage sites, in which two or more lesions are formed within a few helical turns of the DNA after passage of a single radiation track, are signatures of DNA modifications induced by ionizing radiation in mammalian cell. With 60 Co-radiation, the abundance of clustered DNA damage induced in CHO cells is ∼4x that of prompt double strand breaks (DSB) determined by PFGE. Less is known about the processing of non-DSB clustered DNA damage induced in cells. To optimize observation of any additional DSB formed during processing of DNA damage at 37 deg C, xrs-5 cells deficient in non-homologous end joining were used. Surprisingly, ∼30% of the DSB induced by irradiation at 37 deg C are rejoined within 4 minutes in both mutant and wild type cells. No significant mis-repair of these apparent DSB was observed. It is suggested that a class of non-DSB clustered DNA damage is formed which repair correctly within 4 min but, if 'trapped' prior to repair, are converted into DSB during the lysis procedure of PFGE. However at longer times, a proportion of non-DSB clustered DNA damage sites induced by γ-radiation are converted into DSB within ∼30 min following post-irradiation incubation at 37 deg C. The corresponding formation of additional DSB was not apparent in wild type CHO cells. From these observations, it is estimated that only ∼10% of the total yield of non DSB clustered DNA damage sites are converted into DSB through cellular processing. The biological consequences that the majority of non-DSB clustered DNA damage sites are not converted into DSBs may be significant even at low doses, since a finite chance exists of these clusters being formed in a cell by a single radiation track

  4. Epirubicin-adsorbed nanodiamonds kill chemoresistant hepatic cancer stem cells.

    Science.gov (United States)

    Wang, Xin; Low, Xinyi Casuarine; Hou, Weixin; Abdullah, Lissa Nurrul; Toh, Tan Boon; Mohd Abdul Rashid, Masturah; Ho, Dean; Chow, Edward Kai-Hua

    2014-12-23

    Chemoresistance is a primary cause of treatment failure in cancer and a common property of tumor-initiating cancer stem cells. Overcoming mechanisms of chemoresistance, particularly in cancer stem cells, can markedly enhance cancer therapy and prevent recurrence and metastasis. This study demonstrates that the delivery of Epirubicin by nanodiamonds is a highly effective nanomedicine-based approach to overcoming chemoresistance in hepatic cancer stem cells. The potent physical adsorption of Epirubicin to nanodiamonds creates a rapidly synthesized and stable nanodiamond-drug complex that promotes endocytic uptake and enhanced tumor cell retention. These attributes mediate the effective killing of both cancer stem cells and noncancer stem cells in vitro and in vivo. Enhanced treatment of both tumor cell populations results in an improved impairment of secondary tumor formation in vivo compared with treatment by unmodified chemotherapeutics. On the basis of these results, nanodiamond-mediated drug delivery may serve as a powerful method for overcoming chemoresistance in cancer stem cells and markedly improving overall treatment against hepatic cancers.

  5. Restoration of Radiation-Induced Damage Related to the Cell Cycle

    Energy Technology Data Exchange (ETDEWEB)

    Petrovic, D.; Ferle-Vidovic, Ana [Institute Ruder Boskovic, Zagreb, Yugoslavia (Croatia)

    1968-08-15

    A restorative effect of DNA and its precursors in asynchronously growing L-cells after X-irradiation had previously been found. The fact that the precursors were active only if all four of them were added in the form of an equimolar solution, as well as some other d ata, indicated that such treatment might support certain repair processes in the damaged metabolism of nucleic acids. To obtain more information on this problem, synchronized populations of L-cells were irradiated at different stages of the cell cycle with 500 R of X-rays and then treated with either highly polymerized DNA or with nucleotides or nucleosides. The survival of the treated and untreated cells was then calculated and compared. It was found that the cells were over ten times more sensitive in the DNA-synthetic (S) period than in the presynthetic (G{sub 1}) period. The restorative effect of all three materials was related to the S period. The highly polymerized DNA and the deoxytibonucleosides were much more effective than the deoxyribonucleotides. The results indicate that the influence of small molecules and the role they play in the damaged metabolism of nucleic acids could be of considerable importance in the mechanism of the restorative effect produced by nucleic-acid treatment. (author)

  6. Radiation-induced depression of DNA synthesis in cultured mammalian cells

    International Nuclear Information System (INIS)

    Povirk, L.F.

    1977-01-01

    A 313-nm light source was constructed in order to study the mechanisms by which ultraviolet and ionizing radiations inhibit DNA synthesis. It was found that in CHO, MDBK and HeLa cells, grown for one generation in the DNA sensitizer bromodeoxyuridine (BrdUrd), 313-nm light inhibited DNA synthesis with a pattern similar to that of the effect of x-rays on normal cells. A biphasic dose response curve for inhibition of total synthesis was observed, with a sensitive component representing depression of initiation of new replicons and a resistant component representing interference with elongation of replicons already growing at the time of irradiation. Since the BrdUrd plus 313-nm light treatment produces DNA lesions similar to those produced by x-rays (base damage, strand breaks, crosslinks) these results suggest that the effect of x-rays on DNA synthesis is mediated by DNA damage. In experiments with synchronized cells, it was found that in cells in which about half the chromosomes had incorporated BrdUrd, 313-nm light inhibited replication of the BrdUrd-containing DNA, but had no effect on the replication of the unsubstituted DNA in the same cell. Thus the information that DNA is damaged appears to be propagated along the DNA molecule from the sites of damage to the replication initiation sites as some kind of conformational change, possibly a relaxation of superhelical tension. Target theory calculations suggest that a single DNA lesion prevents the initiation of several adjacent replicons

  7. Stem cell therapy for the treatment of radiation-induced normal tissue damage

    International Nuclear Information System (INIS)

    Chapel, A.; Benderitter, M.; Gourmelon, P.; Lataillade, J.J.; Gorin, N.C.

    2013-01-01

    Radiotherapy may induce irreversible damage on healthy tissues surrounding the tumour. In Europe, per year, 1.5 million patients undergo external radiotherapy. Acute adverse effect concern 80% of patients. The late adverse effect of radiotherapy concern 5 to 10% of them, which could be life threatening. Eradication of these manifestations is crucial. The French Institute of Radioprotection and Nuclear Safety (IRSN) contribute to understand effect of radiation on healthy tissue. IRSN is strongly implicated in the field of regeneration of healthy tissue after radiotherapy or radiological accident and in the clinical use of cell therapy in the treatment of irradiated patients. Our first success in cell therapy was the correction of deficient hematopoiesis in two patients. The intravenous injection of Mesenchymal Stem Cells (MSC) has restored bone marrow micro-environment after total body irradiation necessary to sustain hematopoiesis. Cutaneous radiation reactions play an important role in radiation accidents, but also as a limitation in radiotherapy and radio-oncology. We have evidenced for the first time, the efficiency of MSC therapy in the context of acute cutaneous and muscle damage following irradiation in five patients. Concerning the medical management of gastrointestinal disorder after irradiation, we have demonstrated the promising approach of the MSC treatment. We have shown that MSC migrate to damaged tissues and restore gut functions after radiation damage. The evaluation of stem cell therapy combining different sources of adult stem cells is under investigation

  8. Hypoxia- and radiation-inducible, breast cell-specific targeting of retroviral vectors

    International Nuclear Information System (INIS)

    Lipnik, Karoline; Greco, Olga; Scott, Simon; Knapp, Elzbieta; Mayrhofer, Elisabeth; Rosenfellner, Doris; Guenzburg, Walter H.; Salmons, Brian; Hohenadl, Christine

    2006-01-01

    To facilitate a more efficient radiation and chemotherapy of mammary tumours, synthetic enhancer elements responsive to hypoxia and ionizing radiation were coupled to the mammary-specific minimal promoter of the murine whey acidic protein (WAP) encoding gene. The modified WAP promoter was introduced into a retroviral promoter conversion (ProCon) vector. Expression of a transduced reporter gene in response to hypoxia and radiation was analysed in stably infected mammary cancer cell lines and an up to 9-fold increase in gene expression demonstrated in comparison to the respective basic vector. Expression analyses in vitro, moreover, demonstrated a widely preserved mammary cell-specific promoter activity. For in vivo analyses, xenograft tumours consisting of infected human mammary adenocarcinoma cells were established in SCID/beige mice. Immunohistochemical analyses demonstrated a hypoxia-specific, markedly increased WAP promoter-driven expression in these tumours. Thus, this retroviral vector will facilitate a targeted gene therapeutic approach exploiting the unique environmental condition in solid tumours

  9. Molecular Mechanisms of Radiation-Induced Genomic Instability in Human Cells

    Energy Technology Data Exchange (ETDEWEB)

    Howard L. Liber; Jeffrey L. Schwartz

    2005-10-31

    There are many different model systems that have been used to study chromosome instability. What is clear from all these studies is that conclusions concerning chromosome instability depend greatly on the model system and instability endpoint that is studied. The model system for our studies was the human B-lymphoblastoid cell line TK6. TK6 was isolated from a spontaneously immortalized lymphoblast culture. Thus there was no outside genetic manipulation used to immortalize them. TK6 is a relatively stable p53-normal immortal cell line (37). It shows low gene and chromosome mutation frequencies (19;28;31). Our general approach to studying instability in TK6 cells has been to isolate individual clones and analyze gene and chromosome mutation frequencies in each. This approach maximizes the possibility of detecting low frequency events that might be selected against in mass cultures.

  10. Catalase inhibits ionizing radiation-induced apoptosis in hematopoietic stem and progenitor cells.

    Science.gov (United States)

    Xiao, Xia; Luo, Hongmei; Vanek, Kenneth N; LaRue, Amanda C; Schulte, Bradley A; Wang, Gavin Y

    2015-06-01

    Hematologic toxicity is a major cause of mortality in radiation emergency scenarios and a primary side effect concern in patients undergoing chemo-radiotherapy. Therefore, there is a critical need for the development of novel and more effective approaches to manage this side effect. Catalase is a potent antioxidant enzyme that coverts hydrogen peroxide into hydrogen and water. In this study, we evaluated the efficacy of catalase as a protectant against ionizing radiation (IR)-induced toxicity in hematopoietic stem and progenitor cells (HSPCs). The results revealed that catalase treatment markedly inhibits IR-induced apoptosis in murine hematopoietic stem cells and hematopoietic progenitor cells. Subsequent colony-forming cell and cobble-stone area-forming cell assays showed that catalase-treated HSPCs can not only survive irradiation-induced apoptosis but also have higher clonogenic capacity, compared with vehicle-treated cells. Moreover, transplantation of catalase-treated irradiated HSPCs results in high levels of multi-lineage and long-term engraftments, whereas vehicle-treated irradiated HSPCs exhibit very limited hematopoiesis reconstituting capacity. Mechanistically, catalase treatment attenuates IR-induced DNA double-strand breaks and inhibits reactive oxygen species. Unexpectedly, we found that the radioprotective effect of catalase is associated with activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway and pharmacological inhibition of STAT3 abolishes the protective activity of catalase, suggesting that catalase may protect HSPCs against IR-induced toxicity via promoting STAT3 activation. Collectively, these results demonstrate a previously unrecognized mechanism by which catalase inhibits IR-induced DNA damage and apoptosis in HSPCs.

  11. Radiation-induced dissociation of stable DNA-protein complexes in Erlich ascites carcinoma cells

    International Nuclear Information System (INIS)

    Juhasz, P.P.; Sirota, N.P.; Gaziev, A.I.

    1982-01-01

    DNA of Ehrlich ascites carcinoma cells prepared under conditions that were highly denaturing for proteins but not for DNA, contained a group of nonhistone residual proteins. The amount of these proteins increased during DNA replication. The DNA-protein complex observed was sensitive to proteolytic enzymes and/or SH-reagents. γ-irradiation cells with moderate doses leads to a decrease in the amount of DNA-protein complexes. High-dose gamma-irradiation produces enhanced linking of chromosomal proteins with DNA. (author)

  12. Radiation-induced inheritable changes in the death-rate of cells

    International Nuclear Information System (INIS)

    Bychkovskaya, I.B.; Ochinskaya, G.K.

    1980-01-01

    By the use of an original technique (regeneration of individual lines from sister cells) it was demonstrated on various individually cultivated protozoa (Amoeba proteus, Paramecium caudatum and Climacostomum virens) that even weak direct and indirect radiation effects can induce an appreciable increase in the death-rate of descendants. After a certain dose threshold, the effect did not depend on the power of the attack and remained at the same level for as long as 3 years. The observed changes were qualitatively different from known types of inheritable changes leading to cell death

  13. Stimulation of murine stem cell proliferation by circulating activities produced during the recovery of a radiation-induced hemopoietic injury

    International Nuclear Information System (INIS)

    Grande Azanedo, M.T.

    1988-01-01

    The proliferative activity of CFU-S, low in normal steady state, increases after treatment with different aggressors, i.e. radiation. This stimulation has been attributed in part to a local regulation system of stem cell proliferation, and at least in part to a humoral regulatory system. In the present work it has been investigated the role that circulating activities have in the CFU- S stimulation, by means of in vitro and in vivo incubation assays with diffusion chambers. The results show that bone marrow of mice irradiated with 5 Gy produces in vitro diffusible activities capable of stimulating the CFU-S proliferation. As well with this same dose circulating activities are also produced in vivo. In addition we have observed that these activities are only released during the periods of active hemopoietic regeneration that follow irradiation with moderate doses (1.5 and 5 Gy). In another set of experiments we saw that the stimulating activities are also detected in serum of mice irradiated with 5 Gy. These serum activities modify the proliferative state of very primitive precursors (12 d CFU-S). When the serum activities are added to long term bone marrow cultures the CFU-S) are also stimulated to proliferate. Finally, we observed that the radiation-induced serum activities stimulate the proliferation of bone marrow CFU-S when injected into normal mice, suggesting that such activities are involved in the regulation of CFU-S proliferation. (Author)

  14. Influence of radiation-induced grafting process on mechanical properties of ETFE-based membranes for fuel cells

    Energy Technology Data Exchange (ETDEWEB)

    Ben Youcef, H.; Alkan Guersel, S.; Buisson, A.; Gubler, L.; Wokaun, A.; Scherer, G.G. [Electrochemistry Laboratory, Paul Scherrer Institut, Villigen PSI (Switzerland)

    2010-06-15

    The mechanical stability is, in addition to thermal and chemical stability, a primary requirement of polymer electrolyte membranes in fuel cells. In this study, the impact of grafting parameters and preparation steps on stress-strain properties of ETFE-based proton conducting membranes, prepared by radiation-induced grafting and subsequent sulphonation, was studied. No significant change in the mechanical properties of the ETFE base film was observed below an irradiation dose of 50 kGy. It was shown that the elongation at break decreases with increasing both the crosslinker concentration and graft level (GL). However, the tensile strength was positively affected by the crosslinker concentration. Yield strength and modulus of elasticity are almost unaffected by the introduction of crosslinker. Interestingly, yield strength and modulus of elasticity increase gradually with GL without noticeable change of the inherent crystallinity of grafted films. The most brittle membranes are obtained via the combination of high GL and crosslinker concentration. The optimised ETFE-based membrane (GL of {proportional_to}25%, 5% DVB v/v), shows mechanical properties superior to those of Nafion registered 112 membrane. The obtained results were correlated qualitatively to the other ex situ properties, including crystallinity, thermal properties and water uptake of the grafted membranes. (Abstract Copyright [2010], Wiley Periodicals, Inc.)

  15. Radiation-induced chromosomal instability

    International Nuclear Information System (INIS)

    Ritter, S.

    1999-01-01

    Recent studies on radiation-induced chromosomal instability in the progeny of exposed mammalian cells were briefly described as well as other related studies. For the analysis of chromosomal damage in clones, cells were seeded directly after exposure in cell well-dish to form single cell clones and post-irradiation chromosome aberrations were scored. Both exposure to isoeffective doses of X-ray or 270 MeV/u C-ions (13 keV/μm) increased the number of clones with abnormal karyotype and the increase was similar for X-ray and for C-ions. Meanwhile, in the progeny of cells for mass cultures, there was no indication of a delayed expression of chromosomal damage up to 40 population doublings after the exposure. A high number of aberrant cells were only observed directly after exposure to 10.7 MeV/u O-ions, i.e. in the first cycle cells and decreased with subsequent cell divisions. The reason for these differences in the radiation-induced chromosomal instability between clonal isolates and mass culture has not been clarified. Recent studies indicated that genomic instability occurs at a high frequency in the progeny of cells irradiated with both sparsely and densely ionizing radiation. Such genomic instability is thought likely to increase the risk of carcinogenesis, but more data are required for a well understanding of the health risks resulting from radiation-induced delayed instability. (M.N.)

  16. Stem cell targets and dosimetry for radiation-induced leukaemia and bone cancer

    International Nuclear Information System (INIS)

    Richardson, R.B.

    2007-01-01

    The ICRP are proposing changes to the assumed targets for the induction of bone cancer and leukaemias as described by Harrison et al in an accompanying article. This study of radiation targets in the skeleton finds that the endosteum of the long bone medullary cavities is not an important target, especially in the adult, as it supports a very low stem cell population associated with high adiposity, whereas the periosteum has a strong mesenchymal stem cell population throughout lifetime. Quiescent stem cells are found to be preferentially located close to the trabecular bone surface in the osteoblastic niche, whereas progenitors of stem cells prefer to reside in perivascular niches. Evidence is given in support of the suggestion that the absence of excess bone-cancer in atomic bomb survivors may be related to the extremely low prevalence of Paget's disease in Japan. The hypoxic conditions of the endosteum adjacent to quiescent bone surfaces provide a radioprotective stem cell microenvironment by a factor of 2-3 fold, whereas greater radiosensitivity is prevalent in the young and individuals with benign diseases of bone. Increasing the volume of the bone cancer target from a 10 μm thick endosteum to a 50 μm peripheral marrow layer will result in an approximately three-fold decline in the mean dose from alpha-emitters in bone. These new observations are shown to go some way in explaining the low incidences for leukaemia and especially bone cancer in radium dial painters, Thorotrast patients and Mayak nuclear workers. (author)

  17. SIGN-R1 and complement factors are involved in the systemic clearance of radiation-induced apoptotic cells in whole-body irradiated mice

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jin-Yeon; Loh, SoHee; Cho, Eun-hee [Department of Biomedical Science & Technology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul, 143-701 (Korea, Republic of); Choi, Hyeong-Jwa [Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, 215-4, 75 Nowon gil Nowon-Gu, Seoul, 139-706 (Korea, Republic of); Na, Tae-Young [College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-741 (Korea, Republic of); Nemeno, Judee Grace E.; Lee, Jeong Ik [Regenerative Medicine Laboratory, Department of Veterinary Medicine, College of Veterinary Medicine, Konkuk University, Seoul, 143-701 (Korea, Republic of); Yoon, Taek Joon [Department of Food and Nutrition, Yuhan College, Bucheon, Gyeonggi-do, 422-749 (Korea, Republic of); Choi, In-Soo [Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul, 143-701 (Korea, Republic of); Lee, Minyoung [Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, 215-4, 75 Nowon gil Nowon-Gu, Seoul, 139-706 (Korea, Republic of); Lee, Jae-Seon [Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, 400-712 (Korea, Republic of); Kang, Young-Sun, E-mail: kangys1967@naver.com [Department of Biomedical Science & Technology, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul, 143-701 (Korea, Republic of); Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University, 1 Hwayang-dong, Gwangjin-gu, Seoul, 143-701 (Korea, Republic of)

    2015-08-07

    Although SIGN-R1-mediated complement activation pathway has been shown to enhance the systemic clearance of apoptotic cells, the role of SIGN-R1 in the clearance of radiation-induced apoptotic cells has not been characterized and was investigated in this study. Our data indicated that whole-body γ-irradiation of mice increased caspase-3{sup +} apoptotic lymphocyte numbers in secondary lymphoid organs. Following γ-irradiation, SIGN-R1 and complements (C4 and C3) were simultaneously increased only in the mice spleen tissue among the assessed tissues. In particular, C3 was exclusively activated in the spleen. The delayed clearance of apoptotic cells was markedly prevalent in the spleen and liver of SIGN-R1 KO mice, followed by a significant increase of CD11b{sup +} cells. These results indicate that SIGN-R1 and complement factors play an important role in the systemic clearance of radiation-induced apoptotic innate immune cells to maintain tissue homeostasis after γ-irradiation. - Highlights: • Splenic SIGN-R1{sup +} macrophages are activated after γ-irradiation. • C3 and C4 levels increased and C3 was activated in the spleen after γ-irradiation. • SIGN-R1 mediated the systemic clearance of radiation-induced apoptotic cells in spleen and liver.

  18. SIGN-R1 and complement factors are involved in the systemic clearance of radiation-induced apoptotic cells in whole-body irradiated mice

    International Nuclear Information System (INIS)

    Park, Jin-Yeon; Loh, SoHee; Cho, Eun-hee; Choi, Hyeong-Jwa; Na, Tae-Young; Nemeno, Judee Grace E.; Lee, Jeong Ik; Yoon, Taek Joon; Choi, In-Soo; Lee, Minyoung; Lee, Jae-Seon; Kang, Young-Sun

    2015-01-01

    Although SIGN-R1-mediated complement activation pathway has been shown to enhance the systemic clearance of apoptotic cells, the role of SIGN-R1 in the clearance of radiation-induced apoptotic cells has not been characterized and was investigated in this study. Our data indicated that whole-body γ-irradiation of mice increased caspase-3 + apoptotic lymphocyte numbers in secondary lymphoid organs. Following γ-irradiation, SIGN-R1 and complements (C4 and C3) were simultaneously increased only in the mice spleen tissue among the assessed tissues. In particular, C3 was exclusively activated in the spleen. The delayed clearance of apoptotic cells was markedly prevalent in the spleen and liver of SIGN-R1 KO mice, followed by a significant increase of CD11b + cells. These results indicate that SIGN-R1 and complement factors play an important role in the systemic clearance of radiation-induced apoptotic innate immune cells to maintain tissue homeostasis after γ-irradiation. - Highlights: • Splenic SIGN-R1 + macrophages are activated after γ-irradiation. • C3 and C4 levels increased and C3 was activated in the spleen after γ-irradiation. • SIGN-R1 mediated the systemic clearance of radiation-induced apoptotic cells in spleen and liver

  19. Radiation-induced changes in cell proliferation kinetics in uterine cervix cancer

    Energy Technology Data Exchange (ETDEWEB)

    Siracka, E; Siracky, J; Pappova, N [Slovenska Akademia Vied, Bratislava (Czechoslovakia). Cancer Research Inst.; Schreiner, P [Komenskeho Univ., Bratislava (Czechoslovakia). Chair of Oncology and Radiology

    1979-06-01

    In vitro double labeling autoradiography for measuring the labeling index, duration of S phase and potential doubling time has been used to assess the effect of a single and fractionated test dose of irradiation in uterine cervix cancer applied in 21 patients. Tumor-labeling index fell significantly in those tumors which had a high labeling index before irradiation, and these cases were found later to exhibit a good radiation response. Duration of S phase which ranged between 9 and 27 hours prior to irradiation was increased. Differences between the potential doubling time and the actual doubling time suggest a massive cell loss in tumors which were, for the most part, of exophytic type. Fractionated irradiation provides more reliable informations than a single dose and is useful for investigation of dynamic changes in the kinetics of an asynchronous cell population.

  20. The effect of 2-[(aminopropyl)amino] ethanethiol (WR 1065) on radiation-induced DNA damage and repair and cell progression in V79 cells

    International Nuclear Information System (INIS)

    Grdina, D.J.; Nagy, B.

    1986-01-01

    The radioprotector 2-[(aminopropyl)amino] ethanethiol (WR 1065) was investigated with respect to its ability to affect radiation-induced DNA damage and repair in V79 cells. At a concentration of 4mM, WR 1065 protected against the formation of single strand breaks (SSB), when present during irradiation. The protector appeared, however, to inhibit the subsequent postirradiation repair or rejoining of SSB. While repair was complete within 24h, the protector reduced the rate of repair by a factor of 3. This inhibitory effect on the rate of repair did not correlate with either measured differences in cell survival or mutagenesis. WR 1065 present in the growth medium inhibited the progression of cells through S-phase, and cell-doubling time following a 3h exposure to the protector was increased from 11 to 18h. These data are consistent with the property of thiols to inhibit DNA polymerase activity. It was concluded that, while the presence of WR 1065 during irradiation reduced SSB-DNA damage, its effect on the subsequent rejoining of these breaks could not be correlated with its observed effect on protecting against radiation-induced mutagenesis. (author)

  1. Radiation-induced cell mutations as a function of dose rate

    International Nuclear Information System (INIS)

    Kiefer, J.

    1987-01-01

    A brief review of the data in the literature is presented and forms the background of the experimental data given by the author obtained with exponential long-term cultures of V79 hamster cells exposed over a period of up to 35 days to different dose rates of gamma radiation. The experimental results show that at a dose rate of 40 mGy/hour the number of induced mutations is reduced, - which is in agreement with literature data - , but a dose rate of less than 30 mGy/hour makes the induced mutations leap to a value clearly higher than those induced by acute irradiation. As in addition to the mutations recombination is a significant factor of the radiation risk, experiments with a heterozygotic yeast strain have been made, as there is to date no reliable mammalian cell system available for this kind of research. Long-term radiation exposure of the yeast cells over a period of six weeks drastically increased the rate of recombinations, to a value higher by a factor of about 4 than that induced by acute irradiation. (orig.) [de

  2. Lethality of radiation-induced chromosome aberrations in human tumour cell lines with different radiosensitivities.

    Science.gov (United States)

    Coco-Martin, J M; Ottenheim, C P; Bartelink, H; Begg, A C

    1996-03-01

    In order to find an explanation for the eventual disappearance of all chromosome aberrations in two radiosensitive human tumour cell lines, the type and stability of different aberration types was investigated in more detail. To classify the aberrations into unstable and stable types, three-colour fluorescence in situ hybridization was performed, including a whole-chromosome probe, a pancentromere probe, and a stain for total DNA. This technique enables the appropriate classification of the aberrations principally by the presence (stable) or not (unstable) of a single centromere per chromosome. Unstable-type aberrations were found to disappear within 7 days (several divisions) in the two radiosensitive and the two radioresistant tumour lines investigated. Stable-type aberrations were found to remain at an approximately constant level over the duration of the experiment (14 days; 8-10 divisions) in the two radioresistant lines. In contrast, the majority of these stable-type aberrations had disappeared by 14 days in the two radiosensitive lines. The previous findings of disappearance of total aberrations in radiosensitive cells was therefore not due to a reduced induction of stable-type aberrations, but the complete disappearance of cells with this aberration type. These results could not be explained by differences in apoptosis or G1 blocks. Two possible explanations for these unexpected findings involve non-random induction of unstable-type aberrations, or lethality of stable-type aberrations. The results suggest caution in the use of stable-type aberration numbers as a predictor for radiosensitivity.

  3. Radiation-induced senescence-like phenotype in proliferating and plateau-phase vascular endothelial cells

    International Nuclear Information System (INIS)

    Igarashi, Kaori; Sakimoto, Ippei; Kataoka, Keiko; Ohta, Keisuke; Miura, Masahiko

    2007-01-01

    The effects of ionizing radiation (IR) on tumor angiogenesis still remain largely unknown. In this study, we found that IR (8 Gy) induces a high-frequency (80-90%) senescence-like phenotype in vascular endothelial cells (ECs) undergoing exponential growth. This finding allowed us to characterize the IR-induced senescence-like (IRSL) phenotype by examining the gene expression profiles and in vitro angiogenic activities of these ECs. The expression levels of genes associated with cell cycle progression and DNA replication were remarkably reduced in the IRSL ECs. Additionally, the in vitro invasion and migration activities of these cells through Matrigel were significantly suppressed. We also found that confluent ECs exhibited a high-frequency IRSL phenotype when they were replated immediately after irradiation, whereas incubation in plateau-phase conditions reduced the induction of this phenotype and enhanced colony formation. The kinetics of DNA double-strand break repair, which showed a faster time course in confluent ECs than in growing ECs, may contribute to the protective mechanism associated with the IRSL phenotype. These results imply that the IRSL phenotype may be important for determining the angiogenic activity of ECs following irradiation. The present study should contribute to the understanding of the effects of IR on tumor angiogenesis

  4. Radiation-induced alterations in murine lymphocyte homing patterns. II. Recovery and function of memory cells in LBN rats

    International Nuclear Information System (INIS)

    Crouse, D.A.; Feldbush, T.L.; Evans, T.C.

    1978-01-01

    Suspensions of lymph node cells from dinitrophenylated bovine gamma globulin (DNP-BGG)-immune LBN F 1 hybrid rats (Lewis X Brown Norway) were prepared, irradiated, and injected intravenously into unirradiated syngeneic intermediate hosts and irradiated syngeneic adoptive controls. After allowance of 24 hr for homing to occur, the intermediate hosts were killed and cell preparations from the lymph nodes and spleen were injected intravenously into separate irradiated LBN final host groups. All control and experimental groups were challenged (DNP-BGG saline iv) 24 hr after the injection of the lymphoid cells. Rats were bled on Days 7, 11, and 14 after challenge and the antigen-binding capacity (ABC) of the serum was determined. After correction for the fraction of the total cell population transferred from the intermediate host, the peak ABC of the final hosts was related to the number of memory cells present. It was thus possible to determine the relative distribution of the memory cell population to the spleen and lymph nodes of the intermediate hosts. In the intermediate control animals, irradiated memory cells provided a secondary antibody response which was delayed but not suppressed when compared to unirradiated cells. In intermediate hosts, the homing of lymph node memory cells to the spleen and lymph nodes was significantly reduced by an exposure to 200 R of x radiation

  5. P53 Gene Mutation as Biomarker of Radiation Induced Cell Injury and Genomic Instability

    International Nuclear Information System (INIS)

    Mukh-Syaifudin

    2006-01-01

    Gene expression profiling and its mutation has become one of the most widely used approaches to identify genes and their functions in the context of identify and categorize genes to be used as radiation effect markers including cell and tissue sensitivities. Ionizing radiation produces genetic damage and changes in gene expression that may lead to cancer due to specific protein that controlling cell proliferation altered the function, its expression or both. P53 protein encoded by p53 gene plays an important role in protecting cell by inducing growth arrest and or cell suicide (apoptosis) after deoxyribonucleic acid (DNA) damage induced by mutagen such as ionizing radiation. The mutant and thereby dysfunctional of this gene was found in more than 50% of various human cancers, but it is as yet unclear how p53 mutations lead to neoplastic development. Wild-type p53 has been postulated to play a role in DNA repair, suggesting that expression of mutant forms of p53 might alter cellular resistance to the DNA damage caused by radiation. Moreover, p53 is thought to function as a cell cycle checkpoint after irradiation, also suggesting that mutant p53 might change the cellular proliferative response to radiation. P53 mutations affect the cellular response to DNA damage, either by increasing DNA repair processes or, possibly, by increasing cellular tolerance to DNA damage. The association of p53 mutations with increased radioresistance suggests that alterations in the p53 gene might lead to oncogenic transformation. Current attractive model of carcinogenesis also showed that p53 gene is the major target of radiation. The majority of p53 mutations found so far is single base pair changes ( point mutations), which result in amino acid substitutions or truncated forms of the p53 protein, and are widely distributed throughout the evolutionary conserved regions of the gene. Examination of p53 mutations in human cancer also shows an association between particular carcinogens and

  6. A comparative study of radiation induced DNA damage and repair in buccal cells and lymphocytes assessed by single cell gel electrophoresis (comet) assay

    International Nuclear Information System (INIS)

    Dhillon, V.S.; Fenech, M.

    2003-01-01

    Full text: During the past few years, there has been increasing interest in epithelial cells from buccal mucosa for genotoxicity evaluation of different chemical and/or physical agents. In the present study we used the buccal and sublingual epithelial cells to detect both inter- and intra-individual variation in radiation induced DNA damage and repair. For this purpose we used the single cell gel electrophoresis assay which over the years has gained wide spread acceptance as a simple, sensitive and reliable assay to measure genotoxicity related effects as well as kinetics of DNA repair. Buccal and sublingual epithelial cells from six individuals (3 male and 3 females; 35-45 years old) were collected. Cells were then irradiated for 0, 2 and 4 Gy doses using 137 Cs-source (5.58 Gy min-1). After irradiation the cells were either placed immediately on ice or incubated at 37 deg C for 2 1/2 hour to allow cellular repair. We also studied G0 and G1 lymphocytes from the same individuals to compare the radiation-induced DNA damage and repair potential with the two types of buccal cells. Baseline DNA damage rate was significantly greater (p < 0.001) in buccal (28.18%) and sublingual epithelial cells (30.66) as compared to G0 (22.02%) and G1 (21.46%) lymphocytes. Radiation-induced DNA damage in buccal (19.34%, 2Gy; 21.41%, 4 Gy) and sublingual epithelial cells (18.11% and 20.60%) was very similar and significantly lower than that observed in lymphocytes (29.76%, 56.77% for G0 and 32.66%, 59.32% for G1). The extent of DNA repair in buccal and sublingual epithelial cells was significantly lower than that observed in lymphocytes. The results for buccal and sublingual epithelial cells were highly correlated with each other (r 0.9541) as were those of G0 and G1 lymphocytes (r 0.9868). The results suggest a much reduced capacity for cellular repair in buccal and sublingual epithelial cells

  7. Radioprotective action of WR-1065 on radiation-induced DNA strand breaks in cultured Chinese hamster ovary cells

    International Nuclear Information System (INIS)

    Murray, D.; VanAnkeren, S.C.; Milas, L.; Meyn, R.E.

    1988-01-01

    We have examined the radioprotective effect of WR-1065 on cultured Chinese hamster ovary cells. The effects of the drug on the induction and rejoining of gamma-ray-induced DNA single-strand breaks (SSBs) and double-strand breaks (DSBs) were measured using alkaline (pH 12.1) and neutral (pH 7.0) elution, respectively. Molecular protection factors (PFs) calculated from these data allowed us to determine whether the degree of modification of strand breakage accurately predicted the PFs measured using the biological end point of cell survival. The drug did protect against the induction of both SSBs and DSBs, although to an extent that did not appear to fully account for the degree of radioprotection in terms of cell killing measured under identical conditions. It is therefore unlikely that radioprotection by WR-1065 occurs simply as a consequence of a general lowering of all types of gamma-ray-induced DNA lesions, and it is possible that the drug could differentially protect against the induction of subsets of these DNA lesions. The rate of SSB rejoining was retarded following preirradiation treatment of cells with WR-1065, but there was no effect on DSB rejoining. Postirradiation treatment with WR-1065 also appeared to retard SSB rejoining but without an accompanying effect on either DSB rejoining or cell survival; however, this effect was largely reversed by the addition of catalase and was, therefore, probably a result of H 2 O 2 generated by autoxidation of the drug. Based on these observations, it would appear that the molecular actions of aminothiol radioprotective compounds that lead to reduced cell killing are much more complex than previously thought

  8. Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury

    Science.gov (United States)

    Azzam, Edouard I.; Jay-Gerin, Jean-Paul; Pain, Debkumar

    2013-01-01

    Cellular exposure to ionizing radiation leads to oxidizing events that alter atomic structure through direct interactions of radiation with target macromolecules or via products of water radiolysis. Further, the oxidative damage may spread from the targeted to neighboring, non-targeted bystander cells through redox-modulated intercellular communication mechanisms. To cope with the induced stress and the changes in the redox environment, organisms elicit transient responses at the molecular, cellular and tissue levels to counteract toxic effects of radiation. Metabolic pathways are induced during and shortly after the exposure. Depending on radiation dose, dose-rate and quality, these protective mechanisms may or may not be sufficient to cope with the stress. When the harmful effects exceed those of homeostatic biochemical processes, induced biological changes persist and may be propagated to progeny cells. Physiological levels of reactive oxygen and nitrogen species play critical roles in many cellular functions. In irradiated cells, levels of these reactive species may be increased due to perturbations in oxidative metabolism and chronic inflammatory responses, thereby contributing to the long-term effects of exposure to ionizing radiation on genomic stability. Here, in addition to immediate biological effects of water radiolysis on DNA damage, we also discuss the role of mitochondria in the delayed outcomes of ionization radiation. Defects in mitochondrial functions lead to accelerated aging and numerous pathological conditions. Different types of radiation vary in their linear energy transfer (LET) properties, and we discuss their effects on various aspects of mitochondrial physiology. These include short and long-term in vitro and in vivo effects on mitochondrial DNA, mitochondrial protein import and metabolic and antioxidant enzymes. PMID:22182453

  9. Mechanisms of Low Dose Radiation-induced T helper Cell Function

    International Nuclear Information System (INIS)

    Gridley, Daila S.

    2008-01-01

    Exposure to radiation above levels normally encountered on Earth can occur during wartime, accidents such as those at Three Mile Island and Chernobyl, and detonation of 'dirty bombs' by terrorists. Relatively high levels of radiation exposure can also occur in certain occupations (low-level waste sites, nuclear power plants, nuclear medicine facilities, airline industry, and space agencies). Depression or dysfunction of the highly radiosensitive cells of the immune system can lead to serious consequences, including increased risk for infections, cancer, hypersensitivity reactions, poor wound healing, and other pathologies. The focus of this research was on the T helper (Th) subset of lymphocytes that secrete cytokines (proteins), and thus control many actions and interactions of other cell types that make up what is collectively known as the immune system. The Department of Energy (DOE) Low Dose Radiation Program is concerned with mechanisms altered by exposure to high energy photons (x- and gamma-rays), protons and electrons. This study compared, for the first time, the low-dose effects of two of these radiation forms, photons and protons, on the response of Th cells, as well as other cell types with which they communicate. The research provided insights regarding gene expression patterns and capacity to secrete potent immunostimulatory and immunosuppressive cytokines, some of which are implicated in pathophysiological processes. Furthermore, the photon versus proton comparison was important not only to healthy individuals who may be exposed, but also to patients undergoing radiotherapy, since many medical centers in the United States, as well as worldwide, are now building proton accelerators. The overall hypothesis of this study was that whole-body exposure to low-dose photons (gamma-rays) will alter CD4+ Th cell function. We further proposed that exposure to low-dose proton radiation will induce a different pattern of gene and functional changes compared to

  10. Regulatory T Cells Contribute to the Inhibition of Radiation-Induced Acute Lung Inflammation via Bee Venom Phospholipase A₂ in Mice.

    Science.gov (United States)

    Shin, Dasom; Lee, Gihyun; Sohn, Sung-Hwa; Park, Soojin; Jung, Kyung-Hwa; Lee, Ji Min; Yang, Jieun; Cho, Jaeho; Bae, Hyunsu

    2016-04-30

    Bee venom has long been used to treat various inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Previously, we reported that bee venom phospholipase A₂ (bvPLA₂) has an anti-inflammatory effect through the induction of regulatory T cells. Radiotherapy is a common anti-cancer method, but often causes adverse effects, such as inflammation. This study was conducted to evaluate the protective effects of bvPLA₂ in radiation-induced acute lung inflammation. Mice were focally irradiated with 75 Gy of X-rays in the lung and administered bvPLA₂ six times after radiation. To evaluate the level of inflammation, the number of immune cells, mRNA level of inflammatory cytokine, and histological changes in the lung were measured. BvPLA₂ treatment reduced the accumulation of immune cells, such as macrophages, neutrophils, lymphocytes, and eosinophils. In addition, bvPLA₂ treatment decreased inflammasome-, chemokine-, cytokine- and fibrosis-related genes' mRNA expression. The histological results also demonstrated the attenuating effect of bvPLA₂ on radiation-induced lung inflammation. Furthermore, regulatory T cell depletion abolished the therapeutic effects of bvPLA₂ in radiation-induced pneumonitis, implicating the anti-inflammatory effects of bvPLA₂ are dependent upon regulatory T cells. These results support the therapeutic potential of bvPLA₂ in radiation pneumonitis and fibrosis treatments.

  11. Low-dose radiation-induced adaptive response in bone marrow cells of mice

    International Nuclear Information System (INIS)

    Farooqi, Zeba; Kesavan, P.C.

    1993-01-01

    Using bone marrow cells of whole body irradiated mice, the cytogenetic adaptive response induced by low conditioning doses of gamma-rays was investigated. The conditioning doses (0.025 and 0.05 Gy) were given at a dose-rate of 1.67 Gy/min. The challenging dose of 1 Gy was given at a dose-rate of 0.045 Gy/s. The challenging dose was given at different time intervals after the conditioning dose. The time intervals between the conditioning dose and challenging dose were 2, 7.5, 13, 18.5 and 24 h. When the time interval between the conditioning dose and the challenging dose was 2 h, both conditioning doses (0.025 and 0.05 Gy) reduced the frequency of MNPCEs and chromosomal aberrations in the bone marrow cells. The data collected at different time intervals (7.5, 13, 18.5 h) reveal that the radioadaptive response persisted for a longer time when the lower conditioning dose (0.025 Gy) was given. With the higher conditioning dose (0.05 Gy), the radioadaptive response disappeared after a time interval of 13 h. When the time interval between the conditioning dose and the challenging doses was 18.5 or 24 h, only the lower conditioning dose appeared effective in inducing the radioadaptive response

  12. Chemo-thermotherapy for radiation-induced squamous cell carcinoma in anterior chest wall

    Energy Technology Data Exchange (ETDEWEB)

    Kodama, Ken; Doi, Osamu; Higashiyama, Masahiko; Yokouchi, Hideki; Noguchi, Shinzaburo; Koyama, Hiroki (Osaka Prefectural Center for Adult Diseases (Japan))

    1992-09-01

    A 62 years-old woman had visited our hospital with the large and deep ulcer formation on the left anterior chest wall. A biopsy of the ulcerous lesion established the diagnosis of a squamous cell carcinoma which might be induced by the irradiation after mastectomy. Although a wide resection of the chest wall including left arm was performed, it was impossible to resect completely. After then, she had operations for local recurrence three times in three years. However, cure was not obtained, and residual lesions gradually enlarged and all layers of the anterior chest wall were replaced with tumor tissues. Conventional chemotherapy using futraful and mytomycin C was not effective. Therefore, we tried combined therapy with intravenous administration of cisplatin (CDDP) and vindesine (VDS), and local hyperthermia using radiofrequency (RF) wave. A total number of 11 courses of this treatment modality was carried out at once a week intervals. The tumor-temperature was maintained at the range of 40-43degC for 40 min in each treatment session. Chemotherapeutic agents were administered simultaneously with hyperthermia. After these treatment, the recurrent tumor was markedly reduced, and epithelization of the ulcer was recognized from the surrounding normal skin. The residual tumor was then resected completely. The operative wound was successfully closed by surrounding normal tissue mobilization. She is in good postoperative condition. We concluded that the chemo-thermotherapy is safe and promising therapeutic modality for such invasive squamous cell carcinoma, and the normal tissues are not affected. Furthermore, this approach will expand the scope of radical resection for such an uncontrollable tumor. (author).

  13. Chemo-thermotherapy for radiation-induced squamous cell carcinoma in anterior chest wall

    International Nuclear Information System (INIS)

    Kodama, Ken; Doi, Osamu; Higashiyama, Masahiko; Yokouchi, Hideki; Noguchi, Shinzaburo; Koyama, Hiroki

    1992-01-01

    A 62 years-old woman had visited our hospital with the large and deep ulcer formation on the left anterior chest wall. A biopsy of the ulcerous lesion established the diagnosis of a squamous cell carcinoma which might be induced by the irradiation after mastectomy. Although a wide resection of the chest wall including left arm was performed, it was impossible to resect completely. After then, she had operations for local recurrence three times in three years. However, cure was not obtained, and residual lesions gradually enlarged and all layers of the anterior chest wall were replaced with tumor tissues. Conventional chemotherapy using futraful and mytomycin C was not effective. Therefore, we tried combined therapy with intravenous administration of cisplatin (CDDP) and vindesine (VDS), and local hyperthermia using radiofrequency (RF) wave. A total number of 11 courses of this treatment modality was carried out at once a week intervals. The tumor-temperature was maintained at the range of 40-43degC for 40 min in each treatment session. Chemotherapeutic agents were administered simultaneously with hyperthermia. After these treatment, the recurrent tumor was markedly reduced, and epithelization of the ulcer was recognized from the surrounding normal skin. The residual tumor was then resected completely. The operative wound was successfully closed by surrounding normal tissue mobilization. She is in good postoperative condition. We concluded that the chemo-thermotherapy is safe and promising therapeutic modality for such invasive squamous cell carcinoma, and the normal tissues are not affected. Furthermore, this approach will expand the scope of radical resection for such an uncontrollable tumor. (author)

  14. Patterns of x-radiation-induced Schwann cell development in spinal cords of immature rats

    International Nuclear Information System (INIS)

    Gilmore, S.A.; Heard, J.K.; Leiting, J.E.

    1983-01-01

    Schwann cells, Schwann cell myelin, and connective tissue components develop in the spinal cord of the immature rat following exposure to x-rays. For the purposes of this paper, these intraspinal peripheral nervous tissue constituents are referred to as IPNT. A series of investigations are in progress to elucidate factors related to the development of IPNT, and the present study is a light microscopic evaluation of the relationship between the amount of radiation administered (1,000-3,000R) to the lumbosacral spinal cord in 3-day-old rats and the incidence and distribution of IPNT at intervals up to 60 days postirradiation (P-I). The results showed that IPNT was present in only 33% of the rats exposed to 1,000R, whereas its presence was observed in 86% or more of those in the 2,000-, 2,500-, and 3,000R groups. The distribution of IPNT was quite limited in the 1,000R group, where it was restricted to the spinal cord-dorsal root junction and was found in only a few sections within the irradiated area. The distribution was more widespread with increasing amounts of radiation, and IPNT occupied substantial portions of the dorsal funiculi and extended into the dorsal gray matter in the 3,000R group. In all aR mals developing IPNT in the groups receiving 2,000R or more, the IPNT was present in essentially all sections from the irradiated area. Further studies will compare in detail spinal cords exposed to 1,000R in which IPNT is an infrequent, limited occurrence with those exposed to higher doses where IPNT occurs in a more widespread fashion in essentially all animals

  15. Radiation-induced functional damages in the regeneration system for the gastrointestinal epithelium cell and analysis of its nutritional modification

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Kazuhiko; Narita, Mayumi; Ogawa, Yuko; Shinohara, Kiyoko; Nakazawa, Yukiko; Yamada, Keiko [National Inst. of Health and Nutrition, Tokyo (Japan)

    2000-02-01

    It has been known that the stem cells of villus-crypt zone are highly sensitive to radiation exposure. In this study, radiation-induced damages in gastrointestinal cell regeneration system were investigated from an aspect of nutritional factors to clarify the damages in digestive functions caused by X-ray exposure and recovery from them. The activities of digestive enzymes in the small intestine after in vivo X-ray exposure at 100 Gy were determined. The sucrose activity in the upper intestine was gradually reduced to about a half 3 days after the exposure. This change pattern of activity was also observed in other regions in the intestine. This tendency was similar to that of trehalase activity, but the changes in alkaline phosphatase and leucine amino-peptidase activities were less than the above two enzymes. Therefore, time course changes of sucrose and trehalase pattern in the villus-crypt zone were monitored after radiation exposure. Either of the two enzyme activities was low in the crypt and gradually increased from the basement of villus to its top. These activities were dose-dependently reduced by X-ray exposure. Especially it was marked for trehalose activity. Moreover, the amounts of short-chain fatty acids such as acetic acid, propionic acid, butylic acid in the cecum were determined. Significant increases in acetic acid and propionic acid contents were fount at 1 or 2 days after the X-ray exposure. These increases in fatty acids contents were more distinctive in the animals that received forced and free administration of food than those that received free administration alone. The presence of food components in the intestine might be effective for protecting the mucous membrane regeneration from radiation exposure. (M.N.)

  16. Cellular therapy by mesenchymal stem cells in the gamma radiation-induced multi organ dysfunction syndrome

    International Nuclear Information System (INIS)

    Francois, S.; Mouiseddine, M.; Semont, A.; Frick, J.; Sache, A.; Thierry, D.; Voisin, P.; Gourmelon, P.; Chapel, A.; Gorin, N.C.

    2007-01-01

    Mesenchymal stem cells (M.S.C.) have been shown to migrate to various tissues. There is little information on the fate and potential therapeutic efficacy of the re infusion of M.S.C. following total body irradiation (T.B.I.). We addressed this question using human M.S.C. (h.M.S.C.) infused to non obese diabetic/severe combined immuno-deficient (N.O.D./S.C.I.D.) mice submitted to T.B.I.. Further, we tested the impact of additional local irradiation (A.L.I.) superimposed to T.B.I., as a model of accidental irradiation. N.O.D./S.C.I.D. mice were transplanted with h.M.S.C.. Group 1 was not irradiated before receiving h.M.S.C. infusion. Group 2 received only T.B.I. at a dose of 3.5 Gy, group 3 received local irradiation to the abdomen at a dose of 4.5 Gy in addition to T.B.I., and group 4 received local irradiation to the leg at 26.5 Gy in addition to T.B.I.. Fifteen days after gamma irradiation, quantitative and spatial distribution of the h.M.S.C. were studied. Histological analysis of mouse tissues confirmed the presence of radio-induced lesions in the irradiated fields. Following their infusion into nonirradiated animals, h.M.S.C. homed at a very low level to various tissues (lung, bone marrow, and muscles) and no significant engraftment was found in other organs. T.B.I. induced an increase of engraftment levels of h.M.S.C. in the brain, heart, bone marrow, and muscles. Abdominal irradiation (A.I.) as compared with leg irradiation (L.I.) increased h.M.S.C. engraftment in the exposed area (the gut, liver, and spleen). Comparison of two local irradiations has shown that (L.I.) as compared with (A.I.) increased h.M.S.C. engraftment in the exposed area. An increase of h.M.S.C. engraftment in organs outside the fields of the A.L.I. was also observed. Conversely, following L.I., h.M.S.C. engraftment was increased in the brain as compared with A.I.. This study shows that engraftment of h.M.S.C. in N.O.D./ S.C.I.D. mice with significantly increased in response to tissue

  17. F-box protein FBXO31 is a dedicated checkpoint protein to facilitate cell cycle arrest through activation of regulators in radiation induced DNA damage

    International Nuclear Information System (INIS)

    Santra, Manas Kumar

    2017-01-01

    In response to radiation-induced DNA damage, eukaryotic cells initiate a complex signalling pathway, termed the DNA damage response (DDR), which coordinates cell cycle arrest with DNA repair. Previous study showed that induction of G1 arrest in response to radiation induced DNA damage is minimally a two-step process: a fast p53-independent initiation of G1 arrest mediated by cyclin D1 proteolysis and a slower maintenance of arrest resulting from increased p53 stability. We elucidated the molecular mechanism of slow and fast response of radiation induced DDR. We showed that FBXO31, a member of F-box family proteins, plays important role in DDR induced by ionizing radiation. We show that FBXO31 is responsible for promoting MDM2 degradation following radiation. FBXO31 interacts with and directs the degradation of MDM2 in ATM dependent phosphorylation of MDM2. FBXO31-mediated loss of MDM2 leads to elevated levels of p53, resulting in growth arrest. In cells depleted of FBXO31, MDM2 is not degraded and p53 levels do not increase following genotoxic stress. Thus, FBXO31 is essential for the classic robust increase in p53 levels following DNA damage

  18. Dasatinib blocks cetuximab- and radiation-induced nuclear translocation of the epidermal growth factor receptor in head and neck squamous cell carcinoma

    International Nuclear Information System (INIS)

    Li Chunrong; Iida, Mari; Dunn, Emily F.; Wheeler, Deric L.

    2010-01-01

    Background and purpose: The aberrant expression of epidermal growth factor receptor (EGFR) has been linked to the etiology of head and neck squamous cell carcinoma (HNSCC). The first major phase III trial combining cetuximab with radiation confirmed a strong survival advantage. However, both cetuximab and radiation can promote EGFR translocation to the nucleus where it enhances resistance to both of these modalities. In this report we sought to determine how to block cetuximab- and radiation-induced translocation of EGFR to the nucleus in HNSCC cell lines. Material and methods: We utilized three established HNSCC cell lines, SCC1, SCC6 and SCC1483 and measured nuclear translocation of EGFR after treatment with cetuximab or radiation. We then utilized dasatinib (BMS-354825), a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src family kinases, to determine if SFKs blockade could abrogate cetuximab- and radiation-induced nuclear EGFR translocation. Results: Cetuximab and radiation treatment of all three HNSCC lines lead to translocation of the EGFR to the nucleus. Blockade of SFKs abrogated cetuximab- and radiation-induced EGFR translocation to the nucleus. Conclusions: The data presented in this report suggest that both cetuximab and radiation can promote EGFR translocation to the nucleus and dasatinib can inhibit this process. Collectively these findings may suggest that dasatinib can limit EGFR translocation to the nucleus and may enhance radiotherapy plus cetuximab in HNSCC.

  19. Increased radiation-induced transformation in C3H/10T1/2 cells after transfer of an exogenous c-myc gene

    International Nuclear Information System (INIS)

    Sorrentino, V.; Drozdoff, V.; Zeitz, L.; Fleissner, E.

    1987-01-01

    C3H/10T 1/2 cells were infected with a retroviral vector expressing a mouse c-myc oncogene and a drug-selection marker. The resulting cells, morphologically indistinguishable from C3H/10T l/1, displayed a greatly enhanced sensitivity to neoplastic transformation by ionizing radiation or by a chemical carcinogen. Constitutive expression of myc therefore appears to synergize with an initial carcinogenic event, providing a function analogous to a subsequent event that apparently is required for the neoplastic transformation of these cells. This cell system should prove useful in exploring early stages in radiation-induced transformation

  20. Radiation-induced DNA Double Strand Breaks and Their Modulations by Treatments with Moringa oleifera Lam. Leaf Extracts: A Cancer Cell Culture Model

    International Nuclear Information System (INIS)

    Boonsirichai, K.; Jetawattana, S.

    2014-01-01

    Gamma radiation brings deleterious effects upon human cells by inducing oxidative stress and DNA damages. Antioxidants have been shown to confer protective effects on irradiated normal cells. Moringa oleifera Lam. is a widely used nutritional supplement with antioxidant activities. This report showed that antioxidant-containing supplements, in addition to protecting normal cells, could protect cancer cells against genotoxic effects of gamma radiation. γ-H2AX immunofluorescent foci were utilized as an indicator of radiation-induced DNA double strand breaks. MCF-7 human breast adenocarcinoma cells were irradiated with 2-8 Gy gamma radiation. A linear relationship between the formation of γ-H2AX foci and radiation dose was observed with an average of 10 foci per cell per Gy. A 30-minute pretreatment of the cells with either the aqueous or the ethanolic extract of M. oleifera leaves could partially protect the cells from radiation-induced DNA double strand breaks. A pretreatment with 500 µg/mL aqueous extract reduced the number of foci formed by 15% when assayed at 30 minutes post-irradiation. The ethanolic extract was more effective; 500 µg/mL of its concentration reduced the number of foci among irradiated cells by 30%. The results indicated that irradiated cancer cells responded similarly to nutritional supplements containing antioxidants as irradiated normal cells. These natural antioxidants could confer protective effects upon cancer cells against gamma radiation. (author)

  1. Radiation-induced DNA Double Strand Breaks and Their Modulations by Treatments with Moringa oleifera Lam. Leaf Extracts: A Cancer Cell Culture Model

    Directory of Open Access Journals (Sweden)

    K. Boonsirichai

    2014-04-01

    Full Text Available Gamma radiation brings deleterious effects upon human cells by inducing oxidative stress and DNA damages. Antioxidants have been shown to confer protective effects on irradiated normal cells. Moringa oleifera Lam. is a widely used nutritional supplement with antioxidant activities. This report showed that antioxidant-containing supplements, in addition to protecting normal cells, could protect cancer cells against genotoxic effects of gamma radiation. -H2AX immunofluorescent foci were utilized as an indicator of radiation-induced DNA double strand breaks. MCF-7 human breast adenocarcinoma cells were irradiated with 2-8 Gy gamma radiation. A linear relationship between the formation of -H2AX foci and radiation dose was observed with an average of 10 foci per cell per Gy. A 30-minute pretreatment of the cells with either the aqueous or the ethanolic extract of M. oleifera leaves could partially protect the cells from radiation-induced DNA double strand breaks. A pretreatment with 500 µg/mL aqueous extract reduced the number of foci formed by 15% when assayed at 30 minutes post-irradiation. The ethanolic extract was more effective; 500 µg/mL of its concentration reduced the number of foci among irradiated cells by 30%. The results indicated that irradiated cancer cells responded similarly to nutritional supplements containing antioxidants as irradiated normal cells. These natural antioxidants could confer protective effects upon cancer cells against gamma radiation

  2. Gamma radiation induced oxidative stress and apoptosis inhibiting properties of bacterial secondary metabolite RK-IP-006.G in J774A.1 murine cell line

    International Nuclear Information System (INIS)

    Malhotra, Poonam; Gupta, Ashutosh K.; Singh, Praveen K.; Chhachhia, Neha; Singh, Shravan K.; Raj Kumar

    2014-01-01

    Redox imbalance due to radiation induced oxidation of vital bio-macromolecules activates inflammatory response cascade leading to cell death. In present study, bacterial secondary metabolite, RK-IP-006.G, was evaluated for its oxidative stress and apoptosis inhibiting activities in irradiated J774A.1 murine macrophage cell line. Radiation induced intracellular ROS generation and its inhibition upon RK-IP-006.G pretreatment was estimated using 2',7'dichlorodihydroflurescein diacetate (DCFDA). Modulation in mitochondrial membrane potential (MMP) in irradiated cells and its protection by RK-IP-006.G pretreatment was evaluated using Rhodamine-123. Modulation in protein expression in irradiated and RK-IP-006.G treated J774A.1 cells was assessed by SDS-PAGE. Compensatory effect of RK-IP-006.G treatment on TNF-α expression in irradiated cells was estimated using ELISA assay. APO-BrDU assay was performed to evaluate radiation-induced apoptosis in irradiated cells. Radiation-induced cell damage and protective ability of RK-IP-006.G was also evaluated using Differential Interference Contrast Microscopy. Results of the study indicated significant (p< 0.05) decrease in DCFDA fluorescence in irradiated cells that were pretreated (∼2h) with RK-IP-006.G (0.25 μg/ml) as compared to irradiated cells. Similarly, significant (p<0.05) decrease in MMP was observed in irradiated cells pretreated with RK-IP-006.G (0.25 μg/ml) as compared to only irradiated cells at 1 h time point. SDS-PAGE analysis clearly demonstrated up-regulation of some prominent proteins in irradiated cells pretreated with RK-IP-006.G at 2-4h after treatment as compared to irradiated control. Significant (p<0.05) down regulation in TNF-α expression was observed in irradiated cells that pretreated with RK-IP-006.G compared to irradiated controls. APO-BrDU assay revealed significant reduction in apoptosis in irradiated cells pretreated with RK-IP-006.G when compared to irradiated control. The findings

  3. Cell-permeable intrinsic cellular inhibitors of apoptosis protect and rescue intestinal epithelial cells from radiation-induced cell death

    International Nuclear Information System (INIS)

    Matsuzaki-Horibuchi, Shiori; Yasuda, Takeshi; Sakaguchi, Nagako; Yamaguchi, Yoshihiro; Akashi, Makoto

    2015-01-01

    One of the important mechanisms for gastrointestinal (GI) injury following high-dose radiation exposure is apoptosis of epithelial cells. X-linked inhibitor of apoptosis (XIAP) and cellular IAP2 (cIAP2) are intrinsic cellular inhibitors of apoptosis. In order to study the effects of exogenously added IAPs on apoptosis in intestinal epithelial cells, we constructed bacterial expression plasmids containing genes of XIAP (full-length, BIR2 domain and BIR3-RING domain with and without mutations of auto-ubiquitylation sites) and cIAP2 proteins fused to a protein-transduction domain (PTD) derived from HIV-1 Tat protein (TAT) and purified these cell-permeable recombinant proteins. When the TAT-conjugated IAPs were added to rat intestinal epithelial cells IEC6, these proteins were effectively delivered into the cells and inhibited apoptosis, even when added after irradiation. Our results suggest that PTD-mediated delivery of IAPs may have clinical potential, not only for radioprotection but also for rescuing the GI system from radiation injuries. (author)

  4. Radiation-induced phosphorylation of P53 protects radioresistant Spodoptera frugiperda 9 cells by suppressing microRNA-31-Bim-Bax mediated apoptosis

    International Nuclear Information System (INIS)

    Kumar, Ashish; Chandna, Sudhir

    2016-01-01

    In this study, we demonstrate the role of microRNA-31 (miR-31) in the regulation of radiation-induced apoptosis in model radioresistant insect cell line Sf9 (derived from the ovaries of insect Spodoptera frugiperda) which carries well-conserved apoptotic response. We also investigated the miR-31 expression regulation by p53 homologue in these cells. Our initial in silico analysis confirmed perfect conservation of mature miR-31 across various insect orders, hence we designed biotinylated probes from Bombyx mori sequence for successful detection of miR-31 in Sf9 cells

  5. Can dendritic cells improve whole cancer cell vaccines based on immunogenically killed cancer cells?

    Science.gov (United States)

    Cicchelero, Laetitia; Denies, Sofie; Devriendt, Bert; de Rooster, Hilde; Sanders, Niek N

    2015-01-01

    Immunogenic cell death (ICD) offers interesting opportunities in cancer cell (CC) vaccine manufacture, as it increases the immunogenicity of the dead CC. Furthermore, fusion of CCs with dendritic cells (DCs) is considered a superior method for generating whole CC vaccines. Therefore, in this work, we determined in naive mice whether immunogenically killed CCs per se (CC vaccine) elicit an antitumoral immune response different from the response observed when immunogenically killed CCs are associated with DCs through fusion (fusion vaccine) or through co-incubation (co-incubation vaccine). After tumor inoculation, the type of immune response in the prophylactically vaccinated mice differed between the groups. In more detail, fusion vaccines elicited a humoral anticancer response, whereas the co-incubation and CC vaccine mainly induced a cellular response. Despite these differences, all three approaches offered a prophylactic protection against tumor development in the murine mammary carcinoma model. In summary, it can be concluded that whole CC vaccines based on immunogenically killed CCs may not necessarily require association with DCs to elicit a protective anticancer immune response. If this finding can be endorsed in other cancer models, the manufacture of CC vaccines would greatly benefit from this new insight, as production of DC-based vaccines is laborious, time-consuming and expensive. PMID:26587315

  6. Radiation-induced transformation of SV40-immortalized human thyroid epithelial cells by single and fractionated exposure to γ-irradiation in vitro

    International Nuclear Information System (INIS)

    Riches, A.C.; Herceg, Z.; Bryant, P.E.; Wynford-Thomas, D.

    1994-01-01

    Radiation-induced transformation of a human thyroid epithelial cell line (HTori-3) has been investigated following exposure to single and fractionated doses of γ-irradiation. The human epithelial cells were irradiated in vitro and following passaging, transplanted to the athymic nude mouse. Following a single exposure to γ-irradiation in the range 0.5-4Gy, 22 tumours were observed in 45 recipients and following three equal fractions in the range 0.5-4Gy per fraction, 18 tumours were observed in 31 recipients. Tumours were undifferentiated carcinomas and were observed from 7 to 20 weeks after transplantation. They occurred after similar radiation doses to those received by the children in the Belarus region of Ukraine, who developed thyroid tumours. The number of tumours observed, in each group receiving cells irradiated with a single dose of γ-irradiation in the range 0.5-4 Gy, was similar. Cell lines were established from some tumours and the tumorigenicity confirmed by retransplantation. These tumour cell lines were more radiosensitive than the human thyroid epithelial cell line they were derived from. This indicates that transformed cells were not being selected from a subpopulation within the parent cell line but that radiation-induced transformants were being induced de novo. The human origin of the tumours was established by karyotyping, immunocytochemical demonstration of human epithelial cytokeratins and p53 analysis. DNA fingerprinting confirmed that the tumours were derived from the original cell line. (author)

  7. Radiobiology effects of radiation-induced horseradish peroxidase/indole-3-acetic suicide gene expression in lung cancer cells

    International Nuclear Information System (INIS)

    Xiong Jie; Zhou Yunfeng; Wang Weifeng; Sun Wenjie; Liao Zhengkai; Zhou Fuxiang; Xie Conghua

    2010-01-01

    Objective: To detect specific cell killing effect of radiation combined with horseradish peroxidase (HRP)/indole-3-acetic (IAA) suicide gene therapy controlled by a novel radio-inducible and cancer-specific chimeric gene promoter in lung cancer. Methods: We constructed a plasmid expressing HRP enzyme under the control of chimeric human telomerase reverse transcriptase (hTERT) promoter carrying 6 CArG elements, a plasmid expressing HRP enzyme under the control of hTERT promoter carrying single CArG element, and two control plasmids, which named pE6-hTERT-HRP, phTERT-HRP, pControl-HRP, and pControlluc, respectively. After radiation, the proliferation inhibition and apoptosis induction effect of each type of plasmid in lung cancer cells (A549, SPC-A1) and normal lung cells (hEL) was detected by cell counting and Annexin V-FITC staining. The change of radiosensitivity of lung cancer cells with plasmid system was also detected by clonogenic assays. Results: After a single dose radiation of 6 Gy,the average proliferation inhibition rates of pE6-hTERT-HRP, phTERT-HRP, pControl-HRP, and pControlluc systems were 72.92% ,40.60% , 51.00% and 25.19% (F= 67.31, P< 0.01) in A549 cells, 64.63%, 30.02%, 48.23% and 23.16% (F=64.94, P< 0.01) in SPC-A1 cells, and 20.81%, 18.05%, 44.20% and 18.32% (F=52.19, P<0.01) in normal hEL cells, respectively. The average early apoptosis rates of these four plasmid systems were 36.63%, 22.30%, 24.33% and 12.53% (F =50.99, P <0.01) in A549 cells, 33.73%, 17.37%, 22.43% and 11.20% (F = 20. 76, P < 0.01) in SPC-A1 cells, and 13.53 %, 12.5%, 21.93% and 12.16% (F = 15.08, P < 0.01) in normal hEL cells,respectively. The sensitizing enhancement ratios of the four plasmid systems were 3.45, 2.29, 3.05 and 1.21 in A549 cells, while 2.68, 2.15, 3.05 and 1.21 in SPC-A1 cells, respectively. Conclusions: The new suicide gene system controlled by chimeric promoter may provide a novel therapeutic modality for lung cancer. (authors)

  8. Radiation-induced instability of human genome

    International Nuclear Information System (INIS)

    Ryabchenko, N.N.; Demina, Eh.A.

    2014-01-01

    A brief review is dedicated to the phenomenon of radiation-induced genomic instability where the increased level of genomic changes in the offspring of irradiated cells is characteristic. Particular attention is paid to the problems of genomic instability induced by the low-dose radiation, role of the bystander effect in formation of radiation-induced instability, and its relationship with individual radiosensitivity. We believe that in accordance with the paradigm of modern radiobiology the increased human individual radiosensitivity can be formed due to the genome instability onset and is a significant risk factor for radiation-induced cancer

  9. Heritable factors for radiation-induced osteosarcoma and the role of Rb1 in telomere maintenance in mesenchymal stem cells

    International Nuclear Information System (INIS)

    Rosemann, M.; Gonzalez-Vasconcellos, I.; Atkinson, M. J.

    2013-01-01

    that protects them from age related genomic alterations is their ability to keep long telomeres throughout many rounds of cell division. This is facilitated by the expression of the enzyme telomerase, but also requires proper architecture of the telomere structure. In the present study we show first results on the influence of an Rb1+/- deficiency onto the growth kinetics and stability of mesenchymal stem cells (MSC), i.e. the precursors of all osteoblasts in the skeleton. We found that the MSCs from constitutive Rb1+/- mice exhibit a significantly reduced propensity to differentiate in-vitro and go into senescence. This project will focus on the genomic stability of MSCs, in particular in relation to the interaction of Rb1 deficiency and ionising irradiation in the development of secondary, radiation induced tumors. This might lead in the future to find a more optimized balance between therapeutic benefit and long-term risk in individual patients

  10. Differences in inhibition by beta-arabinofuranosyladenine (araA) of radiation induced DNA damage repair in exponentially growing and plateau-phase CHO-cells

    International Nuclear Information System (INIS)

    Iliakis, G.; Seaner, R.

    1988-01-01

    The effect of beta-arabinofuranosyladenine (araA) on the repair of radiation induced DNA damage, as measured by the DNA unwinding technique, was studied in exponentially growing and plateau-phase CHO-cells after exposure to X-rays. Induction of DNA damage by radiation was found to be similar in exponentially growing and plateau-phase cells. In the absence of araA, repair of radiation induced DNA damage proceeded with similar kinetics in exponentially growing and plateau-phase cells. AraA at concentrations between 0-1500 μM inhibited DNA repair both in exponentially growing and in plateau-phase cells. However, the degree of inhibition was significantly higher (by a factor of 3) in plateau-phase cells. A similar degree of repair inhibition by araA was observed in plateau-phase cells treated in their conditioned medium, as well as in plateau-phase cells that were transferred in fresh growth medium just before treatment initiation. These results indicate the importance of biochemical parameters associated with alterations in the growth state of the cells for the inhibitory effect of araA and may help in the elucidation of the molecular mechanism(s) underlying repair inhibition by inhibitors of DNA replication. (orig.)

  11. Comparison of two mathematical models for describing heat-induced cell killing

    International Nuclear Information System (INIS)

    Roti Roti, J.L.; Henle, K.J.

    1980-01-01

    A computer-based minimization algorithm is utilized to obtain the optimum fits of two models to hyperthermic cell killing data. The models chosen are the multitarget, single-hit equation, which is in general use, and the linear-quadratic equation, which has been applied to cell killing by ionizing irradiation but not to heat-induced cell killing. The linear-quadratic equation fits hyperthermic cell killing data as well as the multitarget, single-hit equation. Both parameters of the linear-quadratic equation obey the Arrhenius law, whereas only one of the two parameters of the multitarget, single-hit equation obeys the Arrhenius law. Thus the linear-quadratic function can completely define cell killing as a function of both time and temperature. In addition, the linear-quadratic model will provide a simplified approach to the study of the synergism between heat and X irradiation

  12. Cell killing and mutation induction on Chinese hamster cells by photoradiations

    International Nuclear Information System (INIS)

    Lam, C.K.C.

    1982-11-01

    Applying radiation directly on cells, far-uv is more effective than black light, and black light is more effective than white light in inducing proliferative death and in inducing resistance to 6-thioguanine (6-TG), ouabain and diptheria toxin (DT). Gold light has no killing and mutagenic effects on CHO (Chinese hamster ovary) cells. Use of filters showed that a small percentage of shorter wavelengths in the far-uv region is responsible for most of the killing and mutagenic effects in the unfiltered broad spectra of black and white light

  13. Cell killing and mutation induction on Chinese hamster cells by photoradiations

    Energy Technology Data Exchange (ETDEWEB)

    Lam, C.K.C.

    1982-11-01

    Applying radiation directly on cells, far-uv is more effective than black light, and black light is more effective than white light in inducing proliferative death and in inducing resistance to 6-thioguanine (6-TG), ouabain and diptheria toxin (DT). Gold light has no killing and mutagenic effects on CHO (Chinese hamster ovary) cells. Use of filters showed that a small percentage of shorter wavelengths in the far-uv region is responsible for most of the killing and mutagenic effects in the unfiltered broad spectra of black and white light.

  14. Protection of ionizing radiation-induced cytogenetic damage by hydroalcoholic extract of Cynodon dactylon in Chinese hamster lung fibroblast cells and human peripheral blood lymphocytes.

    Science.gov (United States)

    Rao, Bola Sadashiva Satish; Upadhya, Dinesh; Adiga, Satish Kumar

    2008-01-01

    The radiomodulatory potential of hydroalcoholic extract of a medicinal plant Cynodon dactylon (family: Poaceae) against radiation-induced cytogenetic damage was analyzed using Chinese hamster lung fibroblast (V79) cells and human peripheral blood lymphocytes (HPBLs) growing in vitro. Induction of micronuclei was used as an index of cytogenetic damage, evaluated in cytokinesis blocked binucleate cells. The hydroalcoholic Cynodon dactylon extract (CDE) rendered protection against the radiation-induced DNA damage, as evidenced by the significant (p<0.001) reduction in micronucleated binucleate cells (MNBNC%) after various doses of CDE treatment in V79 cells and HPBLs. The optimum dose of CDE (40 and 50 microg/ml in HPBLs and V79 cells, respectively) with the greatest reduction in micronuclei was further used in combination with various doses of gamma radiation (0.5, 1, 2, 3, and 4 Gy) exposed 1 h after CDE treatment. A linear dose-dependent MNBNC% increase in radiation alone group was observed, while 40/50 microg/ml CDE significantly resulted in the reduction of MNBNC%, compared to the respective radiation alone groups. CDE resulted in a dose-dependent increase in free radical scavenging ability against various free radicals, viz., 2, 2-diphenyl-2-picryl-hydrazyl (DPPH); 2, 2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS); superoxide anion (O2*-); hydroxyl radical (OH*) and nitric oxide radical (NO*) generated in vitro. Also, an excellent (70%) inhibition of lipid peroxidation in vitro was observed at a dose of 300 microg/ml CDE, attaining the saturation point at higher doses. The present findings demonstrated the radioprotective effect of CDE, also rendering protection against radiation-induced genomic instability and DNA damage. The observed radioprotective effect may be partly attributed to the free radical scavenging and antilipid peroxidative potential of CDE.

  15. A Review of Root Causes of SCC Phenomena in BWR/RBMK: An Overview of Radiation-Induced Long Cell Action Relevant to SCC

    International Nuclear Information System (INIS)

    Genn Saji

    2004-01-01

    The author suggests a new hypothetical mechanism: radiation-induced 'long cell action' may cause electrolytic corrosion. In this mechanism, SCC (stress corrosion cracking) results from auto-catalytic growth of cracks in crevice water chemistry that is kept acidic by a combination of hydration of cations released from crack tips. The acidic chemistry is maintained by radiation-induced 'long cell action' in pits which are maintained by a trans-passive corrosion process under a stress field. The pivotal point of the thesis is 'long cell action' which appears not to have been investigated in the nuclear community. It is because the reactor water used in BWR/RBMK systems has a very low electrical conductivity. For 'long cell action' to take place, there must be an unknown ion transport mechanism. One potential mechanism can be the high flow rate of the reactor water, carrying ionic species from the anode to the cathode. The other is the effective removal of ferrous ions by deposition as crud, which enhanced by the decomposition of H 2 O 2 . There are also some surprising similarities between SCC in the reactor systems and the basic mechanism of underground corrosion by long cell action. In this mechanism, the 'long cell action' is induced by a difference in availability of oxygen inside the soil. Conduction of electrons through an electric conductor over a long distance plays a significant role as they are released by dissolution of metallic ions and sucked up from the metal surface. (author)

  16. Radiation-induced genetic instability: no association with changes in radiosensitivity or cell cycle checkpoints in C3H 10T1/2 mouse fibroblasts

    International Nuclear Information System (INIS)

    Crompton, N.E.A.; Emery, G.C.; Shi Yuquan; Sigg, M.; Blattmann, H.

    1998-01-01

    We investigated various phenotypic characteristics of radiation-induced morphologically transformed C3H 10T1/2 mouse fibroblasts. The cells were treated with 8 Gy x-rays, and type II/III foci were isolated. Cell lines were developed from these foci, and subsequently clones were established from these focal lines. The clones were examined for DNA content, radiosensitivity and inducible cell cycle arrests. Besides the morphological changes associated with the transformed state, the major difference between the isolated focal lines or derived clones and the parental C3H 10T1/2 line was one of ploidy. The transformed cells often displayed aneuploid and multiple polyploid populations. No change in the radiosensitivity of the transformed cells was observed. Furthermore, the two major radiation- and staurosporine-induced G1 and G2 cell cycle arrests observed in the parental cell line were also observed in the morphological transformants, suggesting that checkpoint function was normal. (orig.)

  17. Multiple factors and processes involved in host cell killing by bacteriophage Mu: characterization and mapping.

    Science.gov (United States)

    Waggoner, B T; Marrs, C F; Howe, M M; Pato, M L

    1984-07-15

    The regions of bacteriophage Mu involved in host cell killing were determined by infection of a lambda-immune host with 12 lambda pMu-transducing phages carrying different amounts of Mu DNA beginning at the left end. Infecting lambda pMu phages containing 5.0 (+/- 0.2) kb or less of the left end of Mu DNA did not kill the lambda-immune host, whereas lambda pMu containing 5.1 kb did kill, thus locating the right end of the kil gene between approximately 5.0 and 5.1 kb. For the Kil+ phages the extent of killing increased as the multiplicity of infection (m.o.i.) increased. In addition, killing was also affected by the presence of at least two other regions of Mu DNA: one, located between 5.1 and 5.8 kb, decreased the extent of killing; the other, located between 6.3 and 7.9 kb, greatly increased host cell killing. Killing was also assayed after lambda pMu infection of a lambda-immune host carrying a mini-Mu deleted for most of the B gene and the middle region of Mu DNA. Complementation of mini-Mu replication by infecting B+ lambda pMu phages resulted in killing of the lambda-immune, mini-Mu-containing host, regardless of the presence or absence of the Mu kil gene. The extent of host cell killing increased as the m.o.i. of the infecting lambda pMu increased, and was further enhanced by both the presence of the kil gene and the region located between 6.3 and 7.9 kb. These distinct processes of kil-mediated killing in the absence of replication and non-kil-mediated killing in the presence of replication were also observed after induction of replication-deficient and kil mutant prophages, respectively.

  18. Increase in colony-forming efficiency in soft agar of thymus cells from radiation-induced thymomas of NIH Swiss mice

    Energy Technology Data Exchange (ETDEWEB)

    Mori, Nobuko; Takamori, Yasuhiko; Hori, Yasuharu [Radiation Center of Osaka Prefecture, Sakai (Japan)

    1982-03-01

    Colony-forming efficiency in soft agar of radiation-induced thymoma in NIH Swiss mice was determined in the presence of cultured medium of reticulo-epitherial cells from normal thymus of NIH Swiss mouse as conditioned medium. A similar experiment was done with thymomas spontaneously developed in AKR mice. Most of colonies developed in soft agar were not composed of thymic lymphoma cells, but of macrophage-like cells. The ratio of the number of colonies to that of the seeded cells significantly increased in thymomas comparing with that in normal thymus. This result corresponded with the increased number of macrophages in thymoma, as determined by counting phagocytic cells of adherent cells.

  19. 8-prenylnaringenin and tamoxifen inhibit the shedding of irradiated epithelial cells and increase the latency period of radiation-induced oral mucositis. Cell culture and murine model

    Energy Technology Data Exchange (ETDEWEB)

    Ryck, Tine de; Impe, Annouchka van; Bracke, Marc E. [Ghent University, Laboratory of Experimental Cancer Research, Department Radiation Oncology and Experimental Cancer Research, Ghent (Belgium); Vanhoecke, Barbara W. [Ghent University, Laboratory of Experimental Cancer Research, Department Radiation Oncology and Experimental Cancer Research, Ghent (Belgium); Ghent University, Laboratory of Microbial Ecology and Technology (LabMET), Ghent (Belgium); Heyerick, Arne [Ghent University, Laboratory of Pharmacognosy and Phytochemistry, Ghent (Belgium); Vakaet, Luc; Neve, Wilfried de [Ghent University Hospital, Department of Radiation Oncology, Ghent (Belgium); Mueller, Doreen [Medical Faculty and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Department of Radiotherapy and Radiation Oncology, OncoRay-National Center for Radiation Research in Oncology, Dresden (Germany); Schmidt, Margret [Medical Faculty and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Department of Radiotherapy and Radiation Oncology, OncoRay-National Center for Radiation Research in Oncology, Dresden (Germany); German Cancer Consortium (DKTK) partner site Dresden and German Cancer Center (DKFZ), Heidelberg (Germany); Doerr, Wolfgang [Medical Faculty and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Department of Radiotherapy and Radiation Oncology, OncoRay-National Center for Radiation Research in Oncology, Dresden (Germany); Medical University, Department of Radiation Oncology, CCC, and CD-Laboratory RadOnc, Vienna (Austria)

    2015-05-01

    The major component in the pathogenesis of oral radiation-induced mucositis is progressive epithelial hypoplasia and eventual ulceration. Irradiation inhibits cell proliferation, while cell loss at the surface continues. We conceived to slow down this desquamation by increasing intercellular adhesion, regulated by the E-cadherin/catenin complex. We investigated if 8-prenylnaringenin (8-PN) or tamoxifen (TAM) decrease the shedding of irradiated human buccal epithelial cells in vitro and thus delay the ulcerative phase of radiation-induced mucositis in vivo. In vitro, aggregates of buccal epithelial cells were irradiated and cultured in suspension for 11 days. 8-PN or TAM were investigated regarding their effect on cell shedding. In vivo, the lower tongue surface of mice was irradiated with graded single doses of 25 kV X-rays. The incidence, latency, and duration of the resulting mucosal ulcerations were analyzed after topical treatment with 8-PN, TAM or solvent. 8-PN or TAM prevented the volume reduction of the irradiated cell aggregates during the incubation period. This was the result of a higher residual cell number in the treated versus the untreated irradiated aggregates. In vivo, topical treatment with 8-PN or TAM significantly increased the latency of mucositis from 10.9 to 12.1 and 12.4 days respectively, while the ulcer incidence was unchanged. 8-PN and TAM prevent volume reduction of irradiated cell aggregates in suspension culture. In the tongues of mice, these compounds increase the latency period. This suggests a role for these compounds for the amelioration of radiation-induced mucositis in the treatment of head and neck tumors. (orig.) [German] Die wesentliche Komponente in der Pathogenese der radiogenen Mukositis ist eine progressive epitheliale Hypoplasie und letztendlich Ulzeration. Die Bestrahlung hemmt die Zellproliferation, waehrend der Zellverlust an der Oberflaeche fortbesteht. Wir versuchten, diese Desquamation durch eine Stimulation der

  20. Sci—Fri AM: Mountain — 04: Label-free Raman spectroscopy of single tumour cells detects early radiation-induced glycogen synthesis associated with increased radiation resistance

    International Nuclear Information System (INIS)

    Matthews, Q; Lum, JJ; Isabelle, M; Harder, S; Jirasek, A; Brolo, AG

    2014-01-01

    Purpose: To use label-free Raman spectroscopy (RS) for early treatment monitoring of tumour cell radioresistance. Methods: Three human tumour cell lines, two radioresistant (H460, SF 2 = 0.57 and MCF7, SF 2 = 0.70) and one radiosensitive (LNCaP, SF 2 = 0.36), were irradiated with single fractions of 2, 4, 6, 8 or 10 Gy. In additional experiments, H460 and MCF7 cells were irradiated under co-treatment with the anti-diabetic drug metformin, a known radiosensitizing agent. Treated and control cultures were analyzed with RS daily for 3 days post-treatment. Single-cell Raman spectra were acquired from 20 live cells per sample, and experiments were repeated in triplicate. The combined data sets were analyzed with principal component analysis using standard algorithms. Cells from each culture were also subjected to standard assays for viability, proliferation, cell cycle, and radiation clonogenic survival. Results: The radioresistant cells (H460, MCF7) exhibited a RS molecular radiation response signature, detectable as early as 1 day post-treatment, of which radiation-induced glycogen synthesis is a significant contributor. The radiosensitive cells (LNCaP) exhibited negligible glycogen synthesis. Co-treatment with metformin in MCF7 cells blocked glycogen synthesis, reduced viability and proliferation, and increased radiosensitivity. Conversely, metformin co-treatment in H460 cells did not produce these same effects; importantly, both radiation-induced synthesis of glycogen and radiosensitivity were unaffected. Conclusions: Label-free RS can detect early glycogen synthesis post-irradiation, a previously undocumented metabolic mechanism associated with tumour cell radioresistance that can be targeted to increase radiosensitivity. RS monitoring of intratumoral glycogen may provide new opportunities for personalized combined modality radiotherapy treatments

  1. Celecoxib Induced Tumor Cell Radiosensitization by Inhibiting Radiation Induced Nuclear EGFR Transport and DNA-Repair: A COX-2 Independent Mechanism

    International Nuclear Information System (INIS)

    Dittmann, Klaus H.; Mayer, Claus; Ohneseit, Petra A.; Raju, Uma; Andratschke, Nickolaus H.; Milas, Luka; Rodemann, H. Peter

    2008-01-01

    Purpose: The purpose of the study was to elucidate the molecular mechanisms mediating radiosensitization of human tumor cells by the selective cyclooxygenase (COX)-2 inhibitor celecoxib. Methods and Materials: Experiments were performed using bronchial carcinoma cells A549, transformed fibroblasts HH4dd, the FaDu head-and-neck tumor cells, the colon carcinoma cells HCT116, and normal fibroblasts HSF7. Effects of celecoxib treatment were assessed by clonogenic cell survival, Western analysis, and quantification of residual DNA damage by γH 2 AX foci assay. Results: Celecoxib treatment resulted in a pronounced radiosensitization of A549, HCT116, and HSF7 cells, whereas FaDu and HH4dd cells were not radiosensitized. The observed radiosensitization could neither be correlated with basal COX-2 expression pattern nor with basal production of prostaglandin E2, but was depended on the ability of celecoxib to inhibit basal and radiation-induced nuclear transport of epidermal growth factor receptor (EGFR). The nuclear EGFR transport was strongly inhibited in A549-, HSF7-, and COX-2-deficient HCT116 cells, which were radiosensitized, but not in FaDu and HH4dd cells, which resisted celecoxib-induced radiosensitization. Celecoxib inhibited radiation-induced DNA-PK activation in A549, HSF7, and HCT116 cells, but not in FaDu and HH4dd cells. Consequentially, celecoxib increased residual γH2AX foci after irradiation, demonstrating that inhibition of DNA repair has occurred in responsive A549, HCT116, and HSF7 cells only. Conclusions: Celecoxib enhanced radiosensitivity by inhibition of EGFR-mediated mechanisms of radioresistance, a signaling that was independent of COX-2 activity. This novel observation may have therapeutic implications such that COX-2 inhibitors may improve therapeutic efficacy of radiation even in patients whose tumor radioresistance is not dependent on COX-2

  2. Sci—Fri AM: Mountain — 04: Label-free Raman spectroscopy of single tumour cells detects early radiation-induced glycogen synthesis associated with increased radiation resistance

    Energy Technology Data Exchange (ETDEWEB)

    Matthews, Q; Lum, JJ [BC Cancer Agency — Vancouver Island Centre (Canada); Isabelle, M; Harder, S; Jirasek, A [Physics and Astronomy, University of Victoria (Australia); Brolo, AG [Chemistry, University of Victoria (Australia)

    2014-08-15

    Purpose: To use label-free Raman spectroscopy (RS) for early treatment monitoring of tumour cell radioresistance. Methods: Three human tumour cell lines, two radioresistant (H460, SF{sub 2} = 0.57 and MCF7, SF{sub 2} = 0.70) and one radiosensitive (LNCaP, SF{sub 2} = 0.36), were irradiated with single fractions of 2, 4, 6, 8 or 10 Gy. In additional experiments, H460 and MCF7 cells were irradiated under co-treatment with the anti-diabetic drug metformin, a known radiosensitizing agent. Treated and control cultures were analyzed with RS daily for 3 days post-treatment. Single-cell Raman spectra were acquired from 20 live cells per sample, and experiments were repeated in triplicate. The combined data sets were analyzed with principal component analysis using standard algorithms. Cells from each culture were also subjected to standard assays for viability, proliferation, cell cycle, and radiation clonogenic survival. Results: The radioresistant cells (H460, MCF7) exhibited a RS molecular radiation response signature, detectable as early as 1 day post-treatment, of which radiation-induced glycogen synthesis is a significant contributor. The radiosensitive cells (LNCaP) exhibited negligible glycogen synthesis. Co-treatment with metformin in MCF7 cells blocked glycogen synthesis, reduced viability and proliferation, and increased radiosensitivity. Conversely, metformin co-treatment in H460 cells did not produce these same effects; importantly, both radiation-induced synthesis of glycogen and radiosensitivity were unaffected. Conclusions: Label-free RS can detect early glycogen synthesis post-irradiation, a previously undocumented metabolic mechanism associated with tumour cell radioresistance that can be targeted to increase radiosensitivity. RS monitoring of intratumoral glycogen may provide new opportunities for personalized combined modality radiotherapy treatments.

  3. Isolation and characterization of human salivary gland cells for stem cell transplantation to reduce radiation-induced hyposalivation

    International Nuclear Information System (INIS)

    Feng Jielin; Zwaag, Marianne van der; Stokman, Monique A.; Os, Ronald van; Coppes, Robert P.

    2009-01-01

    Background: Recently, we showed that transplantation of 100-300 c-Kit + stem cells isolated from cultured salispheres ameliorates radiation-damage in murine salivary glands. The aim of this study is to optimize and translate these findings from mice to man. Methods: Mouse and human non-malignant parotid and submandibular salivary gland tissue was collected and enzymatically digested. The remaining cell suspension was cultured according to our salisphere culture method optimized for murine salispheres. Salisphere cells were tested using 3D matrix culturing for their in vitro stem cell characteristics such as the potential to differentiate into tissue specific cell types. Several potential mouse and human salivary gland stem cells were selected using FACS. Results: In human salivary gland, c-Kit + cells were only detected in excretory ducts as shown previously in mice. From both human parotid and submandibular gland cell suspensions salispheres could be grown, which when placed in 3D culture developed ductal structures and mucin-expressing acinar-like cells. Moreover, cells dispersed from primary salispheres were able to form secondary spheres in matrigel, a procedure that could be repeated for at least seven passages. Approximately 3000 c-Kit + cells could be isolated from primary human salispheres per biopsy. Conclusion: Human salivary glands contain a similar 'putative' stem cell population as rodents, expressing c-kit and capable of in vitro differentiation and self-renewal. In the future, these cells may have the potential to reduce radiotherapy-induced salivary gland dysfunction in patients.

  4. Radiation-induced lipid peroxidation: influence of oxygen concentration and membrane lipid composition

    International Nuclear Information System (INIS)

    Wolters, H.; Tilburg, C.A.M. van; Konings, A.W.T.

    1987-01-01

    Radiation -induced lipid peroxidation phospholipid liposomes was investigated in terms of its dependence on lipid composition and oxygen concentration. Non-peroxidizable lipid incorporated in the liposomes reduced the rate of peroxidation of the peroxidizable phospholipid acyl chains, possibly by restricting the length of chain reactions. The latter effect is believed to be caused by interference of the non-peroxidizable lipids in the bilayer. At low oxygen concentration lipid peroxidation was reduced. The cause of this limited peroxidation may be a reduced number of radical initiation reactions possibly involving oxygen-derived superoxide radicals. Killing of proliferating mammalian cells, irradiated at oxygen concentrations ranging from 0 to 100%, appeared to be independent of the concentration of peroxidizable phospholipids in the cell membranes. This indicates that lipid peroxidation is not the determining process in radiation-induced reproductive cell death. (author)

  5. Cell damage from radiation-induced bystander effects for different cell densities simulated by a mathematical model via cellular automata

    Energy Technology Data Exchange (ETDEWEB)

    Meireles, Sincler P. de; Santos, Adriano M.; Grynberg, Suely Epsztein, E-mail: spm@cdtn.b, E-mail: amsantos@cdtn.b, E-mail: seg@cdtn.b [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Nunes, Maria Eugenia S., E-mail: mariaeugenia@iceb.ufop.b [Universidade Federal de Ouro Preto (UFOP), MG (Brazil)

    2011-07-01

    During recent years, there has been a shift from an approach focused entirely on DNA as the main target of ionizing radiation to a vision that considers complex signaling pathways in cells and among cells within tissues. Several newly recognized responses were classified as the so-called non-target responses in which the biological effects are not directly related to the amount of energy deposited in the DNA of cells that were traversed by radiation. In 1992 the bystander effect was described referring to a series of responses such as death, chromosomal instability or other abnormalities that occur in non-irradiated cells that came into contact with irradiated cells or medium from irradiated cells. In this work, we have developed a mathematical model via cellular automata, to quantify cell death induced by the bystander effect. The model is based on experiments with irradiated cells conditioned medium which suggests that irradiated cells secrete molecules in the medium that are capable of damaging other cells. The computational model consists of two-dimensional cellular automata which is able to simulate the transmission of bystander signals via extrinsic route and via Gap junctions. The model has been validated by experimental results in the literature. The time evolution of the effect and the dose-response curves were obtained in good accordance to them. Simulations were conducted for different values of bystander and irradiated cell densities with constant dose. From this work, we have obtained a relationship between cell density and effect. (author)

  6. Cell damage from radiation-induced bystander effects for different cell densities simulated by a mathematical model via cellular automata

    International Nuclear Information System (INIS)

    Meireles, Sincler P. de; Santos, Adriano M.; Grynberg, Suely Epsztein; Nunes, Maria Eugenia S.

    2011-01-01

    During recent years, there has been a shift from an approach focused entirely on DNA as the main target of ionizing radiation to a vision that considers complex signaling pathways in cells and among cells within tissues. Several newly recognized responses were classified as the so-called non-target responses in which the biological effects are not directly related to the amount of energy deposited in the DNA of cells that were traversed by radiation. In 1992 the bystander effect was described referring to a series of responses such as death, chromosomal instability or other abnormalities that occur in non-irradiated cells that came into contact with irradiated cells or medium from irradiated cells. In this work, we have developed a mathematical model via cellular automata, to quantify cell death induced by the bystander effect. The model is based on experiments with irradiated cells conditioned medium which suggests that irradiated cells secrete molecules in the medium that are capable of damaging other cells. The computational model consists of two-dimensional cellular automata which is able to simulate the transmission of bystander signals via extrinsic route and via Gap junctions. The model has been validated by experimental results in the literature. The time evolution of the effect and the dose-response curves were obtained in good accordance to them. Simulations were conducted for different values of bystander and irradiated cell densities with constant dose. From this work, we have obtained a relationship between cell density and effect. (author)

  7. Radiation-induced pneumothorax

    International Nuclear Information System (INIS)

    Epstein, D.M.; Littman, P.; Gefter, W.B.; Miller, W.T.; Raney, R.B. Jr.

    1983-01-01

    Pneumothorax is an uncommon complication of radiation therapy to the chest. The proposed pathogenesis is radiation-induced fibrosis promoting subpleural bleb formation that ruptures resulting in pneumothorax. We report on two young patients with primary sarcomas without pulmonary metastases who developed spontaneous pneumothorax after irradiation. Neither patient had antecedent radiographic evidence of pulmonary fibrosis

  8. The use of recombinant DNA techniques to study radiation-induced damage, repair and genetic change in mammalian cells

    International Nuclear Information System (INIS)

    Thacker, J.

    1986-01-01

    A brief introduction is given to appropriate elements of recombinant DNA techniques and applications to problems in radiobiology are reviewed with illustrative detail. Examples are included of studies with both 254 nm ultraviolet light and ionizing radiation and the review progresses from the molecular analysis of DNA damage in vitro through to the nature of consequent cellular responses. The review is dealt with under the following headings: Molecular distribution of DNA damage, The use of DNA-mediated gene transfer to assess damage and repair, The DNA double strand break: use of restriction endonucleases to model radiation damage, Identification and cloning of DNA repair genes, Analysis of radiation-induced genetic change. (UK)

  9. Peroxiredoxin IV Protects Cells From Radiation-Induced Apoptosis in Head-and-Neck Squamous Cell Carcinoma

    International Nuclear Information System (INIS)

    Park, Jung Je; Chang, Hyo Won; Jeong, Eun-Jeong; Roh, Jong-Lyel; Choi, Seung-Ho; Jeon, Sea-Yuong; Ko, Gyung Hyuck; Kim, Sang Yoon

    2009-01-01

    Purpose: Human peroxiredoxins (Prxs) are known as a family of thiol-specific antioxidant enzymes, among which Prx-I and -II play an important role in protecting cells from irradiation-induced cell death. It is not known whether Prx-IV also protects cells from ionizing radiation (IR). Methods and Materials: To evaluate the protective role of Prx-IV in IR, we transfected full-length Prx-IV cDNA into AMC-HN3 cells, which weakly express endogenous Prx-IV, and knocked down the expression of Prx-IV with siRNA methods using AMC-HN7 cells, which express high levels of endogenous Prx-IV. Radiosensitivity profiles in these cells were evaluated using clonogenic assay, FACS analysis, cell viability, and TUNEL assay. Results: Three Prx-IV expressing clones were isolated. Prx-IV regulated intracellular reactive oxygen species (ROS) levels and made cells more resistant to IR-induced apoptosis. Furthermore, the knockdown of Prx-IV with siRNA made cells more sensitive to IR-induced apoptosis. Conclusion: The results of these studies suggest that Prx-IV may play an important role in protecting cells from IR-induced apoptosis in head-and-neck squamous cell carcinoma

  10. Radiation-induced DNA damage in canine hemopoietic cells and stromal cells as measured by the comet assay

    International Nuclear Information System (INIS)

    Kreja, L.; Selig, C.; Plappert, U.; Nothdurft, W.

    1996-01-01

    Stromal cell progenitors (fibroblastoid colony-forming unit; CFU-Fs) are representative of the progenitor cell population of the hemopoietic microenvironment in bone marrow (BM). Previous studies of the radiation dose-effect relationships for colony formation have shown that canine CFU-Fs are relatively radioresistant as characterized by a D 0 value of about 2.4 Gy. In contrast, hemopoietic progenitors are particularly radiosensitive (D 0 values = 0.12-0.60 Gy). In the present study, the alkaline single-cell gel electrophoresis technique for the in situ quantitation of DNA strand breaks and alkalilabile site was employed. Canine buffy coat cells from BM aspirates and cells harvested from CFU-F colonies or from mixed populations of adherent BM stromal cell (SC) layers were exposed to increasing doses of X-rays, embedded in agarose gel on slides, lysed with detergents, and placed in an electric field. DNA migrating from single cells in the gel was made visible as open-quotes cometsclose quotes by ethidium bromide staining. Immediate DNA damage was much less in cultured stromal cells than in hemopoietic cells in BM aspirates. These results suggest that the observed differences in clonogenic survival could be partly due to differences in the type of the initial DNA damage between stromal cells and hemopoietic cells. 37 refs., 2 figs., 1 tab

  11. Hepatocyte growth factor gene-modified adipose-derived mesenchymal stem cells ameliorate radiation induced liver damage in a rat model.

    Directory of Open Access Journals (Sweden)

    Jiamin Zhang

    Full Text Available Liver damage caused by radiotherapy is associated with a high mortality rate, but no established treatment exists. Adipose-derived mesenchymal stem cells (ADSCs are capable of migration to injured tissue sites, where they aid in the repair of the damage. Hepatocyte growth factor (HGF is critical for damage repair due to its anti-apoptotic, anti-fibrotic and cell regeneration-promoting effects. This study was performed to investigate the therapeutic effects of HGF-overexpressing ADSCs on radiation-induced liver damage (RILD. ADSCs were infected with a lentivirus encoding HGF and HGF-shRNA. Sprague-Dawley (SD rats received 60Gy of irradiation to induce liver injury and were immediately given either saline, ADSCs, ADSCs + HGF or ADSCs + shHGF. Two days after irradiation, a significant reduction in apoptosis was observed in the HGF-overexpressing ADSC group compared with the RILD group, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL staining. Scanning electron microscopy showed chromatin condensation after irradiation, which was ameliorated in the group that received ADSCs and was reversed in the group that received HGF-overexpressing ADSCs. HGF-overexpressing ADSCs ameliorated radiation- induced liver fibrosis through down regulation of α-SMA and fibronectin. Hepatocyte regeneration was significantly improved in rats treated with ADSCs compared with rats from the RILD group, as assessed by Ki-67 immunohistochemistry. Rats that received HGF-overexpressing ADSCs showed an even greater level of hepatocyte regeneration. HGF-overexpressing ADSCs completely blocked the radiation-induced increase in the enzymes ALT and AST. The effect of mitigating RILD was compromised in the ADSC + shHGF group compared with the ADSC group. Altogether, these results suggest that HGF-overexpressing ADSCs can significantly improve RILD in a rat model, which may serve as a valuable therapeutic alternative.

  12. Pharmacological inhibition of radiation induced in vitro tumor cell/endothelium cell interactions and in vivo metastasis processes

    International Nuclear Information System (INIS)

    Herzog, Melanie

    2013-01-01

    Exposure of endothelial cells with ionizing radiation (IR) or treatment with inflammatory cytokines (e. g. TNFα) induces a Rho-GTPase and NF-κB dependent activation of the expression of various cell adhesion molecules, including E-selectin. E-selectin mediates the adhesion of tumor cells (TC) to endothelial cells and is probably involved in the extravasation step of circulating tumor cells. HMG-CoA reductase inhibitors (e. g. lovastatin) inhibit the function of Rho-GTPases and thus are anticipated to attenuate Rho-regulated cell-cell-adhesion as well. This study focuses on the influence of IR and TNFα on the expression of endothelial- and/or tumor cell-specific pro-adhesive factors and whether these effects are influenced by lovastatin. To this end, the effect of IR and TNFα on cell-cell-interactions between human colon carcinoma cells (HT29) and human umbilical vein endothelial cells (HUVEC) was investigated using an ELISA-based cell adhesion-assay. Moreover, the influence of pre-treatment with lovastatin and other types of inhibitors on HUVEC-HT29 adhesion was monitored. Additionally, we investigated the effect of lovastatin on mRNA expression level of different cell adhesion molecules, metastatic factors and DNA-repair genes upon radiation exposure by qRT-PCR. To scrutinize the in vivo relevance of the data obtained, we investigated the effect of total body irradiation (TBI) on the mRNA expression of pro-adhesive factors in BALB/c mice. To analyze tumor cell extravasation, tumor cells were injected into the lateral tail vein of immundeficient mice, followed by total body irradiation (TBI, 4 Gy). After four weeks a large increase of lung metastases was monitored, which could be blocked by preatreatment of the mice with lovastatin, the Rac1-specific small-molecule inhibitor NSC23766 as well as the sLe x -mimetic glycyrrhizin. Summarizing, we provide evidence, that irradiation promotes upregulation of different cell adhesion molecules in vitro and stimulates

  13. Low-Dose Radiation Induces Cell Proliferation in Human Embryonic Lung Fibroblasts but not in Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Xinyue Liang

    2016-01-01

    Full Text Available Hormesis and adaptive responses are 2 important biological effects of low-dose ionizing radiation (LDR. In normal tissue, LDR induces hormesis as evinced by increased cell proliferation; however, whether LDR also increases tumor cell proliferation needs to be investigated. In this study, cell proliferation was assayed by total cell numbers and the Cell Counting Kit 8 assay. Mitogen-activated protein kinases (MAPK/extracellular signal-regulated kinase (ERK and phosphatidylinositol 3′ -kinase(PI3K-Akt (PI3K/AKT phosphorylation were determined by Western blot analysis. Human embryonic lung fibroblast 2BS and lung cancer NCI-H446 cell lines were irradiated with LDR at different doses (20-100 mGy. In response to 20 to 75 mGy X-rays, cell proliferation was significantly increased in 2BS but not in NCI-H446 cells. In 2BS cells, LDR at 20 to 75 mGy also stimulated phosphorylation of MAPK/ERK pathway proteins including ERK, MEK, and Raf and of the PI3K/AKT pathway protein AKT. To test whether ERK1/2 and AKT pathway activation was involved in the stimulation of cell proliferation in 2BS cells, the MAPK/ERK and PI3K/AKT pathways were inhibited using their specific inhibitors, U0126 and LY294002. U0126 decreased the phosphorylation of ERK1/2, and LY294002 decreased the phosphorylation of AKT; each could significantly inhibit LDR-induced 2BS cell proliferation. However, LDR did not stimulate these kinases, and kinase inhibitors also did not affect cell proliferation in the NCI-H446 cells. These results suggest that LDR stimulates cell proliferation via the activation of both MAPK/ERK and PI3K/AKT signaling pathways in 2BS but not in NCI-H446 cells. This finding implies the potential for applying LDR to protect normal tissues from radiotherapy without diminishing the efficacy of tumor therapy.

  14. Low concentration of exogenous carbon monoxide protects mammalian cells against proliferation induced by radiation-induced bystander effect

    International Nuclear Information System (INIS)

    Tong, Liping; Yu, K.N.; Bao, Lingzhi; Wu, Wenqing; Wang, Hongzhi; Han, Wei

    2014-01-01

    Highlights: • We show the possibility of modulate proliferation induced by radiation-induced bystander effect with low concentration carbon monoxide. • Carbon monoxide inhibited proliferation via modulating the transforming growth factor β1 (TGF-β1)/nitric oxide (NO) signaling pathway. • Exogenous carbon monoxide has potential application in clinical radiotherapy. - Abstract: Radiation-induced bystander effect (RIBE) has been proposed to have tight relationship with the irradiation-caused secondary cancers beyond the irradiation-treated area after radiotherapy. Our previous studies demonstrated a protective effect of low concentration carbon monoxide (CO) on the genotoxicity of RIBE after α-particle irradiation. In the present work, a significant inhibitory effect of low-dose exogenous CO, generated by tricarbonyldichlororuthenium (II) dimer [CO-releasing molecule (CORM-2)], on both RIBE-induced proliferation and chromosome aberration was observed. Further studies on the mechanism revealed that the transforming growth factor β1/nitric oxide (NO) signaling pathway, which mediated RIBE signaling transduction, could be modulated by CO involved in the protective effects. Considering the potential of exogenous CO in clinical applications and its protective effect on RIBE, the present work aims to provide a foundation for potential application of CO in radiotherapy

  15. Low concentration of exogenous carbon monoxide protects mammalian cells against proliferation induced by radiation-induced bystander effect

    Energy Technology Data Exchange (ETDEWEB)

    Tong, Liping [Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); Yu, K.N. [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong); Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); Bao, Lingzhi; Wu, Wenqing; Wang, Hongzhi [Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); Han, Wei, E-mail: hanw@hfcas.cn [Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China)

    2014-01-15

    Highlights: • We show the possibility of modulate proliferation induced by radiation-induced bystander effect with low concentration carbon monoxide. • Carbon monoxide inhibited proliferation via modulating the transforming growth factor β1 (TGF-β1)/nitric oxide (NO) signaling pathway. • Exogenous carbon monoxide has potential application in clinical radiotherapy. - Abstract: Radiation-induced bystander effect (RIBE) has been proposed to have tight relationship with the irradiation-caused secondary cancers beyond the irradiation-treated area after radiotherapy. Our previous studies demonstrated a protective effect of low concentration carbon monoxide (CO) on the genotoxicity of RIBE after α-particle irradiation. In the present work, a significant inhibitory effect of low-dose exogenous CO, generated by tricarbonyldichlororuthenium (II) dimer [CO-releasing molecule (CORM-2)], on both RIBE-induced proliferation and chromosome aberration was observed. Further studies on the mechanism revealed that the transforming growth factor β1/nitric oxide (NO) signaling pathway, which mediated RIBE signaling transduction, could be modulated by CO involved in the protective effects. Considering the potential of exogenous CO in clinical applications and its protective effect on RIBE, the present work aims to provide a foundation for potential application of CO in radiotherapy.

  16. Effect of an aminothiol (WR-1065) on radiation-induced mutagenesis and cytotoxicity in two repair-deficient mammalian cell lines

    International Nuclear Information System (INIS)

    Grdina, D.J.; Nagy, B.; Meechan, P.J.

    1991-01-01

    WR-2721 and its free thiol WR-1065 have been found to effectively protect against radiation- and/or chemotherapy-induced mutagenesis, transformation and carcinogenesis. With respect to the antimutagenic effect, WR-1065 significantly reduced the frequency of HGPRT mutants even when it was administered up to three hours following exposure of cells to radiation. The mechanisms of action most often attributed to these agents include their ability to scavenge free radicals, enter into chemical repair processes through the donation of hydrogen atoms, and induce intracellular hypoxia by means of auto-oxidative processes. Although evidence exists for each of these processes, none is sufficiently satisfactory to account for the post-irradiation protection of WR-1065 against mutation induction in mammalian cells. The most elegant work describing the role of aminothiols on cellular enzymatic repair processes has focused on well-characterized repair-proficient and -deficient bacterial and yeast cell systems. Protection against radiation-induced cytotoxicity by the aminothiol cysteamine was absent in E. coli cell lines that were characterized as having genetically defective repair systems. Until recently, such studies could not be effectively performed with mammalian cells. However, with the isolation and characterization of rodent cell lines deficient in their ability to repair DNA damage, it is now possible to investigate the role of cell-mediated repair systems on aminothiol radioprotection. Specifically, the authors have investigated the effects of WR-1065 on radiation-induced mutagenesis and cytotoxicity in cell lines EM9 and xrs-5, which are defective in DNA single-strand break (SSB) and double-strand break (DSB) rejoining, respectively. Corresponding parental repair-proficient cell lines, AA8 and K1, were also studied for comparative purposes. 26 refs., 5 figs., 2 tabs

  17. BRCA1, FANCD2 and Chk1 are potential molecular targets for the modulation of a radiation-induced DNA damage response in bystander cells.

    Science.gov (United States)

    Burdak-Rothkamm, Susanne; Rothkamm, Kai; McClelland, Keeva; Al Rashid, Shahnaz T; Prise, Kevin M

    2015-01-28

    Radiotherapy is an important treatment option for many human cancers. Current research is investigating the use of molecular targeted drugs in order to improve responses to radiotherapy in various cancers. The cellular response to irradiation is driven by both direct DNA damage in the targeted cell and intercellular signalling leading to a broad range of bystander effects. This study aims to elucidate radiation-induced DNA damage response signalling in bystander cells and to identify potential molecular targets to modulate the radiation induced bystander response in a therapeutic setting. Stalled replication forks in T98G bystander cells were visualised via bromodeoxyuridine (BrdU) nuclear foci detection at sites of single stranded DNA. γH2AX co-localised with these BrdU foci. BRCA1 and FANCD2 foci formed in T98G bystander cells. Using ATR mutant F02-98 hTERT and ATM deficient GM05849 fibroblasts it could be shown that ATR but not ATM was required for the recruitment of FANCD2 to sites of replication associated DNA damage in bystander cells whereas BRCA1 bystander foci were ATM-dependent. Phospho-Chk1 foci formation was observed in T98G bystander cells. Clonogenic survival assays showed moderate radiosensitisation of directly irradiated cells by the Chk1 inhibitor UCN-01 but increased radioresistance of bystander cells. This study identifies BRCA1, FANCD2 and Chk1 as potential targets for the modulation of radiation response in bystander cells. It adds to our understanding of the key molecular events propagating out-of-field effects of radiation and provides a rationale for the development of novel molecular targeted drugs for radiotherapy optimisation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Effect of EBI3 on radiation-induced immunosuppression of cervical cancer HeLa cells by regulating Treg cells through PD-1/PD-L1 pathway.

    Science.gov (United States)

    Zhang, Song-An; Niyazi, Hu-Er-Xi-Dan; Hong, Wen; Tuluwengjiang, Gu-Li-Xian; Zhang, Lei; Zhang, Yang; Su, Wei-Peng; Bao, Yong-Xing

    2017-03-01

    This study aimed to investigate the effect of EBI3 on radiation-induced immunosuppression of cervical cancer HeLa cells by regulating Treg cells through PD-1/PD-L1 signaling pathway. A total of 43 adult female Wistar rats were selected and injected with HeLa cells in the caudal vein to construct a rat model of cervical cancer. All model rats were randomly divided into the radiotherapy group ( n = 31) and the control group ( n = 12). The immunophenotype of Treg cells was detected by the flow cytometry. The protein expressions of EBI3, PD-1, and PD-L1 in cervical cancer tissues were tested by the streptavidin-peroxidase method. HeLa cells in the logarithmic growth phase were divided into four groups: the blank, the negative control group, the EBI3 mimics group, and the EBI3 inhibitors group. Western blotting was used to detect PD-1 and PD-L1 protein expressions. MTT assay was performed to measure the proliferation of Treg cells. Flow cytometry was used to detect cell cycle and apoptosis, and CD4 + /CD8 + T cell ratio in each group. Compared with before and 1 week after radiotherapy, the percentages of CD4 + T cells and CD8 + T cells were significantly decreased in the radiotherapy group at 1 month after radiotherapy. Furthermore, down-regulation of EBI3 and up-regulation of PD-1 and PD-L1 were observed in cervical cancer tissues at 1 month after radiotherapy. In comparison to the blank and negative control groups, increased expression of EBI3 and decreased expressions of PD-1 and PD-L1 were found in the EBI3 mimics group. However, the EBI3 inhibitors group had a lower expression of EBI3 and higher expressions of PD-1 and PD-L1 than those in the blank and negative control groups. The EBI3 mimics group showed an increase in the optical density value (0.43 ± 0.05), while a decrease in the optical density value (0.31 ± 0.02) was found in the EBI3 inhibitors group. Moreover, compared with the blank and negative control groups, the apoptosis rates

  19. Sci-Thur PM – Colourful Interactions: Highlights 03: Radiation induced glycogen accumulation in non-small cell lung cancer xenografts detected using Raman spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Harder, Samantha J.; Isabelle, Martin; DeVorkin, Lindsay; Smazynski, Julian; Beckham, Wayne; Brolo, Alexandre; Lum, Julian; Jirasek, Andrew [BC Cancer Agency/ Vancouver Island Cancer Centre, Gloucestershire Hospitals NHS Foundation Trust, BC Cancer Agency/ Vancouver Island Cancer Centre, BC Cancer Agency/ Vancouver Island Cancer Centre, BC Cancer Agency/ Vancouver Island Cancer Centre, University of Victoria/ Department of Chemistry, BC Cancer Agency/ Vancouver Island Cancer Centre, University of British Columbia Okanagan (Canada)

    2016-08-15

    Purpose: This study presents the novel application of Raman spectroscopy (RS) to identify biochemical signatures of radiation response in human non-small cell lung cancer (NSCLC) xenografts, irradiated in vivo. Methods: Human NSCLC cells (H460) were subcutaneously injected into the flanks of 12 mice. Tumours were treated with single fraction radiation doses (0, 5 or 15 Gy) and harvested at 3 days post irradiation. A Renishaw inVia Raman microscope coupled to a 785 nm laser was used to collect Raman spectral maps for each tumour. Immunohistochemistry (IHC) staining for CAIX was used to visualize hypoxia, and co-registration between IHC fluorescence and Raman images was carried out. Results: Principal component analysis revealed radiation induced spectral signatures linked to changes in protein, nucleic acid, lipid and carbohydrates. In particular, a marked increase in glycogen for irradiated tumours was observed. Spatial mapping revealed intra-tumoural heterogeneity in the distribution of glycogen within the tumour, suggesting tumour response to radiation is not globally uniform. Furthermore, co-registration of Raman glycogen maps with CAIX IHC staining showed a correlation between glycogen rich and hypoxic regions of the tissue. Conclusions: We identify glycogen as a unique radiation induced response in NSCLC tumour xenografts, which may reflect inherent metabolic changes associated with radiation response in tissue. This study provides unique insight into the biochemical response of tumours, irradiated in vivo, and demonstrates the potential of RS for detecting radiobiological responses in tumours.

  20. Sci-Thur PM – Colourful Interactions: Highlights 03: Radiation induced glycogen accumulation in non-small cell lung cancer xenografts detected using Raman spectroscopy

    International Nuclear Information System (INIS)

    Harder, Samantha J.; Isabelle, Martin; DeVorkin, Lindsay; Smazynski, Julian; Beckham, Wayne; Brolo, Alexandre; Lum, Julian; Jirasek, Andrew

    2016-01-01

    Purpose: This study presents the novel application of Raman spectroscopy (RS) to identify biochemical signatures of radiation response in human non-small cell lung cancer (NSCLC) xenografts, irradiated in vivo. Methods: Human NSCLC cells (H460) were subcutaneously injected into the flanks of 12 mice. Tumours were treated with single fraction radiation doses (0, 5 or 15 Gy) and harvested at 3 days post irradiation. A Renishaw inVia Raman microscope coupled to a 785 nm laser was used to collect Raman spectral maps for each tumour. Immunohistochemistry (IHC) staining for CAIX was used to visualize hypoxia, and co-registration between IHC fluorescence and Raman images was carried out. Results: Principal component analysis revealed radiation induced spectral signatures linked to changes in protein, nucleic acid, lipid and carbohydrates. In particular, a marked increase in glycogen for irradiated tumours was observed. Spatial mapping revealed intra-tumoural heterogeneity in the distribution of glycogen within the tumour, suggesting tumour response to radiation is not globally uniform. Furthermore, co-registration of Raman glycogen maps with CAIX IHC staining showed a correlation between glycogen rich and hypoxic regions of the tissue. Conclusions: We identify glycogen as a unique radiation induced response in NSCLC tumour xenografts, which may reflect inherent metabolic changes associated with radiation response in tissue. This study provides unique insight into the biochemical response of tumours, irradiated in vivo, and demonstrates the potential of RS for detecting radiobiological responses in tumours.

  1. Time-kill profiles and cell-surface morphological effects of crude ...

    African Journals Online (AJOL)

    MK1201 mycelial extract on the viability and cell surface morphology of methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). Methods: Time-kill assays were conducted by incubating test ...

  2. Trypanosoma brucei Co-opts NK Cells to Kill Splenic B2 B Cells.

    Directory of Open Access Journals (Sweden)

    Deborah Frenkel

    2016-07-01

    Full Text Available After infection with T. brucei AnTat 1.1, C57BL/6 mice lost splenic B2 B cells and lymphoid follicles, developed poor parasite-specific antibody responses, lost weight, became anemic and died with fulminating parasitemia within 35 days. In contrast, infected C57BL/6 mice lacking the cytotoxic granule pore-forming protein perforin (Prf1-/- retained splenic B2 B cells and lymphoid follicles, developed high-titer antibody responses against many trypanosome polypeptides, rapidly suppressed parasitemia and did not develop anemia or lose weight for at least 60 days. Several lines of evidence show that T. brucei infection-induced splenic B cell depletion results from natural killer (NK cell-mediated cytotoxicity: i B2 B cells were depleted from the spleens of infected intact, T cell deficient (TCR-/- and FcγRIIIa deficient (CD16-/- C57BL/6 mice excluding a requirement for T cells, NKT cell, or antibody-dependent cell-mediated cytotoxicity; ii administration of NK1.1 specific IgG2a (mAb PK136 but not irrelevant IgG2a (myeloma M9144 prevented infection-induced B cell depletion consistent with a requirement for NK cells; iii splenic NK cells but not T cells or NKT cells degranulated in infected C57BL/6 mice co-incident with B cell depletion evidenced by increased surface expression of CD107a; iv purified NK cells from naïve C57BL/6 mice killed purified splenic B cells from T. brucei infected but not uninfected mice in vitro indicating acquisition of an NK cell activating phenotype by the post-infection B cells; v adoptively transferred C57BL/6 NK cells prevented infection-induced B cell population growth in infected Prf1-/- mice consistent with in vivo B cell killing; vi degranulated NK cells in infected mice had altered gene and differentiation antigen expression and lost cytotoxic activity consistent with functional exhaustion, but increased in number as infection progressed indicating continued generation. We conclude that NK cells in T. brucei

  3. Protease activation involved in resistance of human cells to x-ray cell killing

    International Nuclear Information System (INIS)

    Zhang, Hong-Chang; Takahashi, Shuji; Karata, Kiyonobu; Kita, Kazuko; Suzuki, Nobuo

    2003-01-01

    Little is known of proteases that play roles in the early steps of X-ray irradiation response. In the present study, we first searched for proteases whose activity is induced in human RSa-R cells after X-ray irradiation. The activity was identified as fibrinolytic, using 125 I-labeled fibrin as a substrate. Protease samples were prepared by lysation of cells with a buffer containing MEGA-8. RSa-R cells showed an increased level of protease activity 10 min after X-ray (up to 3 Gy) irradiation. We next examined whether this protease inducibility is causally related with the X-ray susceptibility of cells. Leupeptin, a serine-cysteine protease inhibitor, inhibited the protease activity in samples obtained from X-ray-irradiated RSa-R cells. Treatment of RSa-R cells with the inhibitor before and after X-ray irradiation resulted in an increased susceptibility of the cells to X-ray cell killing. However, the treatment of cells with other inhibitors tested did not modulate the X-ray susceptibility. These results suggest that leupeptin-sensitive proteases are involved in the resistance of human cells to X-ray cell killing. (author)

  4. Radiation-induced DNA breaks detected by immuno labelling of poly(ADP-ribose) in CHO cells. Standardization by pulsed-field gel electrophoresis

    International Nuclear Information System (INIS)

    Varlet, P.; Bidon, N.; Noel, G.; Averbeck, D.; Salamero, J.; DeMurcia, G.

    1998-01-01

    The poly (ADP-ribose) polymerase is an ubiquitous nuclear protein capable of binding specifically to DNA strand breaks. It synthesizes ADP-ribose polymers proportionally to DNA breaks. The actual method of reference to determine DNA double strand breaks is pulsed-field gel electrophoresis, but this requires many cells. It thus appeared of interest to use poly (ADP-ribos)ylation to follow and estimate γ-ray-induced DNA fragmentation at the level of isolated cells after γ-irradiation in chinese hamster ovary cells (CHO-K1). The results obtained by the immuno-labelling technique of ADP-ribose polymers were compared to those obtained by pulsed-field gel electrophoresis. They show that poly (ADP-ribos)ylation reflects the occurrence of radiation-induced DNA strand breaks. A clear relationship exists between the amount of ADP-ribose polymers detected and DNA double strand breaks after γ-irradiation. (authors)

  5. EZH2 Protects Glioma Stem Cells from Radiation-Induced Cell Death in a MELK/FOXM1-Dependent Manner

    DEFF Research Database (Denmark)

    Kim, Sung-Hak; Joshi, Kaushal; Ezhilarasan, Ravesanker

    2015-01-01

    Glioblastoma (GBM)-derived tumorigenic stem-like cells (GSCs) may play a key role in therapy resistance. Previously, we reported that the mitotic kinase MELK binds and phosphorylates the oncogenic transcription factor FOXM1 in GSCs. Here, we demonstrate that the catalytic subunit of Polycomb repr...

  6. Radiation-induced myelopathy

    Energy Technology Data Exchange (ETDEWEB)

    Gaenshirt, H [Heidelberg Univ. (F.R. Germany). Neurologische Klinik

    1975-10-01

    12 cases of radiation-induced myelopathy after /sup 60/Co teletherapy are reported on. Among these were 10 thoracal lesions, one cerviothoracal lesion, and one lesion of the medulla oblongata. In 9 cases, Hodgkin's disease had been the primary disease, tow patients had been irradiated because of suspected vertebral metastases of cancer of the breast, and one patient had suffered from a glomus tumour of the petrous bone. The spinal doses had exceeded the tolerance doses recommended in the relevant literature. There was no close correlation between the radiation dose and the course of the disease. The latency periods between the end of the radiotherapy and the onset of the neurological symptons varied from 6 to 16 mouths and were very constant in 7 cases with 6 to 9 months. The segmental height of the lesion corresponded to the level of irradiation. The presenting symptons of radiation-induced myelopathy are buruing dysaesthesias and Brown-Sequard's paralysis which may develop into transverse lesion of the cord with paraplegia still accompanied by dissociated perception disorders. The disease developed intermittently. Disturbances of the bladder function are frequent. The fluid is normal in most cases. Myelographic examinations were made in 8 cases. 3 cases developed into stationary cases exhibiting. Brown-Sequard syndrome, while 9 patients developed transverse lesion of the cord with paraplegia. 3 patients have died; antopsy findings are given for two of these. In the pathogenesis of radiation-induced myelopathy, the vascular factor is assumed to be of decisive importance.

  7. Enhanced adhesion of early endothelial progenitor cells to radiation-induced senescence-like vascular endothelial cells in vitro

    International Nuclear Information System (INIS)

    Sermsathanasawadi, N.; Inoue, Yoshinori; Iwai, Takehisa; Ishii, Hideto; Yoshida, Masayuki; Igarashi, Kaori; Miura, Masahiko

    2009-01-01

    The effects of ionizing radiation (IR) on tumor neovascularization are still unclear. We previously reported that vascular endothelial cells (ECs) expressing the IR-induced senescence-like (IRSL) phenotype exhibit a significant decrease in angiogenic activity in vitro. In this study, we examined the effects of the IRSL phenotype on adhesion to early endothelial progenitor cells (early EPCs). Adhesion of human peripheral blood-derived early EPCs to human umbilical vein endothelial cells (HUVECs) expressing the IRSL phenotype was evaluated by an adhesion assay under static conditions. It was revealed that the IRSL HUVECs supported significantly more adhesion of early EPCs than normal HUVECs. Expressions of ICAM-1, VCAM-1 and E-selectin were up-regulated in IRSL HUVECs. Pre-treatment of IRSL HUVECs with adhesion-blocking monoclonal antibodies against E-selectin and VCAM-1 significantly reduced early EPC adhesion to IRSL HUVECs, suggesting a potential role for the E-selectin and VCAM-1 in the adhesion between IRSL ECs and early EPCs. Therefore, the IRSL phenotype expressed in ECs may enhance neovascularization via increased homing of early EPCs. Our findings are first to implicate the complex effects of this phenotype on tumor neovascularization following irradiation. (author)

  8. CD47-CAR-T Cells Effectively Kill Target Cancer Cells and Block Pancreatic Tumor Growth.

    Science.gov (United States)

    Golubovskaya, Vita; Berahovich, Robert; Zhou, Hua; Xu, Shirley; Harto, Hizkia; Li, Le; Chao, Cheng-Chi; Mao, Mike Ming; Wu, Lijun

    2017-10-21

    CD47 is a glycoprotein of the immunoglobulin superfamily that is often overexpressed in different types of hematological and solid cancer tumors and plays important role in blocking phagocytosis, increased tumor survival, metastasis and angiogenesis. In the present report, we designed CAR (chimeric antigen receptor)-T cells that bind CD47 antigen. We used ScFv (single chain variable fragment) from mouse CD47 antibody to generate CD47-CAR-T cells for targeting different cancer cell lines. CD47-CAR-T cells effectively killed ovarian, pancreatic and other cancer cells and produced high level of cytokines that correlated with expression of CD47 antigen. In addition, CD47-CAR-T cells significantly blocked BxPC3 pancreatic xenograft tumor growth after intratumoral injection into NSG mice. Moreover, we humanized mouse CD47 ScFv and showed that it effectively bound CD47 antigen. The humanized CD47-CAR-T cells also specifically killed ovarian, pancreatic, and cervical cancer cell lines and produced IL-2 that correlated with expression of CD47. Thus, CD47-CAR-T cells can be used as a novel cellular therapeutic agent for treating different types of cancer.

  9. Radiation-induced DNA damage and cellular lethality

    International Nuclear Information System (INIS)

    Sakai, K.; Okada, S.

    1984-01-01

    Radiation-induced DNA scissions and their repair were investigated in mammalian cells using an alkaline separation method. DNA breaks in mouse L5178Y cells and Chinese hamster V79 cells were grouped into three in terms of their repair profile; fast-reparable breaks (FRBs; T1/2 = 5 min), slow-reparable breaks (SRBs; T1/2 = 70 min) and non-reparable breaks (NRBs). The three types of DNA lesions were studied under conditions where cellular radiosensitivity was modified. The authors obtained the following results: 1. Cell cycle fluctuation: L5178Y showed maximum sensitivity at M and G/sub 1/-S boundary, and minimum sensitivity at G/sub 1/ and late S. Cycle dependency was not found for FRBs or SRBs, but NRBs showed bimodal fluctuation with peaks at M and G/sub 1/-S, and with bottoms at G/sub 1/ and late S. 2. Different sensitivity of L5178Y and V79: L5178Y cells were more sensitive to X-rays (D/sub ο/ = 0.9 Gy) than V79 (D/sub ο/ = 1.8 Gy). The amount of FRBs or SRBs was identical in the two cell lines. However, the amount of NRBs in L5178Y was greater than that in V79. 3. Split dose irradiation: The time interval between two doses resulted in a gradual decrease of NRBs. The time course of the decrease was similar to the split dose recovery in terms of cell death. The parallel relationship between NRBs and cell killing implies that NRBs could play an important role in radiation-induced cell death

  10. 1,4 Naphthoquinone protects radiation induced cell death and DNA damage in lymphocytes by activation Nrf2/are pathway and enhancing DNA repair

    Energy Technology Data Exchange (ETDEWEB)

    Khan, Nazir M; Sandur, Santosh K; Checker, Rahul; Sharma, Deepak; Poduval, T.B., E-mail: nazirbiotech@rediffmail.com [Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai (India)

    2012-07-01

    1,4-Naphthoquinone (NQ) is the parent molecule of many clinically approved anticancer, anti-infective, and antiparasitic drugs such as anthracycline, mitomycin, daunorubicin, doxorubicin, diospyrin, and malarone. Presence of NQ during a-irradiation (4Gy) significantly reduced the death of irradiated murine splenic lymphocytes in a dose dependent manner (0.05-liM), with complete protection at liM as assessed by PI staining. Radioprotection by NQ was further confirmed by inhibition of caspase activation, decrease in cell size, DNA-fragmentation, nuclear-blebbing and clonogenic assay. All trans retinoic acid which is inhibitor of Nrf-2 pathway, completely abrogated the radioprotective effect of NQ, suggesting that radioprotective activity of NQ may be due to activation of Nrf-2 signaling pathways. Further, addition of NQ to lymphocytes activated Nrf-2 in time dependent manner as shown by confocal microscopy, electrophoretic mobility shift assay and quantitative real time PCR. It also increased the expression of Nrf-2 dependent cytoprotective genes like hemeoxygenase-1, MnSOD, catalse as demonstrated by real time PCR and flowcytometry. NQ protected lymphocytes significantly against radiation-induced cell death even when added after irradiation. Complete protection was observed by addition of NQ up to 2 h after irradiation. However, percentage protection decreased with increasing time interval. These results suggested that NQ may offer protection to lymphocytes activating repair pathways. Repair of radiation induced DNA strand breaks was studied by comet assay. Pretreatment of lymphocytes with NQ induced single strand breaks up to 6h but not double strand breaks in DNA. However, NQ mediated single strand breaks were repaired completely at longer time intervals. Addition of NQ to lymphocytes prior to 4 Gy a-radiation exposure showed decrease in the yield of DNA double strand breaks. The observed time-dependent decrease in the DNA strand breaks could be attributed to

  11. Role of neurotensin in radiation-induced hypothermia in rats

    International Nuclear Information System (INIS)

    Kandasamy, S.B.; Hunt, W.A.; Harris, A.H.

    1991-01-01

    The role of neurotensin in radiation-induced hypothermia was examined. Intracerebroventricular (ICV) administration of neurotensin produced dose-dependent hypothermia. Histamine appears to mediate neurotensin-induced hypothermia because the mast cell stabilizer disodium cromoglycate and antihistamines blocked the hypothermic effects of neurotensin. An ICV pretreatment with neurotensin antibody attenuated neurotensin-induced hypothermia, but did not attenuate radiation-induced hypothermia, suggesting that radiation-induced hypothermia was not mediated by neurotensin

  12. A comparative analysis of longitudinal computed tomography and histopathology for evaluating the potential of mesenchymal stem cells in mitigating radiation-induced pulmonary fibrosis.

    Science.gov (United States)

    Perez, Jessica R; Lee, Sangkyu; Ybarra, Norma; Maria, Ola; Serban, Monica; Jeyaseelan, Krishinima; Wang, Li Ming; Seuntjens, Jan; Naqa, Issam El

    2017-08-22

    Radiation-induced pulmonary fibrosis (RIPF) is a debilitating side effect that occurs in up to 30% of thoracic irradiations in breast and lung cancer patients. RIPF remains a major limiting factor to dose escalation and an obstacle to applying more promising new treatments for cancer cure. Limited treatment options are available to mitigate RIPF once it occurs, but recently, mesenchymal stem cells (MSCs) and a drug treatment stimulating endogenous stem cells (GM-CSF) have been investigated for their potential in preventing this disease onset. In a pre-clinical rat model, we contrasted the application of longitudinal computed tomography (CT) imaging and classical histopathology to quantify RIPF and to evaluate the potential of MSCs in mitigating RIPF. Our results on histology demonstrate promises when MSCs are injected endotracheally (but not intravenously). While our CT analysis highlights the potential of GM-CSF treatment. Advantages and limitations of both analytical methods are contrasted in the context of RIPF.

  13. Mechanism of protection of bystander cells by exogenous carbon monoxide: Impaired response to damage signal of radiation-induced bystander effect

    International Nuclear Information System (INIS)

    Han, W.; Yu, K.N.; Wu, L.J.; Wu, Y.C.; Wang, H.Z.

    2011-01-01

    A protective effect of exogenous carbon monoxide (CO), generated by CO releasing molecule ticarbonyldichlororuthenium (II) dimer (CORM-2), on the bystander cells from the toxicity of radiation-induced bystander effect (RIBE) was revealed in our previous study. In the present work, a possible mechanism of this CO effect was investigated. The results from medium transfer experiments showed that α-particle irradiated Chinese hamster ovary (CHO) cells would release nitric oxide (NO), which was detected with specific NO fluorescence probe, to induce p53 binding protein 1 (BP1) formation in the cell population receiving the medium, and the release peak was found to be at 1 h post irradiation. Treating the irradiated or bystander cells separately with CO (CORM-2) demonstrated that CO was effective in the bystander cells but not the irradiated cells. Measurements of NO production and release with a specific NO fluorescence probe also showed that CO treatment did not affect the production and release of NO by irradiated cells. Protection of CO on cells to peroxynitrite, an oxidizing free radical from NO, suggested that CO might protect bystander cells via impaired response of bystander cells to NO, a RIBE signal in our research system.

  14. Mechanism of protection of bystander cells by exogenous carbon monoxide: Impaired response to damage signal of radiation-induced bystander effect

    Energy Technology Data Exchange (ETDEWEB)

    Han, W. [Department of Physics and Materials Science, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon Tong, Kowloon (Hong Kong); Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); Yu, K.N., E-mail: peter.yu@cityu.edu.hk [Department of Physics and Materials Science, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon Tong, Kowloon (Hong Kong); Wu, L.J. [Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); Wu, Y.C. [Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); School of Nuclear Science and Technology, University of Science and Technology of China, Hefei 230029 (China); Wang, H.Z. [Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China)

    2011-05-10

    A protective effect of exogenous carbon monoxide (CO), generated by CO releasing molecule ticarbonyldichlororuthenium (II) dimer (CORM-2), on the bystander cells from the toxicity of radiation-induced bystander effect (RIBE) was revealed in our previous study. In the present work, a possible mechanism of this CO effect was investigated. The results from medium transfer experiments showed that {alpha}-particle irradiated Chinese hamster ovary (CHO) cells would release nitric oxide (NO), which was detected with specific NO fluorescence probe, to induce p53 binding protein 1 (BP1) formation in the cell population receiving the medium, and the release peak was found to be at 1 h post irradiation. Treating the irradiated or bystander cells separately with CO (CORM-2) demonstrated that CO was effective in the bystander cells but not the irradiated cells. Measurements of NO production and release with a specific NO fluorescence probe also showed that CO treatment did not affect the production and release of NO by irradiated cells. Protection of CO on cells to peroxynitrite, an oxidizing free radical from NO, suggested that CO might protect bystander cells via impaired response of bystander cells to NO, a RIBE signal in our research system.

  15. EZH2 Protects Glioma Stem Cells from Radiation-Induced Cell Death in a MELK/FOXM1-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Sung-Hak Kim

    2015-02-01

    Full Text Available Glioblastoma (GBM-derived tumorigenic stem-like cells (GSCs may play a key role in therapy resistance. Previously, we reported that the mitotic kinase MELK binds and phosphorylates the oncogenic transcription factor FOXM1 in GSCs. Here, we demonstrate that the catalytic subunit of Polycomb repressive complex 2, EZH2, is targeted by the MELK-FOXM1 complex, which in turn promotes resistance to radiation in GSCs. Clinically, EZH2 and MELK are coexpressed in GBM and significantly induced in postirradiation recurrent tumors whose expression is inversely correlated with patient prognosis. Through a gain-and loss-of-function study, we show that MELK or FOXM1 contributes to GSC radioresistance by regulation of EZH2. We further demonstrate that the MELK-EZH2 axis is evolutionarily conserved in Caenorhabditis elegans. Collectively, these data suggest that the MELK-FOXM1-EZH2 signaling axis is essential for GSC radioresistance and therefore raise the possibility that MELK-FOXM1-driven EZH2 signaling can serve as a therapeutic target in irradiation-resistant GBM tumors.

  16. The role of the stress-activated protein kinase (SAPK/JNK) signaling pathway in radiation-induced apoptosis

    International Nuclear Information System (INIS)

    Verheij, M.; Ruiter, G.A.; Zerp, S.F.; Bartelink, H.; Blitterswijk, W.J. van; Fuks, Z.; Haimovitz-Friedman, A.

    1998-01-01

    Ionizing radiation, like a variety of other cellular stress factors, initiates apoptosis, or programmed cell death, in many cell systems. This mode of radiation-induced cell kill should be distinguished from clonogenic cell death due to unrepaired DNA damage. Ionizing radiation not only exerts its effect on the nuclear DNA, but also at the plasma membrane level where it may activate multiple signal transduction pathways. One of these pathways is the stress-activated protein kinase (SAPK) cascade which transduces death signals from the cell membrane to the nucleus. This review discusses recent evidence on the critical role of this signaling system in radiation- and stress-induced apoptosis. An improved understanding of the mechanisms involved in radiation-induced apoptosis may ultimately provide novel strategies of intervention in specific signal transduction pathways to favorably alter the therapeutic ratio in the treatment of human malignancies. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  17. Lack of effect of inhibitors of DNA synthesis/repair on the ionizing radiation-induced chromosomal damage in G[sub 2] stage of ataxia telangiectasia cells

    Energy Technology Data Exchange (ETDEWEB)

    Antoccia, A. (Univ. ' La Sapienza' , Rome (Italy). Dipt. di Genetica e Biologia Molecolare); Palitti, F.; Raggi, T. (Univ. del Tuscia, Viterbo (Italy). Dipt. di Agrobiologia ed Agrochimica); Catena, C. (ENEA, Casaccia (Italy). Centro Ricerche Energia); Tanzarella, C. (Rome Univ. 3 (Italy). Dipt. di Biologia)

    1994-09-01

    The relationship between the repair processes occurring at the G[sub 2] phase of the cell cycle and cytogenetic damage in ataxia telangiectasia (AT) cells was studied. Lymphoblastoid cells derived from normal, heterozygote AT (HzAT) and three AT patients were exposed to X-rays or fission neutrons and post-treated with inhibitors of DNA synthesis/repair, such as inhibitors of DNA polymerases [alpha], [sigma] and [epsilon] (cytosine arabinoside, ara-C; aphidicolin, APC; buthylphenyl-guanine, BuPdG) or ribonucleotide reductase (hydroxyurea HU). A strong increase of radiation-induced chromosomal aberrations was observed in normal and HzAT cells post-treated with ara-C, APC and HU, but not in the presence of BuPdG. No enhancing effect was observed in cells derived from AT patients, except for HU post-irradiation treatment. These results suggest that the enzymes that can be inhibited by these agents are not directly involved in the repair of radiation damage induced in G[sub 2] cells from AT patients, indicating that probably the AT cells that we used lack the capability to transform the primary DNA lesions into reparable products, or that AT cells might contain a mutated form of DNA polymerase resistant to the inhibitors. (author).

  18. Effects of Chk1 inhibition on the temporal duration of radiation-induced G2 arrest in HeLa cells

    International Nuclear Information System (INIS)

    Nahar, Kamrun; Goto, Tatsuaki; Kaida, Atsushi; Deguchi, Shifumi; Miura, Masahiko

    2014-01-01

    Chk1 inhibitor acts as a potent radiosensitizer in p53-deficient tumor cells by abrogating the G2/M check-point. However, the effects of Chk1 inhibitor on the duration of G2 arrest have not been precisely analyzed. To address this issue, we utilized a cell-cycle visualization system, fluorescent ubiquitination-based cell-cycle indicator (Fucci), to analyze the change in the first green phase duration (FGPD) after irradiation. In the Fucci system, G1 and S/G2/M cells emit red and green fluorescence, respectively; therefore, G2 arrest is reflected by an elongated FGPD. The system also allowed us to differentially analyze cells that received irradiation in the red or green phase. Cells irradiated in the green phase exhibited a significantly elongated FGPD relative to cells irradiated in the red phase. In cells irradiated in either phase, Chk1 inhibitor reduced FGPD almost to control levels. The results of this study provide the first clear information regarding the effects of Chk1 inhibition on radiation-induced G2 arrest, with special focus on the time dimension. (author)

  19. Effects of oxygen and misonidazole on cell transformation and cell killing in C3H 10T1/2 cells by X rays in vitro

    International Nuclear Information System (INIS)

    Borsa, J.; Sargent, M.D.; Einspenner, M.; Azzam, E.I.; Raaphorst, G.P.

    1984-01-01

    The effects of oxygen (air) and misonidazole on the transformation and killing of 10T1/2 cells by X rays were examined. The oxygen effect for the cell transformation end point was very similar to that for cell killing. Misonidazole enhanced both cell killing and cell transformation to a similar extent. The enhancement of both end points by misonidazole occurred only in the absence of oxygen during irradiation and was of lesser magnitude than that observed for oxygen. These results demonstrate that the radiation chemical processes leading to cell killing and cell transformation, respectively, are affected similarly by these two enhancers of radiation action. 22 references, 3 figures, 2 tables

  20. Effects of cellular non-protein sulfhydryl depletion in radiation induced oncogenic transformation and genotoxicity in mouse C3H 10T1/2 cells

    International Nuclear Information System (INIS)

    Hei, T.K.; Geard, C.R.; Hall, E.J.

    1984-01-01

    A study was made of the effects of cellular non-protein sulfhydryl (NPSH) depletion on cytotoxicity, cell cycle kinetics, oncogenic transformation and sister chromatid exchange (SCE) in C 3 H 10T1/2 cells. Using DL-Buthionine S-R-Sulfoximine (BSO) to deplete thiols, it was found spectrophotometrically that less than 5% of control NPSH level remained in the cells after 24-hour treatment under aerated conditions. Such NPSH depleted cells, when subject to a 3 Gy γ-ray treatment, were found to have no radiosensitizing response either in terms of cell survival or oncogenic transformation. In addition, decreased levels of NPSH had no effect on spontaneous or radiation-induced SCE nor were cell cycle kinetics additionally altered. Therefore, the inability of NPSH depletion to alter γ-ray induced cellular transformation was unrelated to any possible effect of BSO on the cell cycle. These results suggest that such depletion may result in little or no additional oncogenic or genotoxic effects on aerated normal tissues

  1. Individual motile CD4+ T cells can participate in efficient multi-killing through conjugation to multiple tumor cells

    Science.gov (United States)

    Liadi, Ivan; Singh, Harjeet; Romain, Gabrielle; Rey-Villamizar, Nicolas; Merouane, Amine; Adolacion, Jay R T.; Kebriaei, Partow; Huls, Helen; Qiu, Peng; Roysam, Badrinath; Cooper, Laurence J.N.; Varadarajan, Navin

    2015-01-01

    T cells genetically modified to express a CD19-specific chimeric antigen receptor (CAR) for the investigational treatment of B-cell malignancies comprise a heterogeneous population, and their ability to persist and participate in serial killing of tumor cells is a predictor of therapeutic success. We implemented Timelapse Imaging Microscopy In Nanowell Grids (TIMING) to provide direct evidence that CD4+CAR+ T cells (CAR4 cells) can engage in multi-killing via simultaneous conjugation to multiple tumor cells. Comparisons of the CAR4 cells and CD8+CAR+ T cells (CAR8 cells) demonstrate that while CAR4 cells can participate in killing and multi-killing, they do so at slower rates, likely due to the lower Granzyme B content. Significantly, in both sets of T cells, a minor sub-population of individual T cells identified by their high motility, demonstrated efficient killing of single tumor cells. By comparing both the multi-killer and single killer CAR+ T cells it appears that the propensity and kinetics of T-cell apoptosis was modulated by the number of functional conjugations. T cells underwent rapid apoptosis, and at higher frequencies, when conjugated to single tumor cells in isolation and this effect was more pronounced on CAR8 cells. Our results suggest that the ability of CAR+ T cells to participate in multi-killing should be evaluated in the context of their ability to resist activation induced cell death (AICD). We anticipate that TIMING may be utilized to rapidly determine the potency of T-cell populations and may facilitate the design and manufacture of next-generation CAR+ T cells with improved efficacy. PMID:25711538

  2. Preferential killing of cancer cells and activated human T cells using ZnO nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Hanley, Cory; Layne, Janet; Feris, Kevin; Wingett, Denise [Department of Biological Sciences, Boise State University, Boise, ID 83725 (United States); Punnoose, Alex; Reddy, K M; Coombs, Isaac; Coombs, Andrew [Department of Physics, Boise State University, Boise, ID 83725 (United States)], E-mail: denisewingett@boisestate.edu

    2008-07-23

    Nanoparticles are increasingly being recognized for their potential utility in biological applications including nanomedicine. Here we examine the response of normal human cells to ZnO nanoparticles under different signaling environments and compare it to the response of cancerous cells. ZnO nanoparticles exhibit a strong preferential ability to kill cancerous T cells ({approx}28-35 x) compared to normal cells. Interestingly, the activation state of the cell contributes toward nanoparticle toxicity, as resting T cells display a relative resistance while cells stimulated through the T cell receptor and CD28 costimulatory pathway show greater toxicity in direct relation to the level of activation. Mechanisms of toxicity appear to involve the generation of reactive oxygen species, with cancerous T cells producing higher inducible levels than normal T cells. In addition, nanoparticles were found to induce apoptosis and the inhibition of reactive oxygen species was found to be protective against nanoparticle induced cell death. The novel findings of cell selective toxicity, towards potential disease causing cells, indicate a potential utility of ZnO nanoparticles in the treatment of cancer and/or autoimmunity.

  3. Preferential killing of cancer cells and activated human T cells using ZnO nanoparticles

    International Nuclear Information System (INIS)

    Hanley, Cory; Layne, Janet; Feris, Kevin; Wingett, Denise; Punnoose, Alex; Reddy, K M; Coombs, Isaac; Coombs, Andrew

    2008-01-01

    Nanoparticles are increasingly being recognized for their potential utility in biological applications including nanomedicine. Here we examine the response of normal human cells to ZnO nanoparticles under different signaling environments and compare it to the response of cancerous cells. ZnO nanoparticles exhibit a strong preferential ability to kill cancerous T cells (∼28-35 x) compared to normal cells. Interestingly, the activation state of the cell contributes toward nanoparticle toxicity, as resting T cells display a relative resistance while cells stimulated through the T cell receptor and CD28 costimulatory pathway show greater toxicity in direct relation to the level of activation. Mechanisms of toxicity appear to involve the generation of reactive oxygen species, with cancerous T cells producing higher inducible levels than normal T cells. In addition, nanoparticles were found to induce apoptosis and the inhibition of reactive oxygen species was found to be protective against nanoparticle induced cell death. The novel findings of cell selective toxicity, towards potential disease causing cells, indicate a potential utility of ZnO nanoparticles in the treatment of cancer and/or autoimmunity

  4. Tumour-cell killing by X-rays and immunity quantitated in a mouse model system

    International Nuclear Information System (INIS)

    Porteous, D.D.; Porteous, K.M.; Hughes, M.J.

    1979-01-01

    As part of an investigation of the interaction of X-rays and immune cytotoxicity in tumour control, an experimental mouse model system has been used in which quantitative anti-tumour immunity was raised in prospective recipients of tumour-cell suspensions exposed to varying doses of X-rays in vitro before injection. Findings reported here indicate that, whilst X-rays kill a proportion of cells, induced immunity deals with a fixed number dependent upon the immune status of the host, and that X-rays and anti-tumour immunity do not act synergistically in tumour-cell killing. The tumour used was the ascites sarcoma BP8. (author)

  5. The kinematics of cytotoxic lymphocytes influence their ability to kill target cells.

    Directory of Open Access Journals (Sweden)

    Purnima Bhat

    Full Text Available Cytotoxic lymphocytes (CTL have been reported to show a range of motility patterns from rapid long-range tracking to complete arrest, but how and whether these kinematics affect their ability to kill target cells is not known. Many in vitro killing assays utilize cell lines and tumour-derived cells as targets, which may be of limited relevance to the kinetics of CTL-mediated killing of somatic cells. Here, live-cell microscopy is used to examine the interactions of CTL and primary murine skin cells presenting antigens. We developed a qualitative and quantitative killing assay using extended-duration fluorescence time-lapse microscopy coupled with large-volume objective software-based data analysis to obtain population data of cell-to-cell interactions, motility and apoptosis. In vivo and ex vivo activated antigen-specific cytotoxic lymphocytes were added to primary keratinocyte targets in culture with fluorometric detection of caspase-3 activation in targets as an objective determinant of apoptosis. We found that activated CTL achieved contact-dependent apoptosis of non-tumour targets after a period of prolonged attachment - on average 21 hours - which was determined by target cell type, amount of antigen, and activation status of CTL. Activation of CTL even without engagement of the T cell receptor was sufficient to mobilise cells significantly above baseline, while the addition of cognate antigen further enhanced their motility. Highly activated CTL showed markedly increased vector displacement, and velocity, and lead to increased antigen-specific target cell death. These data show that the inherent kinematics of CTL correlate directly with their ability to kill non-tumour cells presenting cognate antigen.

  6. Tumor Cells Surviving Exposure to Proton or Photon Radiation Share a Common Immunogenic Modulation Signature, Rendering Them More Sensitive to T Cell–Mediated Killing

    Energy Technology Data Exchange (ETDEWEB)

    Gameiro, Sofia R.; Malamas, Anthony S. [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States); Bernstein, Michael B. [Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas (United States); Tsang, Kwong Y. [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States); Vassantachart, April; Sahoo, Narayan; Tailor, Ramesh; Pidikiti, Rajesh [Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas (United States); Guha, Chandan P. [Department of Radiation Oncology, Montefiore Medical Center, Bronx, New York (United States); Hahn, Stephen M.; Krishnan, Sunil [Division of Radiation Oncology, M. D. Anderson Cancer Center, Houston, Texas (United States); Hodge, James W., E-mail: jh241d@nih.gov [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States)

    2016-05-01

    Purpose: To provide the foundation for combining immunotherapy to induce tumor antigen–specific T cells with proton radiation therapy to exploit the activity of those T cells. Methods and Materials: Using cell lines of tumors frequently treated with proton radiation, such as prostate, breast, lung, and chordoma, we examined the effect of proton radiation on the viability and induction of immunogenic modulation in tumor cells by flow cytometric and immunofluorescent analysis of surface phenotype and the functional immune consequences. Results: These studies show for the first time that (1) proton and photon radiation induced comparable up-regulation of surface molecules involved in immune recognition (histocompatibility leukocyte antigen, intercellular adhesion molecule 1, and the tumor-associated antigens carcinoembryonic antigen and mucin 1); (2) proton radiation mediated calreticulin cell-surface expression, increasing sensitivity to cytotoxic T-lymphocyte killing of tumor cells; and (3) cancer stem cells, which are resistant to the direct cytolytic activity of proton radiation, nonetheless up-regulated calreticulin after radiation in a manner similar to non-cancer stem cells. Conclusions: These findings offer a rationale for the use of proton radiation in combination with immunotherapy, including for patients who have failed radiation therapy alone or have limited treatment options.

  7. HAMLET kills tumor cells by apoptosis: structure, cellular mechanisms, and therapy.

    Science.gov (United States)

    Gustafsson, Lotta; Hallgren, Oskar; Mossberg, Ann-Kristin; Pettersson, Jenny; Fischer, Walter; Aronsson, Annika; Svanborg, Catharina

    2005-05-01

    New cancer treatments should aim to destroy tumor cells without disturbing normal tissue. HAMLET (human alpha-lactalbumin made lethal to tumor cells) offers a new molecular approach to solving this problem, because it induces apoptosis in tumor cells but leaves normal differentiated cells unaffected. After partial unfolding and binding to oleic acid, alpha-lactalbumin forms the HAMLET complex, which enters tumor cells and freezes their metabolic machinery. The cells proceed to fragment their DNA, and they disintegrate with apoptosis-like characteristics. HAMLET kills a wide range of malignant cells in vitro and maintains this activity in vivo in patients with skin papillomas. In addition, HAMLET has striking effects on human glioblastomas in a rat xenograft model. After convection-enhanced delivery, HAMLET diffuses throughout the brain, selectively killing tumor cells and controlling tumor progression without apparent tissue toxicity. HAMLET thus shows great promise as a new therapeutic with the advantage of selectivity for tumor cells and lack of toxicity.

  8. Radiation-induced DNA damage in tumors and normal tissues. II. Influence of dose, residual DNA damage and physiological factors in oxygenated cells

    International Nuclear Information System (INIS)

    Zhang, H.; Wheeler, K.T.

    1994-01-01

    Detection and quantification of hypoxic cells in solid tumors is important for many experimental and clinical situations. Several laboratories, including ours, have suggested that assays which measure radiation-induced DNA strand breaks and DNA-protein crosslinks (DPCs) might be used to detect or quantify hypoxic cells in tumors and normal tissues. Recently, we demonstrated the feasibility of using an alkaline elution assay that measures strand breaks and DPCs to detect and/or quantify hypoxic cells in tissues. For this approach to be valid, DPCs must not be formed to any great extent in irradiated oxygenated cells, and the formation and repair of strand breaks and DPCs in oxygenated cells must not be modified appreciably by physiological factors (e.g., temperature, pH and nutrient depletion) that are often found in solid tumors. To address these issues, two sets of experiments were performed. In one set of experiments, oxygenated 9L cells in tissue culture, subcutaneous 9L tumors and rat cerebella were irradiated with doses of 15 or 50 Gy and allowed to repair until the residual strand break damage was low enough to detect DPCs. In another set of experiments, oxygenated exponentially growing or plateau-phase 9L cells in tissue culture were irradiated with a dose of 15 Gy at 37 or 20 degrees C, while the cells were maintained at a pH of either 6.6 or 7.3. DNA-protein crosslinks were formed in oxygenated cells about 100 times less efficiently than in hypoxic cells. In addition, temperature, pH, nutrient depletion and growth phase did not appreciably alter the formation and repair of strand breaks or the formation of DPCs in oxygenated 9L cells. These results support the use of this DNA damage assay for the detection and quantification of hypoxic cells in solid tumors. 27 refs., 5 tabs

  9. Radiation-induced apoptosis of stem/progenitor cells in human umbilical cord blood is associated with alterations in reactive oxygen and intracellular pH

    Energy Technology Data Exchange (ETDEWEB)

    Hayashi, Tomonori [Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hijyama Park, Minami Ward, Hiroshima (Japan)]. E-mail: tomo@rerf.or.jp; Hayashi, Ikue [Central Research Laboratory, Hiroshima University Faculty of Dentistry, Hiroshima (Japan); Shinohara, Tomoko [Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hijyama Park, Minami Ward, Hiroshima (Japan); Morishita, Yukari [Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hijyama Park, Minami Ward, Hiroshima (Japan); Nagamura, Hiroko [Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hijyama Park, Minami Ward, Hiroshima (Japan); Kusunoki, Yoichiro [Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hijyama Park, Minami Ward, Hiroshima (Japan); Kyoizumi, Seishi [Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hijyama Park, Minami Ward, Hiroshima (Japan); Seyama, Toshio [Yasuda Women' s University, Hiroshima (Japan); Nakachi, Kei [Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hijyama Park, Minami Ward, Hiroshima (Japan)

    2004-11-22

    To investigate the sensitivity of human hematopoietic stem cell populations to radiation and its relevance to intracellular events, specifically alteration in cellular energy production systems, we examined the frequency of apoptotic cells, generation of superoxide anions (O2-), and changes in cytosol pH in umbilical cord blood (UCB) CD34{sup +}/CD38{sup -}, CD34{sup +}/CD38{sup +} and CD34{sup -}/CD38{sup +} cells before and after 5Gy of X-irradiation. Human UCB mononucleated cells were used in this study. After X-irradiation and staining subgroups of the cells with fluorescence (FITC, PE, or CY)-labeled anti-CD34 and anti-CD38 antibodies, analyses were performed by FACScan using as stains 7-amino-actinomycin D (7-AAD) for the detection of apoptosis, and hydroethidine (HE) for the measurement of O2- generation in the cells. For intracellular pH, image analysis was conducted using confocal laser microscopy after irradiation and staining with carboxy-SNAFR-1. The frequency of apoptotic cells, as determined by cell staining with 7-AAD, was highest in the irradiated CD34{sup +}/CD38{sup -} cell population, where the level of O2- detected by the oxidation of HE was also most highly elevated. Intracellular pH measured with carboxy-SNARF-1-AM by image cytometer appeared to be lowest in the same irradiated CD34{sup +}/CD38{sup -} cell population, and this intracellular pH decreased as early as 4h post-irradiation, virtually simultaneous with the significant elevation of O2- generation. These results suggest that the CD34{sup +}/CD38{sup -} stem cell population is sensitive to radiation-induced apoptosis as well as production of intracellular O2-, compare to more differentiated CD34{sup +}/CD38{sup +} and CD34{sup -}/CD38{sup +} cells and that its intracellular pH declines at an early phase in the apoptosis process.

  10. Radiation-induced apoptosis of stem/progenitor cells in human umbilical cord blood is associated with alterations in reactive oxygen and intracellular pH

    International Nuclear Information System (INIS)

    Hayashi, Tomonori; Hayashi, Ikue; Shinohara, Tomoko; Morishita, Yukari; Nagamura, Hiroko; Kusunoki, Yoichiro; Kyoizumi, Seishi; Seyama, Toshio; Nakachi, Kei

    2004-01-01

    To investigate the sensitivity of human hematopoietic stem cell populations to radiation and its relevance to intracellular events, specifically alteration in cellular energy production systems, we examined the frequency of apoptotic cells, generation of superoxide anions (O2-), and changes in cytosol pH in umbilical cord blood (UCB) CD34 + /CD38 - , CD34 + /CD38 + and CD34 - /CD38 + cells before and after 5Gy of X-irradiation. Human UCB mononucleated cells were used in this study. After X-irradiation and staining subgroups of the cells with fluorescence (FITC, PE, or CY)-labeled anti-CD34 and anti-CD38 antibodies, analyses were performed by FACScan using as stains 7-amino-actinomycin D (7-AAD) for the detection of apoptosis, and hydroethidine (HE) for the measurement of O2- generation in the cells. For intracellular pH, image analysis was conducted using confocal laser microscopy after irradiation and staining with carboxy-SNAFR-1. The frequency of apoptotic cells, as determined by cell staining with 7-AAD, was highest in the irradiated CD34 + /CD38 - cell population, where the level of O2- detected by the oxidation of HE was also most highly elevated. Intracellular pH measured with carboxy-SNARF-1-AM by image cytometer appeared to be lowest in the same irradiated CD34 + /CD38 - cell population, and this intracellular pH decreased as early as 4h post-irradiation, virtually simultaneous with the significant elevation of O2- generation. These results suggest that the CD34 + /CD38 - stem cell population is sensitive to radiation-induced apoptosis as well as production of intracellular O2-, compare to more differentiated CD34 + /CD38 + and CD34 - /CD38 + cells and that its intracellular pH declines at an early phase in the apoptosis process

  11. Protective Role of Hsp27 Protein Against Gamma Radiation-Induced Apoptosis and Radiosensitization Effects of Hsp27 Gene Silencing in Different Human Tumor Cells

    International Nuclear Information System (INIS)

    Aloy, Marie-Therese; Hadchity, Elie; Bionda, Clara; Diaz-Latoud, Chantal; Claude, Line; Rousson, Robert; Arrigo, Andre-Patrick; Rodriguez-Lafrasse, Claire

    2008-01-01

    Purpose: The ability of heat shock protein 27 (Hsp27) to protect cells from stressful stimuli and its increased levels in tumors resistant to anticancer therapeutics suggest that it may represent a target for sensitization to radiotherapy. In this study, we investigate the protective role of Hsp27 against radiation-induced apoptosis and the effect of its attenuation in highly expressing radioresistant cancer cell lines. Methods and Materials: We examined clonogenic death and the kinetics of apoptotic events in different tumor cell lines overexpressing or underexpressing Hsp27 protein irradiated with photons. The radiosensitive Jurkat cell line, which does not express Hsp27 constitutively or in response to γ-rays, was stably transfected with Hsp27 complementary DNA. Attenuation of Hsp27 expression was accomplished by antisense or RNAi (interfering RNA) strategies in SQ20B head-and-neck squamous carcinoma, PC3 prostate cancer, and U87 glioblastoma radioresistant cells. Results: We measured concentration-dependent protection against the cytotoxic effects of radiation in Jurkat-Hsp27 cells, which led to a 50% decrease in apoptotic cells at 48 hours in the highest expressing cells. Underlying mechanisms leading to radiation resistance involved a significant increase in glutathione levels associated with detoxification of reactive oxygen species, a delay in mitochondrial collapse, and caspase activation. Conversely, attenuation of Hsp27 in SQ20B cells, characterized by their resistance to apoptosis, sensitizes cells to irradiation. This was emphasized by increased apoptosis, decreased glutathione basal level, and clonogenic cell death. Sensitization to irradiation was confirmed in PC3 and U87 radioresistant cells. Conclusion: Hsp27 gene therapy offers a potential adjuvant to radiation-based therapy of resistant tumors

  12. Reactivation of neutron killed mammalian cells by gamma irradiation: The observations, possible mechanism and implication

    International Nuclear Information System (INIS)

    Calkins, J.; Harrison, W.; Einspenner, M.

    1990-01-01

    We have observed that combinations of neutron plus gamma ray exposure can significantly increase the colony forming ability of monkey and human cell cultures over the neutron dose alone. The 'reactivation' of neutron killed mammalian cells by gamma rays is analogous to observations made in lower eukaryotic organisms and fits the pattern termed 'T repair' previously postulated for yeast and protozoans. (orig.)

  13. Characterization of cell lysis in Pseudomonas putida induced upon expression of heterologous killing genes

    DEFF Research Database (Denmark)

    Ronchel, M.C.; Molina, L.; Witte, A.

    1998-01-01

    Active biological containment systems are based on the controlled expression of killing genes. These systems are of interest for the Pseudomonadaceae because of the potential applications of these microbes as bioremediation agents and biopesticides, The physiological effects that lead to cell dea...... protein was the killing agent. In both cases, cell death occurred as a result of impaired respiration, altered membrane permeability, and the release of some cytoplasmic contents to the extracellular medium.......Active biological containment systems are based on the controlled expression of killing genes. These systems are of interest for the Pseudomonadaceae because of the potential applications of these microbes as bioremediation agents and biopesticides, The physiological effects that lead to cell death......, respectively. Expression of the killing genes is controlled by the LacI protein, whose expression is initiated from the XylS-dependent Pm promoter. Under induced conditions, killing of P. putida CMC12 cells mediated by phi X174 lysis protein E was faster than that observed for P. putida CMC4, for which the Gef...

  14. Radiation-Induced Bystander Response: Mechanism and Clinical Implications

    Science.gov (United States)

    Suzuki, Keiji; Yamashita, Shunichi

    2014-01-01

    Significance: Absorption of energy from ionizing radiation (IR) to the genetic material in the cell gives rise to damage to DNA in a dose-dependent manner. There are two types of DNA damage; by a high dose (causing acute or deterministic effects) and by a low dose (related to chronic or stochastic effects), both of which induce different health effects. Among radiation effects, acute cutaneous radiation syndrome results from cell killing as a consequence of high-dose exposure. Recent advances: Recent advances in radiation biology and oncology have demonstrated that bystander effects, which are emerged in cells that have never been exposed, but neighboring irradiated cells, are also involved in radiation effects. Bystander effects are now recognized as an indispensable component of tissue response related to deleterious effects of IR. Critical issues: Evidence has indicated that nonapoptotic premature senescence is commonly observed in various tissues and organs. Senesced cells were found to secrete various proteins, including cytokines, chemokines, and growth factors, most of which are equivalent to those identified as bystander factors. Secreted factors could trigger cell proliferation, angiogenesis, cell migration, inflammatory response, etc., which provide a tissue microenvironment assisting tissue repair and remodeling. Future directions: Understandings of the mechanisms and physiological relevance of radiation-induced bystander effects are quite essential for the beneficial control of wound healing and care. Further studies should extend our knowledge of the mechanisms of bystander effects and mode of cell death in response to IR. PMID:24761341

  15. Does autophagy have a license to kill mammalian cells?

    NARCIS (Netherlands)

    Scarlatti, F.; Granata, R.; Meijer, A. J.; Codogno, P.

    2009-01-01

    Macroautophagy is an evolutionarily conserved vacuolar, self-digesting mechanism for cellular components, which end up in the lysosomal compartment. In mammalian cells, macroautophagy is cytoprotective, and protects the cells against the accumulation of damaged organelles or protein aggregates, the

  16. Radiation-induced cancer

    International Nuclear Information System (INIS)

    Dutrillaux, B.; CEA Fontenay-aux-Roses, 92

    1998-01-01

    The induction of malignant diseases is one of the most concerning late effects of ionising radiation. A large amount of information has been collected form atomic bomb survivors, patients after therapeutic irradiation, occupational follow-up and accidentally exposed populations. Major uncertainties persist in the (very) low range i.e, population and workers radioprotection. A review of the biological mechanisms leading to cancer strongly suggests that the vast majority of radiation-induced malignancies arise as a consequence of recessive mutations can be unveiled by ageing, this process being possibly furthered by constitutional or acquired genomic instability. The individual risk is likely to be very low, probably because of the usual dose level. However, the magnitude of medical exposure and the reliance of our societies on nuclear industry are so high that irreproachable decision-making processes and standards for practice are inescapable. (author)

  17. Radiation induced oral mucositis

    Directory of Open Access Journals (Sweden)

    P S Satheesh Kumar

    2009-01-01

    Full Text Available Patients receiving radiotherapy or chemotherapy will receive some degree of oral mucositis The incidence of oral mucositis was especially high in patients: (i With primary tumors in the oral cavity, oropharynx, or nasopharynx; (ii who also received concomitant chemotherapy; (iii who received a total dose over 5,000 cGy; and (iv who were treated with altered fractionation radiation schedules. Radiation-induced oral mucositis affects the quality of life of the patients and the family concerned. The present day management of oral mucositis is mostly palliative and or supportive care. The newer guidelines are suggesting Palifermin, which is the first active mucositis drug as well as Amifostine, for radiation protection and cryotherapy. The current management should focus more on palliative measures, such as pain management, nutritional support, and maintenance, of good oral hygiene

  18. Radiation induced pesticidal microbes

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ki Yup; Lee, Y. K.; Kim, J. S.; Kim, J. K.; Lee, S. J.; Lim, D. S

    2001-01-01

    To isolate pesticidal microbes against plant pathogenic fungi, 4 strains of bacteria(K1. K3, K4, YS1) were isolated from mushroom compost and hot spring. K4, K1, K3, YS1 strain showed wide antifungal spectrum and high antifungal activities against 12 kinds of fungi. Specific proteins and the specific transcribed genes were found from the YS1 and its radiation-induced mutants. And knock-out mutants of antifungal activity were derived by transposon mutagenesis. From these knock-out mutants, the antifungal activity related genes and its modification by gamma-ray radiation are going to be studied. These results suggested that radiation could be an useful tool for the induction of functional mutants.

  19. Radiation induced pesticidal microbes

    International Nuclear Information System (INIS)

    Kim, Ki Yup; Lee, Y. K.; Kim, J. S.; Kim, J. K.; Lee, S. J.; Lim, D. S.

    2001-01-01

    To isolate pesticidal microbes against plant pathogenic fungi, 4 strains of bacteria(K1. K3, K4, YS1) were isolated from mushroom compost and hot spring. K4, K1, K3, YS1 strain showed wide antifungal spectrum and high antifungal activities against 12 kinds of fungi. Specific proteins and the specific transcribed genes were found from the YS1 and its radiation-induced mutants. And knock-out mutants of antifungal activity were derived by transposon mutagenesis. From these knock-out mutants, the antifungal activity related genes and its modification by gamma-ray radiation are going to be studied. These results suggested that radiation could be an useful tool for the induction of functional mutants

  20. Glucocorticoids and Polyamine Inhibitors Synergize to Kill Human Leukemic CEM Cells1

    Science.gov (United States)

    Miller, Aaron L; Johnson, Betty H; Medh, Rheem D; Townsend, Courtney M; Thompson, E Brad

    2002-01-01

    Abstract Glucocorticoids are well-known apoptotic agents in certain classes of lymphoid cell malignancies. Reduction of intracellular polyamine levels by use of inhibitors that block polyamine synthesis slows or inhibits growth of many cells in vitro. Several such inhibitors have shown efficacy in clinical trials, though the toxicity of some compounds has limited their usefulness. We have tested the effects of combinations of the glucocorticoid dexamethasone (Dex) and two polyamine inhibitors, difluoromethylornithine (DFMO) and methyl glyoxal bis guanylhydrazone (MGBG), on the clonal line of human acute lymphoblastic leukemia cells, CEM-C7-14. Dex alone kills these cells, though only after a delay of at least 24 hours. We also evaluated a partially glucocorticoid-resistant c-Myc-expressing CEM-C7-14 clone. We show that Dex downregulates ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine synthesis. Pretreatment with the ODC inhibitor DFMO, followed by addition of Dex, enhances steroid-evoked kill slightly. The combination of pretreatment with sublethal concentrations of both DFMO and the inhibitor of S-adenosylmethionine decarboxylase, MGBG, followed by addition of Dex, results in strong synergistic cell kill. Both the rapidity and extent of cell kill are enhanced compared to the effects of Dex alone. These results suggest that use of such combinations in vivo may result in apoptosis of malignant cells with lower overall toxicity. PMID:11922393

  1. Glucocorticoids and Polyamine Inhibitors Synergize to Kill Human Leukemic CEM Cells

    Directory of Open Access Journals (Sweden)

    Aaron L. Miller

    2002-01-01

    Full Text Available Glucocorticoids are well-known apoptotic agents in certain classes of lymphoid cell malignancies. Reduction of intracellular polyamine levels by use of inhibitors that block polyamine synthesis slows or inhibits growth of many cells in vitro. Several such inhibitors have shown efficacy in clinical trials, though the toxicity of some compounds has limited their usefulness. We have tested the effects of combinations of the glucocorticoid dexamethasone. (20Dex and two polyamine inhibitors, difluoromethylornithine. (20DFMO and methyl glyoxal bis guanylhydrazone. (20MGBG, on the clonal line of human acute lymphoblastic leukemia cells, CEM-C7-14. Dex alone kills these cells, though only after a delay of at least 24 hours. We also evaluated a partially glucocorticoid-resistant c-Myc-expressing CEM-C7-14 clone. We show that Dex downregulates ornithine decarboxylase. (20ODC, the rate-limiting enzyme in polyamine synthesis. Pretreatment with the ODC inhibitor DFMO, followed by addition of Dex, enhances steroid-evoked kill slightly. The combination of pretreatment with sublethal concentrations of both DFMO and the inhibitor of S-adenosylmethionine decarboxylase, MGBG, followed by addition of Dex, results in strong synergistic cell kill. Both the rapidity and extent of cell kill are enhanced compared to the effects of Dex alone. These results suggest that use of such combinations in vivo may result in apoptosis of malignant cells with lower overall toxicity.

  2. Flow cytometric analysis of cell killing by the jumper ant venom peptide pilosulin 1.

    Science.gov (United States)

    King, M A; Wu, Q X; Donovan, G R; Baldo, B A

    1998-08-01

    Pilosulin 1 is a synthetic 56-amino acid residue polypeptide that corresponds to the largest allergenic polypeptide found in the venom of the jumper ant Myrmecia pilosula. Initial experiments showed that pilosulin 1 lysed erythrocytes and killed proliferating B cells. Herein, we describe how flow cytometry was used to investigate the cytotoxicity of the peptide for human white blood cells. Cells were labeled with fluorochrome-conjugated antibodies, incubated with the peptide and 7-aminoactinomycin D (7-AAD), and then analyzed. The effects of varying the peptide concentration, serum concentration, incubation time, and incubation temperature were measured, and the cytotoxicity of pilosulin 1 was compared with that of the bee venom peptide melittin. The antibodies and the 7-AAD enabled the identification of cell subpopulations and dead cells, respectively. It was possible, using the appropriate mix of antibodies and four-color analysis, to monitor the killing of three or more cell subpopulations simultaneously. We found that 1) pilosulin 1 killed cells within minutes, with kinetics similar to those of melittin; 2) pilosulin 1 was a slightly more potent cytotoxic agent than melittin; 3) both pilosulin 1 and melittin were more potent against mononuclear leukocytes than against granulocytes; and 4) serum inhibited killing by either peptide.

  3. Radiation-induced alterations in binding of concanavalin A to cells and in their susceptibility to agglutination

    International Nuclear Information System (INIS)

    Takahashi, Kazuhide; Kaneko, Ichiro

    1986-01-01

    Cell susceptibility to agglutination mediated by a plant lectin, concanavalin A (Con A), and the binding capacity of Con A to cells following γ-irradiation have been examined in mouse myeloid leukaemia cells cultured in suspension. Irradiation caused an immediate decrease in the amount of Con A bound to the cell surface, whereas susceptibility of irradiated cells to agglutination by Con A was unchanged when compared to that of the unirradiated cells. Post-irradiation incubation of cells at 37 0 resulted in a temporary, more than 1.3-fold increase in cell susceptibility to agglutination 60 min after irradiation, whereas binding capacity of cells for Con A gradually-recovered following irradiation, reaching a comparable level to that of unirradiated cells 3 h after irradiation. Cell susceptibility to agglutination by Con A does not depend strongly on its binding capacity. (author)

  4. Does autophagy have a license to kill mammalian cells?

    Science.gov (United States)

    Scarlatti, F; Granata, R; Meijer, A J; Codogno, P

    2009-01-01

    Macroautophagy is an evolutionarily conserved vacuolar, self-digesting mechanism for cellular components, which end up in the lysosomal compartment. In mammalian cells, macroautophagy is cytoprotective, and protects the cells against the accumulation of damaged organelles or protein aggregates, the loss of interaction with the extracellular matrix, and the toxicity of cancer therapies. During periods of nutrient starvation, stimulating macroautophagy provides the fuel required to maintain an active metabolism and the production of ATP. Macroautophagy can inhibit the induction of several forms of cell death, such as apoptosis and necrosis. However, it can also be part of the cascades of events that lead to cell death, either by collaborating with other cell death mechanisms or by causing cell death on its own. Loss of the regulation of bulk macroautophagy can prime self-destruction by cells, and some forms of selective autophagy and non-canonical forms of macroautophagy have been shown to be associated with cell demise. There is now mounting evidence that autophagy and apoptosis share several common regulatory elements that are crucial in any attempt to understand the dual role of autophagy in cell survival and cell death.

  5. The effect of age at exposure on the inactivating mechanisms and relative contributions of key tumor suppressor genes in radiation-induced mouse T-cell lymphomas

    Energy Technology Data Exchange (ETDEWEB)

    Sunaoshi, Masaaki [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Department of Biological Sciences, College of Science, Ibaraki University, Bunkyo 2-1-1, Mito, Ibaraki 310-8512 (Japan); Amasaki, Yoshiko; Hirano-Sakairi, Shinobu; Blyth, Benjamin J. [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Morioka, Takamitsu [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Radiation Effect Accumulation and Prevention Project, Fukushima Project Headquarters, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Kaminishi, Mutsumi [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Shang, Yi [Radiation Effect Accumulation and Prevention Project, Fukushima Project Headquarters, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Nishimura, Mayumi; Shimada, Yoshiya [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Radiation Effect Accumulation and Prevention Project, Fukushima Project Headquarters, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Tachibana, Akira [Department of Biological Sciences, College of Science, Ibaraki University, Bunkyo 2-1-1, Mito, Ibaraki 310-8512 (Japan); and others

    2015-09-15

    Highlights: • T-cell lymphoma incidence, latency and weight did not change with age at exposure. • Lymphomas had frequent loss of heterozygosity on chromosomes 4, 11 and 19. • These lesions targeted the Cdkn2a, Ikaros and Pten tumor suppressor genes. • Age at exposure may influence which tumor suppressor genes are lost in each tumor. • The mechanisms of tumor suppressor gene loss were different at each locus. - Abstract: Children are considered more sensitive to radiation-induced cancer than adults, yet any differences in genomic alterations associated with age-at-exposure and their underlying mechanisms remain unclear. We assessed genome-wide DNA copy number and mutation of key tumor suppressor genes in T-cell lymphomas arising after weekly irradiation of female B6C3F1 mice with 1.2 Gy X-rays for 4 consecutive weeks starting during infancy (1 week old), adolescence (4 weeks old) or as young adults (8 weeks old). Although T-cell lymphoma incidence was similar, loss of heterozygosity at Cdkn2a on chromosome 4 and at Ikaros on chromosome 11 was more frequent in the two older groups, while loss at the Pten locus on chromosome 19 was more frequent in the infant-irradiated group. Cdkn2a and Ikaros mutation/loss was a common feature of the young adult-irradiation group, with Ikaros frequently (50%) incurring multiple independent hits (including deletions and mutations) or suffering a single hit predicted to result in a dominant negative protein (such as those lacking exon 4, an isoform we have designated Ik12, which lacks two DNA binding zinc-finger domains). Conversely, Pten mutations were more frequent after early irradiation (60%) than after young adult-irradiation (30%). Homozygous Pten mutations occurred without DNA copy number change after irradiation starting in infancy, suggesting duplication of the mutated allele by chromosome mis-segregation or mitotic recombination. Our findings demonstrate that while deletions on chromosomes 4 and 11 affecting Cdkn2

  6. Effects of a Mangifera indica L. stem bark extract and mangiferin on radiation-induced DNA damage in human lymphocytes and lymphoblastoid cells.

    Science.gov (United States)

    Rodeiro, I; Delgado, R; Garrido, G

    2014-02-01

    Mangifera indica L. (mango) stem bark aqueous extract (MSBE) that has antioxidant, anti-inflammatory and immunomodulatory properties, can be obtained in Cuba. It is rich in polyphenols, where mangiferin is the main component. In this study, we have tested DNA damage and protection effects of MSBE and mangiferin on primary human lymphocytes and lymphoblastoid cells. Cell suspensions were incubated with the products (50-1000 μg/ml) for experiments on damage induction, and evaluation of any potential protective effects (5-100 μg/ml) for 60 min at 37 °C. Irradiation was performed using a γ-ray source, absorbed dose 5 Gy. At the end of exposure, DNA damage, protection and repair processes were evaluated using the comet assay. MSBE (100-1000 μg/ml) induced DNA damage in a concentration dependent manner in both cell types tested, primary cells being more sensitive. Mangiferin (200 μg/ml) only induced light DNA damage at higher concentrations. DNA repair capacity was not affected after MSBE or mangiferin exposure. On the other hand, MSBE (25 and 50 μg/ml) and mangiferin (5-25 ug/ml) protected against gamma radiation-induced DNA damage. These results show MSBE has protector or harmful effects on DNA in vitro depending on the experimental conditions, which suggest that the extract could be acting as an antioxidant or pro-oxidant product. Mangiferin was involved in protective effects of the extract. © 2013 John Wiley & Sons Ltd.

  7. DNA hybrids suggesting a recombination process repairing radiation-induced DNA double-strand breaks in Ehrlich Ascites tumor cells

    International Nuclear Information System (INIS)

    Barthel, H.R.

    1984-01-01

    The results presented suggest the possibility of repair of DNA double-strand breaks by recombination, at least in the S and G 2 -phases of the cell cycle, in mammalian cells. Further experiments with synchronized cell cultures will have to show whether this process may also occur in the G 1 -phase of the cell cycle. (orig./AJ) [de

  8. The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures

    Energy Technology Data Exchange (ETDEWEB)

    Ali, Haytham [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University (Egypt); Galal, Omima [Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University (Egypt); Urata, Yoshishige; Goto, Shinji; Guo, Chang-Ying; Luo, Lan [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Abdelrahim, Eman [Department of Medical Histology, Qena Faculty of Medicine, South Valley University (Egypt); Ono, Yusuke [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Mostafa, Emtethal [Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University (Egypt); Li, Tao-Sheng, E-mail: litaoshe@nagasaki-u.ac.jp [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)

    2014-09-26

    Highlights: • Nicaraven mitigated the radiation-induced reduction of c-kit{sup +} stem cells. • Nicaraven enhanced the function of hematopoietic stem/progenitor cells. • Complex mechanisms involved in the protection of nicaraven to radiation injury. - Abstract: Nicaraven, a hydroxyl radical-specific scavenger has been demonstrated to attenuate radiation injury in hematopoietic stem cells with 5 Gy γ-ray exposures. We explored the effect and related mechanisms of nicaraven for protecting radiation injury induced by sequential exposures to a relatively lower dose γ-ray. C57BL/6 mice were given nicaraven or placebo within 30 min before exposure to 50 mGy γ-ray daily for 30 days in sequences (cumulative dose of 1.5 Gy). Mice were victimized 24 h after the last radiation exposure, and the number, function and oxidative stress of hematopoietic stem cells were quantitatively estimated. We also compared the gene expression in these purified stem cells from mice received nicaraven and placebo treatment. Nicaraven increased the number of c-kit{sup +} stem/progenitor cells in bone marrow and peripheral blood, with a recovery rate around 60–90% of age-matched non-irradiated healthy mice. The potency of colony forming from hematopoietic stem/progenitor cells as indicator of function was completely protected with nicaraven treatment. Furthermore, nicaraven treatment changed the expression of many genes associated to DNA repair, inflammatory response, and immunomodulation in c-kit{sup +} stem/progenitor cells. Nicaraven effectively protected against damages of hematopoietic stem/progenitor cells induced by sequential exposures to a relatively low dose radiation, via complex mechanisms.

  9. The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures

    International Nuclear Information System (INIS)

    Ali, Haytham; Galal, Omima; Urata, Yoshishige; Goto, Shinji; Guo, Chang-Ying; Luo, Lan; Abdelrahim, Eman; Ono, Yusuke; Mostafa, Emtethal; Li, Tao-Sheng

    2014-01-01

    Highlights: • Nicaraven mitigated the radiation-induced reduction of c-kit + stem cells. • Nicaraven enhanced the function of hematopoietic stem/progenitor cells. • Complex mechanisms involved in the protection of nicaraven to radiation injury. - Abstract: Nicaraven, a hydroxyl radical-specific scavenger has been demonstrated to attenuate radiation injury in hematopoietic stem cells with 5 Gy γ-ray exposures. We explored the effect and related mechanisms of nicaraven for protecting radiation injury induced by sequential exposures to a relatively lower dose γ-ray. C57BL/6 mice were given nicaraven or placebo within 30 min before exposure to 50 mGy γ-ray daily for 30 days in sequences (cumulative dose of 1.5 Gy). Mice were victimized 24 h after the last radiation exposure, and the number, function and oxidative stress of hematopoietic stem cells were quantitatively estimated. We also compared the gene expression in these purified stem cells from mice received nicaraven and placebo treatment. Nicaraven increased the number of c-kit + stem/progenitor cells in bone marrow and peripheral blood, with a recovery rate around 60–90% of age-matched non-irradiated healthy mice. The potency of colony forming from hematopoietic stem/progenitor cells as indicator of function was completely protected with nicaraven treatment. Furthermore, nicaraven treatment changed the expression of many genes associated to DNA repair, inflammatory response, and immunomodulation in c-kit + stem/progenitor cells. Nicaraven effectively protected against damages of hematopoietic stem/progenitor cells induced by sequential exposures to a relatively low dose radiation, via complex mechanisms

  10. A comparative study on the frequencies of radiation-induced chromosome aberrations in the somatic and germ cells in mouse and monkey

    International Nuclear Information System (INIS)

    Sobels, F.H.

    1976-06-01

    Two systems were mainly used for studying the relationship between radiation induced chromosome aberration frequencies in somatic and germ cells. The first consists of reciprocal translocation induced in bone-marrow cells of mice compared to reciprocal translocation induced spermatogonia (scored in descending spermatocytes) of the same mice. Dose-response curves for induced aberrations in both cell types (0-100-200-300-400-500 and 600 R X-rays) and dose rate effects indicated that (130-1.92-0.0287 R/min) of a 400 R γ-ray exposure of the two cell types mitotically dividing germ cells respond to radiation similarly to mitotic dividing germ cells. Clonal proliferation or selective elimination of aberration-carrying cells, and other post-irradiation factors can, however, cause great differences in absolute aberration frequencies. A similar study was attempted, using the rhesus monkey as a second system. Its bone-marrow cells were proved unsuitable for induced reciprocal translocations. Stimulated peripheral blood lymphocytes were studied instead. Following 100, 200 and 300 R of X-rays, the frequencies of induced dicentric chromosomes were compared to those of induced reciprocal translocations in spermatogonia. Human peripheral blood was studied similarly. It was concluded that: (a) The absolute frequencies of chromosome aberrations in somatic and germ cells of the rhesus monkey are low compared to most other mammalian species. (b) The ratio between dicentric frequencies and reciprocal translocation frequencies at 100 R and 200 R differed significantly from 4:1 reported for mouse and Chinese hamster and 2:1 for marmoset and man. (c) Although the numbers of 'effective chromosome arms' in man and rhesus monkey are similar (81 vs 83), the rhesus monkey showed at all doses a lower rate of induction of dicentrics in blood lymphocytes than man, reaching statistical significance at the 300 R level

  11. Salinomycin kills cancer stem cells by sequestering iron in lysosomes

    Science.gov (United States)

    Mai, Trang Thi; Hamaï, Ahmed; Hienzsch, Antje; Cañeque, Tatiana; Müller, Sebastian; Wicinski, Julien; Cabaud, Olivier; Leroy, Christine; David, Amandine; Acevedo, Verónica; Ryo, Akihide; Ginestier, Christophe; Birnbaum, Daniel; Charafe-Jauffret, Emmanuelle; Codogno, Patrice; Mehrpour, Maryam; Rodriguez, Raphaël

    2017-10-01

    Cancer stem cells (CSCs) represent a subset of cells within tumours that exhibit self-renewal properties and the capacity to seed tumours. CSCs are typically refractory to conventional treatments and have been associated to metastasis and relapse. Salinomycin operates as a selective agent against CSCs through mechanisms that remain elusive. Here, we provide evidence that a synthetic derivative of salinomycin, which we named ironomycin (AM5), exhibits a more potent and selective activity against breast CSCs in vitro and in vivo, by accumulating and sequestering iron in lysosomes. In response to the ensuing cytoplasmic depletion of iron, cells triggered the degradation of ferritin in lysosomes, leading to further iron loading in this organelle. Iron-mediated production of reactive oxygen species promoted lysosomal membrane permeabilization, activating a cell death pathway consistent with ferroptosis. These findings reveal the prevalence of iron homeostasis in breast CSCs, pointing towards iron and iron-mediated processes as potential targets against these cells.

  12. Radiation induced bystander signals are independent of DNA damage and DNA repair capacity of the irradiated cells

    Energy Technology Data Exchange (ETDEWEB)

    Kashino, Genro [Gray Cancer Institute, P.O. Box 100, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR (United Kingdom); Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010 Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494 (Japan); Suzuki, Keiji [Division of Radiation Biology, Department of Radiology and Radiation Biology, Course of Life Sciences and Radiation Research, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521 (Japan); Matsuda, Naoki [Division of Radiation Biology and Protection, Center for Frontier Life Sciences, Nagasaki University, Nagasaki 852-8102 (Japan); Kodama, Seiji [Radiation Biology Laboratory, Radiation Research Center, Frontier Science Innovation Center, Organization for University-Industry-Government Cooperation, Osaka Prefecture University, 1-2 Gakuen-cho, Sakai, Osaka 599-8570 (Japan); Ono, Koji [Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010 Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494 (Japan); Watanabe, Masami [Laboratory of Radiation Biology, Division of Radiation Life Science, Department of Radiation Life Science and Radiation Medical Science, Kyoto University Research Reactor Institute, 2-1010 Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494 (Japan); Prise, Kevin M [Gray Cancer Institute, P.O. Box 100, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR (United Kingdom) and Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Lisburn Road, Belfast BT9 7AB (United Kingdom)]. E-mail: prise@gci.ac.uk

    2007-06-01

    Evidence is accumulating that irradiated cells produce signals, which interact with non-exposed cells in the same population. Here, we analysed the mechanism for bystander signal arising in wild-type CHO cells and repair deficient varients, focussing on the relationship between DNA repair capacity and bystander signal arising in irradiated cells. In order to investigate the bystander effect, we carried out medium transfer experiments after X-irradiation where micronuclei were scored in non-targeted DSB repair deficient xrs5 cells. When conditioned medium from irradiated cells was transferred to unirradiated xrs5 cells, the level of induction was independent of whether the medium came from irradiated wild-type, ssb or dsb repair deficient cells. This result suggests that the activation of a bystander signal is independent of the DNA repair capacity of the irradiated cells. Also, pre-treatment of the irradiated cells with 0.5% DMSO, which suppresses micronuclei induction in CHO but not in xrs5 cells, suppressed bystander effects completely in both conditioned media, suggesting that DMSO is effective for suppression of bystander signal arising independently of DNA damage in irradiated cells. Overall the work presented here adds to the understanding that it is the repair phenotype of the cells receiving bystander signals, which determines overall response rather than that of the cell producing the bystander signal.

  13. Comparison of Radiation-Induced Bystander Effect in QU-DB Cells after Acute and Fractionated Irradiation: An In Vitro Study.

    Science.gov (United States)

    Soleymanifard, Shokouhozaman; Bahreyni Toossi, Mohammad Taghi; Kamran Samani, Roghayeh; Mohebbi, Shokoufeh

    2016-01-01

    Radiation effects induced in non-irradiated cells are termed radiation-induced bystander effects (RIBE). The present study intends to examine the RIBE response of QU-DB bystander cells to first, second and third radiation fractions and compare their cumulative outcome with an equal, single acute dose. This experimental study irradiated three groups of target cells for one, two and three times with(60)Co gamma rays. One hour after irradiation, we transferred their culture media to non-irradiated (bystander) cells. We used the cytokinesis block micronucleus assay to evaluate RIBE response in the bystander cells. The numbers of micronuclei generated in bystander cells were determined. RIBE response to single acute doses increased up to 4 Gy, then decreased, and finally at the 8 Gy dose disappeared. The second and third fractions induced RIBE in bystander cells, except when RIBE reached to the maximum level at the first fraction. We split the 4 Gy acute dose into two fractions, which decreased the RIBE response. However, fractionation of 6 Gy (into two fractions of 3 Gy or three fractions of 2 Gy) had no effect on RIBE response. When we split the 8 Gy acute dose into two fractions we observed RIBE, which had disappeared following the single 8 Gy dose. The impact of dose fractionation on RIBE induced in QU-DB cells de- pended on the RIBE dose-response relationship. Where RIBE increased proportion- ally with the dose, fractionation reduced the RIBE response. In contrast, at high dos- es where RIBE decreased proportionally with the dose, fractionation either did not change RIBE (at 6 Gy) or increased it (at 8 Gy).

  14. Preferential repair of ionizing radiation-induced damage in the transcribed strand of an active human gene is defective in Cockayne syndrome

    International Nuclear Information System (INIS)

    Leadon, S.A.; Copper, P.K.

    1993-01-01

    Cells from patients with Cockayne syndrome (CS), which are sensitive to killing by UV although overall damage removal appears normal, are specifically defective in repair of UV damage in actively transcribe genes. Because several CS strains display cross-sensitivity to killing by ionizing radiation, the authors examined whether ionizing radiation-induced damage in active genes is preferentially repaired by normal cells and whether the radiosensitivity of CS cells can be explained by a defect in this process. They found that ionizing radiation-induced damage was repaired more rapidly in the transcriptionally active metallothionein IIA (MTIIA) gene than in the inactive MTIIB gene or in the genome overall in normal cells as a result of faster repair on the transcribed strand of MTIIA. Cells of the radiosensitive CS strain CS1AN are completely defective in this strand-selective repair of ionizing radiation-induced damage, although their overall repair rate appears normal. CS3BE cells, which are intermediate in radiosensitivity, do exhibit more rapid repair of the transcribed strand but at a reduced rate compared to normal cells. Xeroderma pigmentosum complementation group A cells, which are hypersensitive to UV light because of a defect in the nucleotide excision repair pathway but do not show increased sensitivity to ionizing radiation, preferentially repair ionizing radiation-induced damage on the transcribed strand of MTIIA. Thus, the ability to rapidly repair ionizing radiation-induced damage in actively transcribing genes correlates with cell survival. The results extend the generality of preferential repair in active genes to include damage other than bulky lesions

  15. Evidence for Radiation-Induced Disseminated Intravascular Coagulation as a Major Cause of Radiation-Induced Death in Ferrets

    Energy Technology Data Exchange (ETDEWEB)

    Krigsfeld, Gabriel S.; Savage, Alexandria R.; Billings, Paul C.; Lin, Liyong; Kennedy, Ann R., E-mail: akennedy@mail.med.upenn.edu

    2014-03-15

    Purpose: The studies reported here were performed as part of a program in space radiation biology in which proton radiation like that present in solar particle events, as well as conventional gamma radiation, were being evaluated in terms of the ability to affect hemostasis. Methods and Materials: Ferrets were exposed to 0 to 2 Gy of whole-body proton or gamma radiation and monitored for 30 days. Blood was analyzed for blood cell counts, platelet clumping, thromboelastometry, and fibrin clot formation. Results: The lethal dose of radiation to 50% of the population (LD{sub 50}) of the ferrets was established at ∼1.5 Gy, with 100% mortality at 2 Gy. Hypocoagulability was present as early as day 7 postirradiation, with animals unable to generate a stable clot and exhibiting signs of platelet aggregation, thrombocytopenia, and fibrin clots in blood vessels of organs. Platelet counts were at normal levels during the early time points postirradiation when coagulopathies were present and becoming progressively more severe; platelet counts were greatly reduced at the time of the white blood cell nadir of 13 days. Conclusions: Data presented here provide evidence that death at the LD{sub 50} in ferrets is most likely due to disseminated intravascular coagulation (DIC). These data question the current hypothesis that death at relatively low doses of radiation is due solely to the cell-killing effects of hematopoietic cells. The recognition that radiation-induced DIC is the most likely mechanism of death in ferrets raises the question of whether DIC is a contributing mechanism to radiation-induced death at relatively low doses in large mammals.

  16. Killing of tumor cells: a drama in two acts.

    Science.gov (United States)

    Giansanti, Vincenzo; Tillhon, Micol; Mazzini, Giuliano; Prosperi, Ennio; Lombardi, Paolo; Scovassi, A Ivana

    2011-11-15

    Cancer still represents a major health problem worldwide, which urges the development of more effective strategies. Resistance to chemotherapy, a major obstacle for cancer eradication, is mainly related to an intrinsic failure to activate the apoptotic pathways. However, a protective effect of autophagy toward cancer cells has been recently observed, thus adding further complexity to the development of an effective approach counteracting cancer cell growth and improving the response to therapy. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. Modulation of DNA methylation levels sensitizes doxorubicin-resistant breast adenocarcinoma cells to radiation-induced apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Luzhna, Lidia [Department of Biological Sciences, University of Lethbridge, AB, Canada T1K 3M4 (Canada); Kovalchuk, Olga, E-mail: olga.kovalchuk@uleth.ca [Department of Biological Sciences, University of Lethbridge, AB, Canada T1K 3M4 (Canada)

    2010-02-05

    Chemoresistant tumors often fail to respond to other cytotoxic treatments such as radiation therapy. The mechanisms of chemo- and radiotherapy cross resistance are not fully understood and are believed to be epigenetic in nature. We hypothesize that MCF-7 cells and their doxorubicin-resistant variant MCF-7/DOX cells may exhibit different responses to ionizing radiation due to their dissimilar epigenetic status. Similar to previous studies, we found that MCF-7/DOX cells harbor much lower levels of global DNA methylation than MCF-7 cells. Furthermore, we found that MCF-7/DOX cells had lower background apoptosis levels and were less responsive to radiation than MCF-7 cells. Decreased radiation responsiveness correlated to significant global DNA hypomethylation in MCF-7/DOX cells. Here, for the first time, we show that the radiation resistance of MCF-7/DOX cells can be reversed by an epigenetic treatment - the application of methyl-donor SAM. SAM-mediated reversal of DNA methylation led to elevated radiation sensitivity in MCF-7/DOX cells. Contrarily, application of SAM on the radiation sensitive and higher methylated MCF-7 cells resulted in a decrease in their radiation responsiveness. This data suggests that a fine balance of DNA methylation is needed to insure proper radiation and drug responsiveness.

  18. Ionizing radiation-induced MEK and Erk activation does not enhance survival of irradiated human squamous carcinoma cells

    International Nuclear Information System (INIS)

    Bonner, James A.; Vroman, Benjamin T.; Christianson, Teresa J.H.; Karnitz, Larry M.

    1998-01-01

    Purpose: Ionizing radiation (IR) triggers several intracellular signaling cascades that have commonly been regarded as mitogenic, including the Raf-MEK-Erk kinase cascade. In addition to promoting proliferation, activated MEK and Erk may also prevent cell death induced by cytotoxic stimuli. Because Raf, MEK, and Erk are activated by IR in some tumor cell lines, this suggests that IR-induced activation of the kinase cascade may enhance the survival of irradiated cells. Methods and Materials: IR-induced activation of MEK and Erk was assessed in irradiated UM-SCC-6 cells, a human squamous carcinoma cell line. Activation of MEK and Erk was blocked with the pharmacological inhibitor of MEK activation, PD098059. Clonogenic survival was assessed in irradiated UM-SCC-6 cells that were pretreated with nothing or with the MEK inhibitor. Results: In UM-SCC-6 cells, IR doses as low as 2 Gy rapidly activated MEK and Erk. Pretreatment of the cells with the pharmacological inhibitor of MEK activation, PD098059, effectively blocked IR-induced activation of MEK and Erk. However, inhibition of the kinase cascade did not affect the clonogenic survival of irradiated cells in either early or delayed-plating experiments. Conclusion: Taken together, these results suggest that although MEK and Erk are rapidly activated by IR treatment, these protein kinases do not affect the clonogenic survival of irradiated UM-SCC6 cells

  19. Melatonin Protects Human Cells from Clustered DNA Damages, Killing and Acquisition of Soft Agar Growth Induced by X-rays or 970 MeV/n Fe ions

    Energy Technology Data Exchange (ETDEWEB)

    Das, B.; Sutherland, B.; Bennett, P. V.; Cutter, N. C.; Sutherland, J. C.

    2011-06-01

    We tested the ability of melatonin (N-acetyl-5 methoxytryptamine), a highly effective radical scavenger and human hormone, to protect DNA in solution and in human cells against induction of complex DNA clusters and biological damage induced by low or high linear energy transfer radiation (100 kVp X-rays, 970 MeV/nucleon Fe ions). Plasmid DNA in solution was treated with increasing concentrations of melatonin (0.0-3.5 mM) and were irradiated with X-rays. Human cells (28SC monocytes) were also irradiated with X-rays and Fe ions with and without 2 mM melatonin. Agarose plugs containing genomic DNA were subjected to Contour Clamped Homogeneous Electrophoretic Field (CHEF) followed by imaging and clustered DNA damages were measured by using Number Average length analysis. Transformation experiments on human primary fibroblast cells using soft agar colony assay were carried out which were irradiated with Fe ions with or without 2 mM melatonin. In plasmid DNA in solution, melatonin reduced the induction of single- and double-strand breaks. Pretreatment of human 28SC cells for 24 h before irradiation with 2 mM melatonin reduced the level of X-ray induced double-strand breaks by {approx}50%, of abasic clustered damages about 40%, and of Fe ion-induced double-strand breaks (41% reduction) and abasic clusters (34% reduction). It decreased transformation to soft agar growth of human primary cells by a factor of 10, but reduced killing by Fe ions only by 20-40%. Melatonin's effective reduction of radiation-induced critical DNA damages, cell killing, and striking decrease of transformation suggest that it is an excellent candidate as a countermeasure against radiation exposure, including radiation exposure to astronaut crews in space travel.

  20. TU-CD-303-04: Radiation-Induced Long Distance Tumor Cell Migration Into and Out of the Radiation Field and Its Clinical Implication

    Energy Technology Data Exchange (ETDEWEB)

    Graves, E. [Stanford University (United States)

    2015-06-15

    Recent advances in cancer research have shed new light on the complex processes of how therapeutic radiation initiates changes at cellular, tissue, and system levels that may lead to clinical effects. These new advances may transform the way we use radiation to combat certain types of cancers. For the past two decades many technological advancements in radiation therapy have been largely based on the hypothesis that direct radiation-induced DNA double strand breaks cause cell death and thus tumor control and normal tissue damage. However, new insights have elucidated that in addition to causing cellular DNA damage, localized therapeutic radiation also initiates cascades of complex downstream biological responses in tissue that extend far beyond where therapeutic radiation dose is directly deposited. For instance, studies show that irradiated dying tumor cells release tumor antigens that can lead the immune system to a systemic anti-cancer attack throughout the body of cancer patient; targeted irradiation to solid tumor also increases the migration of tumor cells already in bloodstream, the seeds of potential metastasis. Some of the new insights may explain the long ago discovered but still unexplained non-localized radiation effects (bystander effect and abscopal effect) and the efficacy of spatially fractionated radiation therapy (microbeam radiation therapy and GRID therapy) where many “hot” and “cold” spots are intentionally created throughout the treatment volume. Better understanding of the mechanisms behind the non-localized radiation effects creates tremendous opportunities to develop new and integrated cancer treatment strategies that are based on radiotherapy, immunology, and chemotherapy. However, in the multidisciplinary effort to advance new radiobiology, there are also tremendous challenges including a lack of multidisciplinary researchers and imaging technologies for the microscopic radiation-induced responses. A better grasp of the essence of

  1. TU-CD-303-04: Radiation-Induced Long Distance Tumor Cell Migration Into and Out of the Radiation Field and Its Clinical Implication

    International Nuclear Information System (INIS)

    Graves, E.

    2015-01-01

    Recent advances in cancer research have shed new light on the complex processes of how therapeutic radiation initiates changes at cellular, tissue, and system levels that may lead to clinical effects. These new advances may transform the way we use radiation to combat certain types of cancers. For the past two decades many technological advancements in radiation therapy have been largely based on the hypothesis that direct radiation-induced DNA double strand breaks cause