Inhibition of cyclic AMP response element-directed transcription by decoy oligonucleotides enhances tumor-specific radiosensitivity

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Park, Serk In, E-mail: serkin@korea.edu [Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of); The BK21 Plus Program for Biomedical Sciences, Korea University College of Medicine, Seoul (Korea, Republic of); Department of Medicine and Center for Bone Biology, Vanderbilt University School of Medicine, Nashville, TN (United States); Park, Sung-Jun [Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of); Laboratory of Obesity and Aging Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (United States); Lee, Junghan; Kim, Hye Eun; Park, Su Jin; Sohn, Jeong-Won [Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of); Park, Yun Gyu, E-mail: parkyg@korea.ac.kr [Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of)

2016-01-15

The radiation stress induces cytotoxic responses of cell death as well as cytoprotective responses of cell survival. Understanding exact cellular mechanism and signal transduction pathways is important in improving cancer radiotherapy. Increasing evidence suggests that cyclic AMP response element binding protein (CREB)/activating transcription factor (ATF) family proteins act as a survival factor and a signaling molecule in response to stress. We postulated that CREB inhibition via CRE decoy oligonucleotide increases tumor cell sensitization to γ-irradiation-induced cytotoxic stress. In the present study, we demonstrate that CREB phosphorylation and CREB DNA-protein complex formation increased in time- and radiation dose-dependent manners, while there was no significant change in total protein level of CREB. In addition, CREB was phosphorylated in response to γ-irradiation through p38 MAPK pathway. Further investigation revealed that CREB blockade by decoy oligonucleotides functionally inhibited transactivation of CREB, and significantly increased radiosensitivity of multiple human cancer cell lines including TP53- and/or RB-mutated cells with minimal effects on normal cells. We also demonstrate that tumor cells ectopically expressing dominant negative mutant CREB (KCREB) and the cells treated with p38 MAPK inhibitors were more sensitive to γ-irradiation than wild type parental cells or control-treated cells. Taken together, we conclude that CREB protects tumor cells from γ-irradiation, and combination of CREB inhibition plus ionizing radiation will be a promising radiotherapeutic approach. - Highlights: • γ-Irradiation induced CREB phosphorylation and CRE-directed transcription in tumor. • γ-Irradiation-induced transcriptional activation of CREB was via p38 MAPK pathway. • CRE blockade increased radiosensitivity of tumor cells but not of normal cells. • CRE decoy oligonucleotides or p38 MAPK inhibitors can be used as radiosensitizers.

Inhibition of cyclic AMP response element-directed transcription by decoy oligonucleotides enhances tumor-specific radiosensitivity

International Nuclear Information System (INIS)

Park, Serk In; Park, Sung-Jun; Lee, Junghan; Kim, Hye Eun; Park, Su Jin; Sohn, Jeong-Won; Park, Yun Gyu

2016-01-01

The radiation stress induces cytotoxic responses of cell death as well as cytoprotective responses of cell survival. Understanding exact cellular mechanism and signal transduction pathways is important in improving cancer radiotherapy. Increasing evidence suggests that cyclic AMP response element binding protein (CREB)/activating transcription factor (ATF) family proteins act as a survival factor and a signaling molecule in response to stress. We postulated that CREB inhibition via CRE decoy oligonucleotide increases tumor cell sensitization to γ-irradiation-induced cytotoxic stress. In the present study, we demonstrate that CREB phosphorylation and CREB DNA-protein complex formation increased in time- and radiation dose-dependent manners, while there was no significant change in total protein level of CREB. In addition, CREB was phosphorylated in response to γ-irradiation through p38 MAPK pathway. Further investigation revealed that CREB blockade by decoy oligonucleotides functionally inhibited transactivation of CREB, and significantly increased radiosensitivity of multiple human cancer cell lines including TP53- and/or RB-mutated cells with minimal effects on normal cells. We also demonstrate that tumor cells ectopically expressing dominant negative mutant CREB (KCREB) and the cells treated with p38 MAPK inhibitors were more sensitive to γ-irradiation than wild type parental cells or control-treated cells. Taken together, we conclude that CREB protects tumor cells from γ-irradiation, and combination of CREB inhibition plus ionizing radiation will be a promising radiotherapeutic approach. - Highlights: • γ-Irradiation induced CREB phosphorylation and CRE-directed transcription in tumor. • γ-Irradiation-induced transcriptional activation of CREB was via p38 MAPK pathway. • CRE blockade increased radiosensitivity of tumor cells but not of normal cells. • CRE decoy oligonucleotides or p38 MAPK inhibitors can be used as radiosensitizers.

ADPRT inhibitors and hyperthermia as radiosensitizers

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Jonsson, G.G.

1985-01-01

Hyperthermia given in combination with gamma radiation has given considerable improvement in the therapeutic results for treatment of malignant tumors. The mechanism behind the hyperthermia effect is probably operative at the tissue level as well as at the molecular level. The metabolism of NAD + in relation to the activity of the chromosomal enzyme ADP-ribosyl transferase (ADPRT) has been studied as a possible molecular mechanism for this effect. The ADPRT activity was measured after radiosensitization with both hyperthermia and nicotinamide, which is a potent inhibitor of ADPRT. The results indicate that hyperthermia can improve the effect of radiotherapy by reducing the supply of NAD + , which is a co-substrate for ADPRT, while nicotinamide functions as a radiosensitizing agent by direct inhibition of the enzyme. The hypothesis is discussed in the thesis where inhibition of ADPRT might increase the radiosensitivity because the radiation-induced DNA damage can not be repaired with normal efficiency. The function of nicotinamide as a radiosensitizer was verified by studies on C3H mice with transplanted spontaneous mammary tumors. Because nicotinamide is not toxic, it seems quite attractive to test this vitamin as a radiosensitizing agent against human tumors. (251 refs.) (author)

Radiosensitization In Vivo by Histone Deacetylase Inhibition with No Increase in Early Normal Tissue Radiation Toxicity.

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Groselj, Blaz; Ruan, Jia-Ling; Scott, Helen; Gorrill, Jessica; Nicholson, Judith; Kelly, Jacqueline; Anbalagan, Selvakumar; Thompson, James; Stratford, Michael R L; Jevons, Sarah J; Hammond, Ester M; Scudamore, Cheryl L; Kerr, Martin; Kiltie, Anne E

2018-02-01

As the population ages, more elderly patients require radiotherapy-based treatment for their pelvic malignancies, including muscle-invasive bladder cancer, as they are unfit for major surgery. Therefore, there is an urgent need to find radiosensitizing agents minimally toxic to normal tissues, including bowel and bladder, for such patients. We developed methods to determine normal tissue toxicity severity in intestine and bladder in vivo , using novel radiotherapy techniques on a small animal radiation research platform (SARRP). The effects of panobinostat on in vivo tumor growth delay were evaluated using subcutaneous xenografts in athymic nude mice. Panobinostat concentration levels in xenografts, plasma, and normal tissues were measured in CD1-nude mice. CD1-nude mice were treated with drug/irradiation combinations to assess acute normal tissue effects in small intestine using the intestinal crypt assay, and later effects in small and large intestine at 11 weeks by stool assessment and at 12 weeks by histologic examination. In vitro effects of panobinostat were assessed by qPCR and of panobinostat, TMP195, and mocetinostat by clonogenic assay, and Western blot analysis. Panobinostat resulted in growth delay in RT112 bladder cancer xenografts but did not significantly increase acute (3.75 days) or 12 weeks' normal tissue radiation toxicity. Radiosensitization by panobinostat was effective in hypoxic bladder cancer cells and associated with class I HDAC inhibition, and protein downregulation of HDAC2 and MRE11. Pan-HDAC inhibition is a promising strategy for radiosensitization, but more selective agents may be more useful radiosensitizers clinically, resulting in fewer systemic side effects. Mol Cancer Ther; 17(2); 381-92. ©2017 AACR See all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology." ©2017 American Association for Cancer Research.

SHP1-mediated cell cycle redistribution inhibits radiosensitivity of non-small cell lung cancer

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Cao, Rubo; Ding, Qian; Li, Pindong; Xue, Jun; Zou, Zhenwei; Huang, Jing; Peng, Gang

2013-01-01

Radioresistance is the common cause for radiotherapy failure in non-small cell lung cancer (NSCLC), and the degree of radiosensitivity of tumor cells is different during different cell cycle phases. The objective of the present study was to investigate the effects of cell cycle redistribution in the establishment of radioresistance in NSCLC, as well as the signaling pathway of SH2 containing Tyrosine Phosphatase (SHP1). A NSCLC subtype cell line, radioresistant A549 (A549S1), was induced by high-dose hypofractionated ionizing radiations. Radiosensitivity-related parameters, cell cycle distribution and expression of cell cycle-related proteins and SHP1 were investigated. siRNA was designed to down-regulate SHP1expression. Compared with native A549 cells, the proportion of cells in the S phase was increased, and cells in the G0/G1 phase were consequently decreased, however, the proportion of cells in the G2/M phase did not change in A549S1 cells. Moreover, the expression of SHP1, CDK4 and CylinD1 were significantly increased, while p16 was significantly down-regulated in A549S1 cells compared with native A549 cells. Furthermore, inhibition of SHP1 by siRNA increased the radiosensitivity of A549S1 cells, induced a G0/G1 phase arrest, down-regulated CDK4 and CylinD1expressions, and up-regulated p16 expression. SHP1 decreases the radiosensitivity of NSCLC cells through affecting cell cycle distribution. This finding could unravel the molecular mechanism involved in NSCLC radioresistance

Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers

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Dongping Wei

2015-02-01

Full Text Available In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1, an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells.

Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model

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Blattmann, C.; University Children's Hospital of Heidelberg; Thiemann, M.; Stenzinger, A.

2013-01-01

Background: Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo. Methods: Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling. Results: Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis. Conclusion: Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS. (orig.)

Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model

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Blattmann, C. [Olgahospital, Stuttgart (Germany). Paediatrie 5; University Children' s Hospital of Heidelberg (Germany). Dept. of Pediatric Oncology, Hematology and Immunology; Thiemann, M. [German Cancer Research Center (DKFZ), Heidelberg (Germany). Dept. of Radiotherapy, Molecular- and Translational Radiation Oncology; Stenzinger, A. [Heidelberg Univ. (Germany). Inst. of Pathology; and others

2013-11-15

Background: Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo. Methods: Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling. Results: Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis. Conclusion: Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS. (orig.)

Icotinib enhances lung cancer cell radiosensitivity in vitro and in vivo by inhibiting MAPK/ERK and AKT activation.

Science.gov (United States)

Fu, Yonghong; Zhang, Sen; Wang, Dongjie; Wang, Jing

2018-05-16

Icotinib hydrochloride is a small epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that was developed by Chinese scientists. While clinical trials have revealed its efficacy in the treatment of lung cancer, very little is known about its role in enhancing radiosensitivity. In this study, we investigated the effectiveness of Icotinib in enhancing lung cancer cell radiosensitivity and have detailed its underlying molecular mechanism. The lung cancer cell line H1650 was pretreated with or without Icotinib for 24 hours before radiation, and clonogenic survival assay was performed. Cell apoptosis was also analyzed by flow cytometry, while western blotting was performed to examine the activation of EGFR and its downstream kinases in H1650 cells after Icotinib and radiation treatment. Furthermore, a xenograft animal model was established to evaluate the radiosensitivity of Icotinib in vivo and to confirm its mechanism. Our results demonstrate that pretreatment with Icotinib reduced clonogenic survival after radiation, inhibited EGFR activation, and increased radiation-induced apoptosis in H1650 cells. The phosphorylation of protein kinase B (AKT), extracellular regulated protein kinase 1/2 (ERK1/2), and EGFR was inhibited after Icotinib and radiation combination treatment in vitro and in vivo compared with individual treatments. Combination treatment also affected the expression of the DNA repair protein H2A histone family member X (γ-H2AX). In conclusion, our results reveal that Icotinib enhances radiosensitivity in lung cancers in vitro and in vivo and the mechanism of this may involve blocking the EGFR-AKT and MAPK-ERK pathways and limiting DNA repair. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

On enhancing drugs effect on radiosensitivity of HeLa cells by inhibiting P13K/Akt signal transduction

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Xia Shu; Yu Shiying

2006-01-01

Objective: To explore the mechanism of PI3K/Akt in radiosensitization of docetaxel and cisplatin by inhibiting PI3K/Akt pathway in HeLa cells. Methods: To detect the 50% inhibition concentration (IC 50 ) of cisplatin and docetaxel in Hela cells by mono-nuclear cell direct cytotoxicity assay (MTT) in vitro. Using the IC 20 of cisplatin and docetaxel in Hela cell or in association with LY294002 for 24 h, then, the cells were irradiated by X-ray with 2,3,4,6,8 Gy. The cell survival fraction was computed by clone formation. Cell survival curve was fitted by multitarget one-hit model, and D q , D 0 , SF 2 , sensitizing enhancing ratio(SER) was calculated. The expression of pAkt and total Akt by western blot were detected. Apoptosis was detected by flow cytometry. Results: 1. Docetaxel and cisplatin improved the phosphorylation of Akt by irradiation obviously. 2. The SER of docetaxel + LY294002 + irradiation group (1.92) was higher than that of docetaxel + irradiation group(1.41). The SER of cisplatin + LY294002 + irradiation group(1.71) was higher than the cisplatin + irradiation group (1.37). 3. Apoptosis rate of docetaxel + LY294002 + irradiation and cisplatin + LY294002 + irradiation groups(12.5%, 10.2%) were higher than those of docetaxel + irradiation and cisplatin + irradiation groups(6.1%, 5.1%). Conclusions: PI3K/Akt signal transduction activation may be as an important reason of radiosensitization reduction of docetaxel and cisplatin in the HeLa cells. Our results show that inhibiting PI3K/Akt can improve the radiosensitization of docetaxel and cisplatin in the HeLa cells. (authors)

E3 Ligase cIAP2 Mediates Downregulation of MRE11 and Radiosensitization in Response to HDAC Inhibition in Bladder Cancer.

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Nicholson, Judith; Jevons, Sarah J; Groselj, Blaz; Ellermann, Sophie; Konietzny, Rebecca; Kerr, Martin; Kessler, Benedikt M; Kiltie, Anne E

2017-06-01

The MRE11/RAD50/NBS1 (MRN) complex mediates DNA repair pathways, including double-strand breaks induced by radiotherapy. Meiotic recombination 11 homolog (MRE11) is downregulated by histone deacetylase inhibition (HDACi), resulting in reduced levels of DNA repair in bladder cancer cells and radiosensitization. In this study, we show that the mechanism of this downregulation is posttranslational and identify a C-terminally truncated MRE11, which is formed after HDAC inhibition as full-length MRE11 is downregulated. Truncated MRE11 was stabilized by proteasome inhibition, exhibited a decreased half-life after treatment with panobinostat, and therefore represents a newly identified intermediate induced and degraded in response to HDAC inhibition. The E3 ligase cellular inhibitor of apoptosis protein 2 (cIAP2) was upregulated in response to HDAC inhibition and was validated as a new MRE11 binding partner whose upregulation had similar effects to HDAC inhibition. cIAP2 overexpression resulted in downregulation and altered ubiquitination patterns of MRE11 and mediated radiosensitization in response to HDAC inhibition. These results highlight cIAP2 as a player in the DNA damage response as a posttranscriptional regulator of MRE11 and identify cIAP2 as a potential target for biomarker discovery or chemoradiation strategies in bladder cancer. Cancer Res; 77(11); 3027-39. ©2017 AACR . ©2017 American Association for Cancer Research.

Correlation of RAD51 and radiosensitization of methotrexate

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Du Liqing; Bai Jianqiang; Liu Qiang; Wang Yan; Zhao Peng; Chen Fenghua; Wang Hong; Fan Feiyue

2012-01-01

Objective: To evaluate the correlation between homologous recombination repair protein RAD51 and methotrexate-enhanced radiosensitivity. Methods: Western blot and RT-PCR assays were used to detect RAD51 expression in HOS osteosarcoma cells exposed to γ-ray irradiation alone and in combination with methotrexate. Colony formation assay was used to test the survival fraction of HOS cells exposed to γ-rays and methotrexate. Results: Methotrexate inhibited both protein and RNA expressions of RAD51, and the combination of radiation and methotrexate enhanced the inhibition of RAD51 expression. Moreover, transfection of cells with RAD51 gene decreased cellular sensitivity to methotrexate and γ-rays. The sensitizer enhancement ratios after irradiation in combination with methotrexate were 1.51 and 0.99, respectively. Methotrexate was a preferred radiosensitizer to HOS cell. Conclusions: RAD51 might be involved in the methotrexate-enhanced radiosensitivity. (authors)

Metformin enhances radiosensitivity via inhibition of DNA repair pathway in colorectal cancer

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Jeong, Youn Kyoung; Kim, Mi Sook; Lee, Ji Young; Song, Kyung Hee; Choi, Kyul; Kim, Eun Ho; Ha, Hun Joo [Ewha Womans University, Seoul (Korea, Republic of)

2014-04-15

In this study, we provide a scientific rationale for the clinical application of metformin as a radiosensitizer in colorectal cancer. Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide. Currently, it is one of the commonest chemoradiotherapy worked better than the radiotherapy or chemotherapy in colorectal cancer. To enhance radiosensitivity of tumor cells for chemoradiotherapy, it is to use potential anticancer agents that act as radiosensitizers. Metformin, one of the most widely used antidiabetic drugs, has recently been associated with potential antitumorigenic effects. Our data shows that metformin combined with radiation enhances the efficacy of radiotherapy and down-regulates DNA repair proteins. Therefore, we provides a scientific rationale for the clinical application of metformin as a radiosensitizer in colorectal cancer.

Metformin enhances radiosensitivity via inhibition of DNA repair pathway in colorectal cancer

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Jeong, Youn Kyoung; Kim, Mi Sook; Lee, Ji Young; Song, Kyung Hee; Choi, Kyul; Kim, Eun Ho; Ha, Hun Joo

2014-01-01

In this study, we provide a scientific rationale for the clinical application of metformin as a radiosensitizer in colorectal cancer. Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide. Currently, it is one of the commonest chemoradiotherapy worked better than the radiotherapy or chemotherapy in colorectal cancer. To enhance radiosensitivity of tumor cells for chemoradiotherapy, it is to use potential anticancer agents that act as radiosensitizers. Metformin, one of the most widely used antidiabetic drugs, has recently been associated with potential antitumorigenic effects. Our data shows that metformin combined with radiation enhances the efficacy of radiotherapy and down-regulates DNA repair proteins. Therefore, we provides a scientific rationale for the clinical application of metformin as a radiosensitizer in colorectal cancer

SN-38 Acts as a Radiosensitizer for Colorectal Cancer by Inhibiting the Radiation-induced Up-regulation of HIF-1α.

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Okuno, Takayuki; Kawai, Kazushige; Hata, Keisuke; Murono, Koji; Emoto, Shigenobu; Kaneko, Manabu; Sasaki, Kazuhito; Nishikawa, Takeshi; Tanaka, Toshiaki; Nozawa, Hiroaki

2018-06-01

Hypoxia offers resistance to therapy in human solid tumors. The aim of the study was to investigate whether SN-38, the active metabolite of irinotecan, acts as a radiosensitizer through inhibition of hypoxia-inducible factor (HIF)-1α in the human colorectal cancer (CRC) cells. HT29 and SW480 cells were cultured with SN-38 (0-4 μM) immediately after irradiation (0-8 Gy). HIF-1α expression was assessed using flow-cytometry and western blot analysis. Cell proliferation was evaluated by the calcein assay. Apoptosis and cell cycle were determined by flow-cytometry. Radiation up-regulated HIF-1α, and SN-38 inhibited the radiation-induced HIF-1α. The combination of radiation and SN-38 inhibited cell proliferation more than radiation alone; treatment with SN-38 after radiation exposure did not increase the number of apoptotic cells, whereas, it enhanced the S and G 2 /M cell-cycle arrest and decreased the population of cells in G 1 Conclusion: SN-38 inhibits the radiation-induced up-regulation of HIF-1α and acts as a radiosensitizer by inducing cell-cycle arrest in CRC cells. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Radiosensitization by PARP inhibition to proton beam irradiation in cancer cells

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Hirai, Takahisa [Department of Radiation Oncology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo (Japan); Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Saito, Soichiro; Fujimori, Hiroaki [Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Matsushita, Keiichiro; Nishio, Teiji [Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima-shi, Hiroshima (Japan); Okayasu, Ryuichi [International Open Laboratory, National Institute of Radiological Science, Chiba-shi, Chiba (Japan); Masutani, Mitsuko, E-mail: mmasutan@nagasaki-u.ac.jp [Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (Japan)

2016-09-09

The poly(ADP-ribose) polymerase (PARP)-1 regulates DNA damage responses and promotes base excision repair. PARP inhibitors have been shown to enhance the cytotoxicity of ionizing radiation in various cancer cells and animal models. We have demonstrated that the PARP inhibitor (PARPi) AZD2281 is also an effective radiosensitizer for carbon-ion radiation; thus, we speculated that the PARPi could be applied to a wide therapeutic range of linear energy transfer (LET) radiation as a radiosensitizer. Institutes for biological experiments using proton beam are limited worldwide. This study was performed as a cooperative research at heavy ion medical accelerator in Chiba (HIMAC) in National Institute of Radiological Sciences. HIMAC can generate various ion beams; this enabled us to compare the radiosensitization effect of the PARPi on cells subjected to proton and carbon-ion beams from the same beam line. After physical optimization of proton beam irradiation, the radiosensitization effect of the PARPi was assessed in the human lung cancer cell line, A549, and the pancreatic cancer cell line, MIA PaCa-2. The effect of the PARPi, AZD2281, on radiosensitization to Bragg peak was more significant than that to entrance region. The PARPi increased the number of phosphorylated H2AX (γ-H2AX) foci and enhanced G2/M arrest after proton beam irradiation. This result supports our hypothesis that a PARPi could be applied to a wide therapeutic range of LET radiation by blocking the DNA repair response. - Highlights: • Effective radiosensitizers for particle radiation therapy have not been reported. • PARP inhibitor treatment radiosensitized after proton beam irradiation. • The sensitization at Bragg peak was greater than that at entrance region. • DSB induction and G2/M arrest is involved in the sensitization mechanism.

Membrane specific drugs as radiosensitizers

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George, K.C.; Mishra, K.P.; Shenoy, M.A.; Singh, B.B.; Srinivasan, V.T.; Verma, N.C.

1981-01-01

Procaine, paracetamol, and chlorpromazine showed inhibition of post irradiation repair. The chlorpromazie effect could be further augmented by treatment of cells with procaine. Chlorpromazine was also found to be preferentially toxic to hypoxid bacterial cells, and the survivors showed extreme radiosensitivity to gamma rays. Chlorpromazine was found to inhibit tumour growth in swiss mice when given intraperitoneally as well as when injected directly into the tumour. When combined with single x-ray doses, significant radiosensitization was observed in two in vivo tumours sarcoma 180A and fibrosarcoma. These results indicated that chlorpromazine may prove a good drug for combined chemo-radiotherapy of solid tumours. Investigations continued studying various aspects such as effectiveness in other tumour lines, distribution in healthy and tumour bearing animals, hyperthermia and drug combination effects, and encapsulation of the drug in artificial liposomes and blood cells. (ERB)

Enhanced Radiosensitivity of Tumor Cells Treated with Vanadate in Vitro

International Nuclear Information System (INIS)

Lee, Myung Za; Lee, Won Young

1994-01-01

Intracellular ions which have a major role in cellular function have been reported to affect repair of radiation damage. Recently it has been reported that ouabain sensitizes A549 tumor cells hut not CCL-120 normal cells to radiation. Ouabain inhibits the Na+-K+-pump rapidly thus it increases intracellular Na concentration. Vanadate which is distributed extensively in almost all living organisms in known to be a Na+-K+-ATPase inhibitors. This study was performed to see any change in radiosensitivity of tumor cell by vanadate and any role of Na+-K+-ATPase in radiosensitization. Experiments have been carried out by pretreatment with vanadate in human cell line(A549, JMG) and mouse cell line(L1210, spleen). For the cell survival MTT assay was performed for A549 and JMG cell and trypan blue dye exclusion test for L120, and spleen cells. Measurements of Na+-K+-ATPase activity in control, vanadate treated cell, radiation treated cell (9 Gy for A549 and JMG, 2 Gy for L1201, spleen), and combined 10-6 M vanadate and radiation treated cells were done. The results were summarized as follows. 1. L1210 cell was most radiosensitive, and spleen cell and JMG cell were intermediate, and A549 cell was least radiosensitive. 2. Minimum or cytotoxicity was seen with vanadate below concentration of 10-6 M. 3. In A549 cells there was a little change in radiosensitivity with treatment of vanadate. However radiation sensitization was shown in low dose level of radiation i. E. 2-Gy. In JMG cells no change in radiosensitivity was noted. Both L1210 and spleen cell had radiosensitization but change was greater in tumor cell. 4. Na+-K+-ATPase activity was inhibited significantly in tumor cell by treatment of vanadate. 5. Radiation itself inhibited Na+-K+-ATPase activity of tumor cell with high Na+- K+-ATPase concention. Increase in radiosensitivity by vanadate was closely associated with original Na+-K+-ATPase contents. From the above results vanadate had little cytotoxicity and it sensitized

Genetic components for radiosensitivity. Gene expression in radiosensitive monocygotic twins. Final report

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Dikomey, Ekkehard

2012-01-01

The underlying hypothesis of this project was that the variation of individual radiosensitivity is determined by the different expression of single gens. This concept was tested using 60 monozygotic twin pairs, followed by an evaluation with 80 prostate cancer patients. Radiosensitivity was assessed for both G0- as well as G2-phase using chromosomal assays. G0- radiosensitivity is determined by lethal chromosomal aberrations and reflects the individual amount of cell killing, while G2-sensitivity is determined by chromatid breaks and is taken as an indicator of individual cancer risk. For both populations, G0- and G2-radiosensitivity are characterized by substantial variation with a CV of 11 and 14% or 27 and 21%, respectively. While the mean G0-sensitivity is the same for both populations, there is a slight difference for G2. The slightly higher value of G2-sensitivity found for prostate cancer patients might result from the higher age of this group. For both populations gene expression profiles were determined using the Affymetrix chip HG-U133+2.0. Overall gene expression was characterized by a huge variation covering more than four decades. However, for single genes, expression showed little variation with CV generally ranging only between 2 and 8%. Analysis of data using several different methods revealed that variation of both G0- as well as G2-radiosensitivity cannot be ascribed to the different expression of single genes. For twins, random forests can be used to identify 8 to 10 genes than are relevant either for G0- or G2-radiosensitivity. However, these genes cannot be confirmed by an evaluation with 80 prostate cancer patients. This finding clearly demonstrates that the hypothesis, due to which variation of individual radiosensitivity is caused by different expression of single genes, has to be rejected. It appears more likely that this parameter is determined by complex interactions of several genes in functional networks. (orig.)

Glyoxylic compounds as radiosensitizers of hypoxic cells

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Cornago, M.P.; Lopez Zumel, M.C.; Alvarez, M.V.; Izquierdo, M.C.

1990-01-01

The radiosensitizing effect of five glyoxal derivatives on the survival of TC-SV40 cells has been measured, under aerobic and hypoxic conditions. A toxicity study was previously performed in order to use nontoxic concentrations. The OER for the TC-SV40 cells was 2.74. None of the glyoxylic compounds showed radiosensitizing activity under aerobic conditions while in hypoxia their radiosensitizing factors decreased in the order phenylglyoxylic acid (1.68 at 8 x 10(-3) mole dm-3) greater than phenylglyoxal (1.55 at 5 x 10(-6) mole dm-3) greater than 2-2' furil (1.48 at 5 x 10(-5) mole dm-3) greater than glyoxylic acid (1.39 at 1 x 10(-3) mole dm-3) greater than glyoxal (1.30 at 5 x 10(-5) mole dm-3). The dose-modifying factors were also determined at two equimolar concentrations 5 x 10(-5) and 5 x 10(-6) mole dm-3. A concentration effect was noticed for all the compounds although their relative radiosensitizing activity kept, independently of the concentration, the same order noted above. Glyoxals with aromatic or heterocyclic rings exert a greater radiosensitization than the others. The acidic compounds have less radiosensitizing activity than their aldehydic counterparts. Interaction of these glyoxals with NPSH cellular groups was tested and the low degree of inhibition shows that this mechanism would contribute very little, if any, to the radiosensitization effect

In vivo radiosensitization by diethyldithiocarbamate

International Nuclear Information System (INIS)

Kent, C.R.; Blekkenhorst, G.H.

1988-01-01

Diethyldithiocarbamate (DDC) has been suggested to have both radiosensitizing (due to superoxide dismutase (SOD) inhibition) and radioprotective properties. We have studied the activity of SOD up to 24 h after intratumoral administration of 50, 100, 150, and 300 mg/kg DDC in 3-methylcholanthrene-induced tumors in BALB/c mice. Maximal inhibition of SOD (8% of control) was obtained 1 h after administration of 100 mg/kg DDC. Tumor response to DDC and X irradiation was assessed using a tumor growth-delay assay, after 11 Gy 100-kVp X rays given up to 24 h after DDC administration. Radiation-induced tumor growth delay (7.11 +/- 1.76 days) was enhanced only when tumors were irradiated 2-4 h after 50 mg/kg DDC. When higher doses of DDC were used, tumor cure was noted when DDC was injected 1-6 h before irradiation. We suggest our findings are consistent with radiosensitization being due to SOD inhibition, but that if insufficient time is allowed between DDC injection and irradiation, the sensitization is masked by a radioprotective effect. We believe that further investigations as to the therapeutic potential of DDC in human patients with cancer are warranted

The radiosensitizing effect of doranidazole on human colorectal cancer cells exposed to high doses of irradiation

International Nuclear Information System (INIS)

Zhang, Li; Gong, Aimin; Ji, Jun; Wu, Yuanyuan; Zhu, Xiaoyu; Lv, Suqing; Lv, Hongzhu; Sun, Xizhuo

2007-01-01

This paper investigates the effects of a new radiosensitizer, doranidazole, and enhancing irradiation on colorectal cancer cells. The radiosensitizing effect of doranidazole was determined using colony formation and propidium iodide (PI) assays to measure cell growth inhibition and the cell killing effect of human colorectal cancer cell lines exposed to high doses of γ-ray irradiation under hypoxic conditions in vitro. Fluorescence staining and cell migration assays were also used to assess the radiosensitizing effect. Cell proliferation evaluated by clonogenic survival curves was significantly inhibited by 5 mmol/L doranidazole, particularly at doses ranging from 10 to 30 Gy of irradiation. The radiosensitizing effect of doranidazole on colorectal cancer cells occurs in a time- and dose-dependent manner. Doranidazole also inhibited the mobility of cell invasion and migration. Doranidazole can enhance the killing effect and the cell growth inhibition of colorectal cancer after high-dose irradiation in a time and dose-dependent manner

ATM-induced radiosensitization in vitro and in vivo

International Nuclear Information System (INIS)

Choi, E. K.; Ahn, S. D.; Rhee, Y. H.; Chung, H. S.; Ha, S. W; Song, C. W.; Griffin, R. J.; Park, H. J.

2003-01-01

It has been known that ATM plays a central role in response of cells to ionizing radiation by enhancing DNA repair. We have investigated the feasibility of increasing radiosensitivity of tumor cells with the use of ATM inhibitors such as caffeine, pentoxifylline and wortmannin. Human colorectal cancer RKO.C cells and RKO-ATM cells (RKO cells overexpressing ATM) were used in the present study. The clonogenic cell survival in vitro indicated that RKO-ATM cells were markedly radioresistant than RKO.C cells. Treatment with 3 mM of caffeine significantly increased the radiosensitivity of cells, particulary the RKO-ATM cells, so that the radiosensitivity of RKO.C cells and RKO-ATM cells were almost similar. The radiation induced G2/M arrest in RKO-ATM cells was noticeably longer than that in RKO.C cells and caffeine treatment significantly reduced the length of the radiation induced G2/M arrest in both RKO.C and RKO-ATM cells. Pentoxifylline and wortmannin were also less effective than caffeine to radiosensitize RKO.C or RKO-ATM cells. However, wortmannin was more effective than caffeine against human lung adenocarcinoma A549 cells indicating the efficacy of ATM inhibitor to increase radiosensitivity is cell line dependent. For in vivo study, RKO.C cells were injected s.c. into the hind-leg of BALB/c-nuslc nude mice, and allowed to grow to 130mm3 tumor. The mice were i.p. injected with caffeine solution or saline and the tumors irradiated with 10 Gy of X-rays. The radiation induced growth delay was markedly increased by 1-2 mg/g of caffeine. It was concluded that caffeine increases radiosensitivity of tumor cells by inhibiting ATM kinase function, thereby inhibiting DNA repair, that occurs during the G2/M arrest after radiation

Allosuppressor T lymphocytes abolish migration inhibition factor production in autoimmune thyroid disease: evidence from radiosensitivity experiments

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Topliss, D.J.; Okita, N.; Lewis, M.; Row, V.V.; Volpe, R.

1981-01-01

The ability of normal T lymphocytes to abolish the production of migration inhibition factor by antigen-sensitized T lymphocytes of Graves' disease (GD) and Hashimoto's thyroiditis (HT) in response to thyroid antigen has been studied by a modified migration inhibition factor test using isolated T lymphocytes alone. The production of migration inhibition factor was consistently abolished when normal T lymphocytes were mixed with GD or HT T lymphocytes in various ratios (1:9, 2:8, 5:5) as reported previously (Okita et al., 1980b). However, prior in-vitro irradiation (1000 rad) of the normal T lymphocytes resulted in loss of their ability to abolish migration inhibition factor production by the antigen-sensitized T lymphocytes of GD and HT. The effect is consistent with the radiosensitivity of suppressor T lymphocytes and indicates that the effect of normal T lymphocytes on GD and HT T lymphocytes is one of allosuppression. The results support the view that there is a defect in suppressor T cell function in GD and HT. (author)

Development of Radiosensitizer using farnesyltransferase inhibitors

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Lim, Jong Seok; Choe, Yong Kyung; Han, Mi Young; Kim, Kwang Dong [Korea Research Institute of Bioscience and Biotechnology, Taejon (Korea)

1999-03-01

We selected some compounds that were reported to have an activity of farneyltransferase inhibitor and tested the hypothesis that they might be used to radiosensitize cells transformed by ras oncogenes. The inhibition of ras processing using some, but not all, inhibitors resulted in higher levels of cell death after {gamma}-irradiation and increased radiosensitivity in H-ras-transformed NIH3T3 cells and MCF-10A human tumor cells. They did not induce additional cell death in control cells that doe not have ras mutation. Furthermore, the treatment of inhibitors alone induced a weak G0/G1 block, whereas inhibitors in combination with {gamma}-irradiation induced an additional enrichment in the G2/M phase of the cell cycle that typically represents irradiation-induced growth arrest. At present, the underling mechanism by which the farnesylltransferase inhibitors exert radiosensitizing effect is not known. In summary, our results suggest and lead to the possibility that some of farnesylation inhibitors may prove clinically useful not only as antitumor agents, but also radiosensitizers of tumors whose growth is dependent on ras function. (author). 15 refs., 10 figs., 4 tabs.

Effect of quercetin and 17-AAG on radiosensitivity of rat peripheral blood lymphocyte

International Nuclear Information System (INIS)

Chu Xuegang; Hong Chengjiao; Zhang Baoguo

2012-01-01

To investigate the effect of quercetin and 17-AAG on proliferation and on radiosensitivity of blood lymphocyte cells. CCK-8 assay is performed to evaluate the cytotoxicity of Quercetin on proliferation of blood lymphocyte cells. CCK-8 assay employed to observe its effects on the radiosensitivity of the cells quantified by calculating the sensitive enhancement ratio (SER). CCK-8 results showed that the inhibition of Quercetin on the cells was the dose-dependent and time-dependent, and the results of assay showed the inhibition of 17-AAG on blood lymphocyte cells was the dose-dependent and time-dependent. The study showed that Quercetin and 17-AAG have no effect on the radiosensitivity of the blood lymphocyte cells. (authors)

Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

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Zeng, Jing; Aziz, Khaled; Chettiar, Sivarajan T. [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Aftab, Blake T. [Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Armour, Michael; Gajula, Rajendra; Gandhi, Nishant; Salih, Tarek; Herman, Joseph M.; Wong, John [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Rudin, Charles M. [Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Tran, Phuoc T. [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Hales, Russell K., E-mail: rhales1@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (United States)

2013-05-01

Purpose: Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported. Methods and Materials: We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras{sup G12D}-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning. Results: In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis. Conclusions: Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.

Growth inhibition and radiosensitization of Celecoxib in nasopharyngeal caricnoma cell line CNE-2

International Nuclear Information System (INIS)

Xu Xinhua; Yi Fang; Fu Xiangyang; Zhang Xiaohong; Wang Yanlin; Zhang Changju; Du Jingtao

2009-01-01

Objective: To investigate the growth inhibition and radiosensitization of Celecoxib in human nasopharyngeal carcinoma cell line CNE-2. Methods: CNE-2 growth inhibition by Celecoxib was evaluated by MTT method. Apoptosis-related changes in morphology were observed by transmission electron microscopy(TEM). Cell cycle distribution and apoptosis rate were measured by flowcytometry(FCM). The expression of COX-2 protein was observed by SP method after the treatment of Celecoxib. Cells were randomly planted into four groups: irradiation control (Ci), drug group (Cd), irradiation group (R), and Celecoxib plus irradiation group (D + R). Single irradiation of 2,4,6,8, and 10 Gy were administered for colonogenic assay. Cell cycle distribution and apoptosis rate were analyzed at 6 Gy irradiation. Results: The growth of CNE-2 cell was inhibited by celecoxib in a dose-and time-dependent manner, the IC 50 was 80 μmol/L. After the treatment, cell ratio of G 0 and G 1 phases wasinereased (47.03 ± 2.76 vs 56.17 ± 1.95, t=4.68, P=0.010), whereas the ratio of S and G 2 /M phases was decreased (33.07 ± 1.86 vs 24.87 ± 1.76, t=5.54,P =0.010;19.30 ± 0.53:17.73 ± 0.83, t=2.75, P=0.050), and the apoptosis rate was increased (1.57 ± 0.47:10.47 ± 0.31,t=27.39, P=0.000) in a dose-dependent manner. Apoptosis with nuclear chromatin condensation, fragmentation and cell shrinkage was found by TEM. SP method showed that Celeib decreased COX-2 expression (17.48 ± 0.34 vs 12.82 ± 0.51, t=13.20, P=0.00). The sensitivity ratio (D 0 ) was 1.15. FCM showed that the percentage of cells in G 2 /M phase was significanty more in R and D + R groups than in Ci and Cd groups (68.00 ± 1.65, 54.27 ± 5.74,17.60 ± 0.80,14.86 ± 1.23, t=47.70,P=0.000; t=11.63, P=0.000), and also significantly different between R group and D + R group (t=3.99, P= 0.020). The apoptosis rate was higher in R and D + R groups than Ci and Cd groups(4.83 ± 0.97,9.50 ± 1.35,1.33 ± 0.86 and 2.28 ± 0.42, t=4.67, P=0.010; t

Radiosensitization by the histone deacetylase inhibitor vorinostat under hypoxia and with capecitabine in experimental colorectal carcinoma

International Nuclear Information System (INIS)

Saelen, Marie Grøn; Ree, Anne Hansen; Kristian, Alexandr; Fleten, Karianne Giller; Furre, Torbjørn; Hektoen, Helga Helseth; Flatmark, Kjersti

2012-01-01

The histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC). Radiosensitivity is critically influenced by hypoxia; hence, it is important to evaluate the efficacy of potential radiosensitizers under variable tissue oxygenation. Since fluoropyrimidine-based chemoradiotherapy (CRT) is the only clinically validated regimen in LARC, efficacy in combination with this established regimen should be assessed in preclinical models before a candidate drug enters clinical trials. Radiosensitization by vorinostat under hypoxia was studied in four colorectal carcinoma cell lines and in one colorectal carcinoma xenograft model by analysis of clonogenic survival and tumor growth delay, respectively. Radiosensitizing effects of vorinostat in combination with capecitabine were assessed by evaluation of tumor growth delay in two colorectal carcinoma xenografts models. Under hypoxia, radiosensitization by vorinostat was demonstrated in vitro in terms of decreased clonogenicity and in vivo as inhibition of tumor growth. Adding vorinostat to capecitabine-based CRT increased radiosensitivity of xenografts in terms of inhibited tumor growth. Vorinostat sensitized colorectal carcinoma cells to radiation under hypoxia in vitro and in vivo and improved therapeutic efficacy in combination with capecitabine-based CRT in vivo. The results encourage implementation of vorinostat into CRT in LARC trials

Radiosensitization by the histone deacetylase inhibitor vorinostat under hypoxia and with capecitabine in experimental colorectal carcinoma.

Science.gov (United States)

Saelen, Marie Grøn; Ree, Anne Hansen; Kristian, Alexandr; Fleten, Karianne Giller; Furre, Torbjørn; Hektoen, Helga Helseth; Flatmark, Kjersti

2012-09-27

The histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC). Radiosensitivity is critically influenced by hypoxia; hence, it is important to evaluate the efficacy of potential radiosensitizers under variable tissue oxygenation. Since fluoropyrimidine-based chemoradiotherapy (CRT) is the only clinically validated regimen in LARC, efficacy in combination with this established regimen should be assessed in preclinical models before a candidate drug enters clinical trials. Radiosensitization by vorinostat under hypoxia was studied in four colorectal carcinoma cell lines and in one colorectal carcinoma xenograft model by analysis of clonogenic survival and tumor growth delay, respectively. Radiosensitizing effects of vorinostat in combination with capecitabine were assessed by evaluation of tumor growth delay in two colorectal carcinoma xenografts models. Under hypoxia, radiosensitization by vorinostat was demonstrated in vitro in terms of decreased clonogenicity and in vivo as inhibition of tumor growth. Adding vorinostat to capecitabine-based CRT increased radiosensitivity of xenografts in terms of inhibited tumor growth. Vorinostat sensitized colorectal carcinoma cells to radiation under hypoxia in vitro and in vivo and improved therapeutic efficacy in combination with capecitabine-based CRT in vivo. The results encourage implementation of vorinostat into CRT in LARC trials.

Radiosensitization in esophageal squamous cell carcinoma. Effect of polo-like kinase 1 inhibition

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Chen, Jenny Ling-Yu [National Taiwan University, Institute of Biomedical Engineering, College of Medicine and College of Engineering, Taipei (China); National Taiwan University Hospital Hsin-Chu Branch, Department of Radiation Oncology, Hsin-Chu (China); National Taiwan University Hospital and National Taiwan University Cancer Center, Department of Oncology, Taipei (China); Chen, Jo-Pai [National Taiwan University Hospital and National Taiwan University Cancer Center, Department of Oncology, Taipei (China); National Taiwan University Hospital Yun-Lin Branch, Department of Oncology, Yun-Lin (China); Huang, Yu-Sen [National Taiwan University, Institute of Biomedical Engineering, College of Medicine and College of Engineering, Taipei (China); National Taiwan University Hospital, Department of Medical Imaging, Taipei (China); National Taiwan University Hospital Yun-Lin Branch, Department of Medical Imaging, Yun-Lin (China); Tsai, Yuan-Chun; Tsai, Ming-Hsien; Jaw, Fu-Shan [National Taiwan University, Institute of Biomedical Engineering, College of Medicine and College of Engineering, Taipei (China); Cheng, Jason Chia-Hsien; Kuo, Sung-Hsin [National Taiwan University Hospital and National Taiwan University Cancer Center, Department of Oncology, Taipei (China); National Taiwan University, Graduate Institute of Oncology, Taipei (China); Shieh, Ming-Jium [National Taiwan University, Institute of Biomedical Engineering, College of Medicine and College of Engineering, Taipei (China); National Taiwan University Hospital and National Taiwan University Cancer Center, Department of Oncology, Taipei (China)

2016-04-15

This study examined the efficacy of polo-like kinase 1 (PLK1) inhibition on radiosensitivity in vitro and in vivo by a pharmacologic approach using the highly potent PLK1 inhibitor volasertib. Human esophageal squamous cell carcinoma (ESCC) cell lines KYSE 70 and KYSE 150 were used to evaluate the synergistic effect of volasertib and irradiation in vitro using cell viability assay, colony formation assay, cell cycle phase analysis, and western blot, and in vivo using ectopic tumor models. Volasertib decreased ESCC cell proliferation in a dose- and time-dependent manner. Combination of volasertib and radiation caused G2/M cell cycle arrest, increased cyclin B levels, and induced apoptosis. Volasertib significantly enhanced radiation-induced death in ESCC cells by a mechanism involving the enhancement of histone H3 phosphorylation and significant cell cycle interruption. The combination of volasertib plus irradiation delayed the growth of ESCC tumor xenografts markedly compared with either treatment modality alone. The in vitro results suggested that targeting PLK1 might be a viable approach to improve the effects of radiation in ESCC. In vivo studies showed that PLK1 inhibition with volasertib during irradiation significantly improved local tumor control when compared to irradiation or drug treatment alone. (orig.) [German] Diese Studie untersucht die Wirksamkeit der Polo-like -Kinase 1-(PLK1-)Inhibition auf die Strahlenempfindlichkeit in vitro und in vivo beim oesophagealen Plattenepithelkarzinom durch eine pharmakologische Herangehensweise mit dem hochwirksamen PLK1-Inhibitor Volasertib. Menschliche Zelllinien des oesophagealen Plattenepithelkarzinoms (ESCC), KYSE 70 und KYSE 150, wurden verwendet, um den synergistischen Effekt von Volasertib und Bestrahlung in vitro zu bewerten. Hierzu wurden Zellviabilitaets- und Koloniebildungsuntersuchungen sowie Zellwachstumsanalysen, Immunblots und ektopische In-vivo-Tumormodelle herangezogen. Volasertib verminderte die ESCC

Inhibition of UBE2D3 expression attenuates radiosensitivity of MCF-7 human breast cancer cells by increasing hTERT expression and activity.

Directory of Open Access Journals (Sweden)

Wenbo Wang

Full Text Available The known functions of telomerase in tumor cells include replenishing telomeric DNA and maintaining cell immortality. We have previously shown the existence of a negative correlation between human telomerase reverse transcriptase (hTERT and radiosensitivity in tumor cells. Here we set out to elucidate the molecular mechanisms underlying regulation by telomerase of radiosensitivity in MCF-7 cells. Toward this aim, yeast two-hybrid (Y2H screening of a human laryngeal squamous cell carcinoma radioresistant (Hep2R cDNA library was first performed to search for potential hTERT interacting proteins. We identified ubiquitin-conjugating enzyme E2D3 (UBE2D3 as a principle hTERT-interacting protein and validated this association biochemically. ShRNA-mediated inhibition of UBE2D3 expression attenuated MCF-7 radiosensitivity, and induced the accumulation of hTERT and cyclin D1 in these cells. Moreover, down-regulation of UBE2D3 increased hTERT activity and cell proliferation, accelerating G1 to S phase transition in MCF-7 cells. Collectively these findings suggest that UBE2D3 participates in the process of hTERT-mediated radiosensitivity in human breast cancer MCF-7 cells by regulating hTERT and cyclin D1.

Radiosensitization of colorectal carcinoma cell lines by histone deacetylase inhibition

International Nuclear Information System (INIS)

Flatmark, Kjersti; Nome, Ragnhild V; Folkvord, Sigurd; Bratland, Åse; Rasmussen, Heidi; Ellefsen, Mali Strand; Fodstad, Øystein; Ree, Anne Hansen

2006-01-01

The tumor response to preoperative radiotherapy of locally advanced rectal cancer varies greatly, warranting the use of experimental models to assay the efficacy of molecular targeting agents in rectal cancer radiosensitization. Histone deacetylase (HDAC) inhibitors, agents that cause hyperacetylation of histone proteins and thereby remodeling of chromatin structure, may override cell cycle checkpoint responses to DNA damage and amplify radiation-induced tumor cell death. Human colorectal carcinoma cell lines were exposed to ionizing radiation and HDAC inhibitors, and cell cycle profiles and regulatory factors, as well as clonogenicity, were analyzed. In addition to G 2 /M phase arrest following irradiation, the cell lines displayed cell cycle responses typical for either intact or defective p53 function (the presence or absence, respectively, of radiation-induced expression of the cell cycle inhibitor p21 and subsequent accumulation of G 1 phase cells). In contrast, histone acetylation was associated with complete depletion of the G 1 population of cells with functional p53 but accumulation of both G 1 and G 2 /M populations of cells with defective p53. The cellular phenotypes upon HDAC inhibition were consistent with the observed repression of Polo-like kinase-1, a regulatory G 2 /M phase kinase. Following pre-treatment with HDAC inhibitors currently undergoing clinical investigation, the inhibitory effect of ionizing radiation on clonogenicity was significantly amplified. In these experimental models, HDAC inhibition sensitized the tumor cells to ionizing radiation, which is in accordance with the concept of increased probability of tumor cell death when chromatin structure is modified

Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma.

Science.gov (United States)

Markowitz, Daniel; Powell, Caitlin; Tran, Nhan L; Berens, Michael E; Ryken, Timothy C; Vanan, Magimairajan; Rosen, Lisa; He, Mingzu; Sun, Shan; Symons, Marc; Al-Abed, Yousef; Ruggieri, Rosamaria

2016-08-01

Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule inhibitor of MRK, M443, which binds to MRK in an irreversible fashion and inhibits its activity. We found that M443 strongly radiosensitizes UW228 medulloblastoma cells as well as UI226 patient-derived primary cells, whereas it does not affect the response to radiation of normal brain cells. M443 also inhibits radiation-induced activation of both p38 and Chk2, two proteins that act downstream of MRK and are involved in DNA damage-induced cell-cycle arrest. Importantly, in an animal model of medulloblastoma that employs orthotopic implantation of primary patient-derived UI226 cells in nude mice, M443 in combination with radiation achieved a synergistic increase in survival. We hypothesize that combining radiotherapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects. Mol Cancer Ther; 15(8); 1799-808. ©2016 AACR. ©2016 American Association for Cancer Research.

Effect of retinoic acid on the radiosensitivity of normal human oral keratinocyte

International Nuclear Information System (INIS)

Lee, Jean; Heo, Min Suk; Lee, Sam Sun; Oh, Sung Ook; Choi, Soon Chul; Park, Tae Won; Lee, Sul Mi; Choi, Hang Moon

2003-01-01

To evaluate the effect of all-trans-retinotic acid (ATRA) on the radiosensitivity of normal human oral keratinocyte (NHOK). Relative cell survival fraction including SF2 (survival fraction at 2 Gy) was calculated on the basis of colony formation assay. Data were fitted to the linear-quadratic model to establish the survival curve and calculate α and β values. Using flow cytometry at 1, 2, 3, 4, and 5 days after exposure to 2 and 10 Gy irradiation, cell cycle arrest and apoptosis were analysed. To understand the molecular mechanism of the radiosensitization of ATRA on NHOK, proteins related with apoptosis and cell cycle arrest were investigated by Western blot analysis. Treatment with ATRA resulted in a significant decrease of SF2 value for NHOK from 0.63 to 0.27, and increased α and β value, indicating that ATRA increased radiosensitivity of NHOK. ATRA increased LDH significantly, but increasing irradiation dose decreased LDH, suggesting that the radiosensitizing effect of ATRA is not directly related with increasing cell necrosis by ATRA. ATRA did not induce appotosis but increased G2 arrest after 10 Gy irradiation, implying that the increased radiosensitivity of NHOK may be due to a decrease in mitosis caused by increasing G2 arrest. ATRA inhibited the reduction of p53 at 3 days after 10 Gy irradiation and increased p21 at 1 day after 10 Gy irradiation. Further study is required to determine the precise relationship between this effect and the radiosensitizing effect of ATRA. These results suggested that ATRA increase radiosensitivity by inhibiting mitosis caused by increasing G2 arrest.

Radiosensitization by the histone deacetylase inhibitor vorinostat under hypoxia and with capecitabine in experimental colorectal carcinoma

Directory of Open Access Journals (Sweden)

Saelen Marie

2012-09-01

Full Text Available Abstract Background The histone deacetylase inhibitor vorinostat is a candidate radiosensitizer in locally advanced rectal cancer (LARC. Radiosensitivity is critically influenced by hypoxia; hence, it is important to evaluate the efficacy of potential radiosensitizers under variable tissue oxygenation. Since fluoropyrimidine-based chemoradiotherapy (CRT is the only clinically validated regimen in LARC, efficacy in combination with this established regimen should be assessed in preclinical models before a candidate drug enters clinical trials. Methods Radiosensitization by vorinostat under hypoxia was studied in four colorectal carcinoma cell lines and in one colorectal carcinoma xenograft model by analysis of clonogenic survival and tumor growth delay, respectively. Radiosensitizing effects of vorinostat in combination with capecitabine were assessed by evaluation of tumor growth delay in two colorectal carcinoma xenografts models. Results Under hypoxia, radiosensitization by vorinostat was demonstrated in vitro in terms of decreased clonogenicity and in vivo as inhibition of tumor growth. Adding vorinostat to capecitabine-based CRT increased radiosensitivity of xenografts in terms of inhibited tumor growth. Conclusions Vorinostat sensitized colorectal carcinoma cells to radiation under hypoxia in vitro and in vivo and improved therapeutic efficacy in combination with capecitabine-based CRT in vivo. The results encourage implementation of vorinostat into CRT in LARC trials.

Radiosensitization of non-small cell lung cancer by kaempferol.

Science.gov (United States)

Kuo, Wei-Ting; Tsai, Yuan-Chung; Wu, His-Chin; Ho, Yung-Jen; Chen, Yueh-Sheng; Yao, Chen-Han; Yao, Chun-Hsu

2015-11-01

The aim of the present study was to determine whether kaempferol has a radiosensitization potential for lung cancer in vitro and in vivo. The in vitro radio-sensitization activity of kaempferol was elucidated in A-549 lung cancer cells by using an MTT (3-(4 5-dimethylthiazol-2-yl)-25-diphenyl-tetrazolium bromide) assay, cell cycle analysis and clonogenic assay. The in vivo activity was evaluated in the BALB/c nude mouse xenograft model of A-549 cells by hematoxylin and eosin staining and immunohistochemistry, and the tumor volume was recorded. Protein levels of the apoptotic pathway were detected by western blot analysis. Treatment with kaempferol inhibited the growth of A-549 cells through activation of apoptotic pathway. However, the same doses did not affect HFL1 normal lung cell growth. Kaempferol induced G2/M cell cycle arrest and the enhancement of radiation-induced death and clonogenic survival inhibition. The in vivo data showed that kaempferol increased tumor cell apoptosis and killing of radiation. In conclusion, the findings demonstrated that kaempferol increased tumor cell killing by radiation in vitro and in vivo through inhibition of the AKT/PI3K and ERK pathways and activation of the mitochondria apoptosis pathway. The results of the present study provided solid evidence that kaempferol is a safe and potential radiosensitizer.

Prenyltransferase inhibitor radiosensitization of pancreatic ductal carcinoma (PaCa) cells

International Nuclear Information System (INIS)

Brunner, T.B.; Hahn, S.M.; Rustgi, A.K.

2003-01-01

Farnesyltransferase inhibitors (FTIs) radiosensitize tumor cell lines expressing activated H-Ras. K-Ras however remains active after FTI treatment due to prenylation by geranylgeranyltransferase. Up to 90% of pancreatic carcinomas (PaCa) are mutant in K-ras. We hypothesized that combined FTI and geranylgeranyltransferase inhibitor (GGTI) treatment could radiosensitize PaCa cells. Nine human PaCa lines (7 K-ras-mutant, 2 ras-wt) and transgenic mouse pancreatic ductal cells (PDC) expressing wt-ras or mutant K-ras were tested in clonogenic assays with combined FTI-A +/- GGTI-B (Merck and Co Inc.). Inhibition of PI3- kinase (with LY294002) or inhibition of MEK1/2 (with U0126) served to assess the significance of the PI3-kinase and MAPK to radiation survival in these cells. H- and K-Ras prenylation status and changes in phosphorylation of AKT and MAPK were monitored as were changes in cell cycle distribution. FTI+GGTI treatment achieved inhibition of K-Ras prenylation in all PaCa cell lines. This treatment radiosensitized the K-ras mutant cell lines AsPC-1, Capan-2, MiaPaCa-2 and PSN-1, PancM, but not Capan-1 or the ras-wt cell lines (BxPC-3, HS766T, PDC-wt). L-778,123, a dual action inhibitor, sensitized all K-ras mutant cells. Surprisingly, PancM, Panc-1, MiaPaCa-2 and PDC K-Ras cells were radiosensitized by FTI treatment alone. R11577, another FTI without GGTI activity, also sensitized Panc-1 and MiaPaCa-2 and additionally AsPC-1 cells. Radiosensitization was also achieved after treatment with LY294002 in all PaCa lines expressing mutant-K-ras and the ras-wt line BxPC-3 overexpressing Akt2. However these lines were not sensitized by U0126. FTI+GGTI sensitize K-ras mt PaCa cell lines to radiation. PI3-kinase signaling but not MAPK signaling appears to contribute to radiation survival in PaCa cells. Radiosensitization of certain PaCa cells by FTI alone indicates that alternate pathways or farnesylated targets other than K-Ras may also be involved in radiation survival

Radiosensitization in esophageal squamous cell carcinoma. Effect of polo-like kinase 1 inhibition

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Chen, Jenny Ling-Yu; Chen, Jo-Pai; Huang, Yu-Sen; Tsai, Yuan-Chun; Tsai, Ming-Hsien; Jaw, Fu-Shan; Cheng, Jason Chia-Hsien; Kuo, Sung-Hsin; Shieh, Ming-Jium

2016-01-01

This study examined the efficacy of polo-like kinase 1 (PLK1) inhibition on radiosensitivity in vitro and in vivo by a pharmacologic approach using the highly potent PLK1 inhibitor volasertib. Human esophageal squamous cell carcinoma (ESCC) cell lines KYSE 70 and KYSE 150 were used to evaluate the synergistic effect of volasertib and irradiation in vitro using cell viability assay, colony formation assay, cell cycle phase analysis, and western blot, and in vivo using ectopic tumor models. Volasertib decreased ESCC cell proliferation in a dose- and time-dependent manner. Combination of volasertib and radiation caused G2/M cell cycle arrest, increased cyclin B levels, and induced apoptosis. Volasertib significantly enhanced radiation-induced death in ESCC cells by a mechanism involving the enhancement of histone H3 phosphorylation and significant cell cycle interruption. The combination of volasertib plus irradiation delayed the growth of ESCC tumor xenografts markedly compared with either treatment modality alone. The in vitro results suggested that targeting PLK1 might be a viable approach to improve the effects of radiation in ESCC. In vivo studies showed that PLK1 inhibition with volasertib during irradiation significantly improved local tumor control when compared to irradiation or drug treatment alone. (orig.) [de

MicroRNA-375 Inhibits Growth and Enhances Radiosensitivity in Oral Squamous Cell Carcinoma by Targeting Insulin Like Growth Factor 1 Receptor

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Bin Zhang

2017-08-01

Full Text Available Background: MicroRNAs (miRNAs have emerged as key players in various human biological processes, including tumorigenesis. Here, we investigated the roles of miR-375 in the pathogenesis of oral squamous cell carcinoma (OSCC. Methods: We performed quantitative real-time PCR (qRT-PCR to detect miR-375 expression in OSCC tissues and corresponding normal oral epithelial tissues and analyze the correlation of miR-375 expression with OSCC metastasis and patient’s survival. Then, the effects of miR-375 expression on proliferation, cell cycle, apoptosis and radiosensitivity in OSCC cells were determined by using MTT, flow cytometry and clonogenic survival assays. A dual-luciferase reporter assay was performed to test whether miR-375 binds to the 3’-untranslated region (3’-UTR of target mRNA. Results: The expression level of miR-375 in OSCC tissues was significantly lower than that in normal oral epithelial tissues, and low miR-375 expression was correlated with higher incidence of lymph node metastasis and poor survival of OSCC patients. Upregulation of miR-375 significantly inhibits growth, induces cell cycle arrest in G0/G1 phase, increases apoptosis and enhances radiosensitivity in OSCC cells. Analysis of luciferase activity demonstrated that miR-375 binds to the 3’-UTR of insulin like growth factor 1 receptor (IGF-1R. Small interfering RNA (shRNA-mediated IGF-1R knockdown mimics the effects of miR-375 upregulation, while overexpression of IGF-1R partially reverses those effects in OSCC cells. Conclusion: It was obviously demonstrated that miRNA-375 inhibits growth and enhances radiosensitivity in OSCC cells by targeting IGF-1R, suggesting that miR-375 may be a potential therapeutic target for OSCC patients.

Radiosensitivity of higher plants

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Feng Zhijie

1992-11-01

The general views on radiosensitivity of higher plants have been introduced from published references. The radiosensitivity varies with species, varieties and organs or tissues. The main factors of determining the radiosensitivity in different species are nucleus volume, chromosome volume, DNA content and endogenous compounds. The self-repair ability of DNA damage and chemical group of biological molecules, such as -SH thiohydroxy of proteins, are main factors to determine the radiosensitivity in different varieties. The moisture, oxygen, temperature radiosensitizer and protector are important external factors for radiosensitivity. Both the multiple target model and Chadwick-Leenhouts model are ideal mathematical models for describing the radiosensitivity of higher plants and the latter has more clear significance in biology

Inhibition of HAS2 induction enhances the radiosensitivity of cancer cells via persistent DNA damage

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Shen, Yan Nan; Shin, Hyun-Jin; Joo, Hyun-Yoo; Park, Eun-Ran; Kim, Su-Hyeon; Hwang, Sang-Gu; Park, Sang Jun; Kim, Chun-Ho; Lee, Kee-Ho

2014-01-01

Highlights: •HAS2 may be a promising target for the radiosensitization of human cancer. •HAS2 is elevated (up to ∼10-fold) in irradiated radioresistant and -sensitive cancer cells. •HAS2 knockdown sensitizes cancer cells to radiation. •HAS2 knockdown potentiates irradiation-induced DNA damage and apoptotic death. •Thus, the irradiation-induced up-regulation of HAS2 contributes to the radioresistance of cancer cells. -- Abstract: Hyaluronan synthase 2 (HAS2), a synthetic enzyme for hyaluronan, regulates various aspects of cancer progression, including migration, invasion and angiogenesis. However, the possible association of HAS2 with the response of cancer cells to anticancer radiotherapy, has not yet been elucidated. Here, we show that HAS2 knockdown potentiates irradiation-induced DNA damage and apoptosis in cancer cells. Upon exposure to radiation, all of the tested human cancer cell lines exhibited marked (up to 10-fold) up-regulation of HAS2 within 24 h. Inhibition of HAS2 induction significantly reduced the survival of irradiated radioresistant and -sensitive cells. Interestingly, HAS2 depletion rendered the cells to sustain irradiation-induced DNA damage, thereby leading to an increase of apoptotic death. These findings indicate that HAS2 knockdown sensitizes cancer cells to radiation via persistent DNA damage, further suggesting that the irradiation-induced up-regulation of HAS2 contributes to the radioresistance of cancer cells. Thus, HAS2 could potentially be targeted for therapeutic interventions aimed at radiosensitizing cancer cells

Apoptosis and radiosensitization of Hodgkin cells by proteasome inhibition

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Pajonk, Frank; Pajonk, Katja; McBride, William H.

2000-01-01

Purpose: Malignant cells from Hodgkin's disease have been reported to be defective in regulation of NF-κB activity. Ionizing radiation is known to activate NF-κB, and it has been suggested that this pathway may protect cells from apoptosis following exposure to radiation and other therapeutic agents. Defective NF-κB regulation in Hodgkin cells could therefore dictate the response of this disease to therapy, as well as be responsible for maintaining the malignant phenotype. The purpose of this study was to explore whether NF-κB activity could be modulated in Hodgkin cells and whether it determines the response of these cells to treatment with ionizing radiation and/or dexamethasone. Methods and Materials: Activation of NF-κB in cells is accomplished in large part by degradation of its inhibitor IκB through the 26s proteasome. HD-My-Z Hodgkin cells were treated with the proteasome inhibitor MG-132 or transduced with a dominant negative super-repressor IκBα. Clonogenic survival, apoptosis, proteasome activity, and NF-κB binding activity were monitored in response to ionizing radiation and/or dexamethasone treatment. Results: HD-My-Z Hodgkin cells had modest NF-κB levels but, unlike other cell types, did not decrease their level of constitutively active NF-κB in response to proteasome inhibition with MG-132. In contrast, transduction with a non-phosphorable IκBα construct abolished expression. MG-132 did, however, induce apoptosis in HD-My-Z cells and sensitized them to ionizing radiation. Dexamethasone treatment had no effect on NF-κB activity or clonogenic survival of Hodgkin cells, but protected them from irradiation. Conclusion: We conclude that inhibition of 26s proteasome activity can induce apoptosis in HD-My-Z Hodgkin cells and radiosensitize them, in spite of the fact that their constitutively active NF-κB levels are unaltered. The proteasome may be a promising new therapeutic target for intervention in this disease. In contrast, the use of

Radiosensitizing effects of 9401 on mice bearing H22 hepatoma

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Liu Xiaoqiu; Wang Qin; Zhou Zewei; Han Ying; Wang Dezhi; Shen Xiu

2013-01-01

Objective: To investigate the radiosensitizing effects of 9401 on mice bearing H22 hepatoma. Methods: Mouse model bearing H22 hepatoma cells were established. Mice were randomly divided into six groups, the control group,the radiation group and four treatment groups including 9401 at high, medium and low dosages and nicotinamide combined with radiation. After irradiated, the growth of tumor was observed, the time of tumor growth was recorded, the delay time of tumor growth and enhancement factor (EF) were calculated. After 28 days, the mice were killed, the tumors were stripped and inhibition rate was calculated. Results: Groups of 9401 combined with radiation could postpone tumor growth. The difference was statistically significant between 9401 groups at high, medium dosages combined with radiation and nicotinamide combined with radiation group (t=24.7 and 7.5, both P<0.01). Compared with radiation alone group, groups of 9401 combined with radiation had significant radiosensitizing effect. The enhancement factor of 9401 combined with radiation groups at high and medium dosages were 2.13 and 1.73 respectively, they were significant higher than nicotinamide combined with radiation group (t=2.26 and 9.04, both P<0.05). The inhibition rate of 9401 groups at high, medium and low dosages combined with radiation were 64.5%, 50.9% and 42.6% respectively. The inhibition rate of nicotinamide group combined radiation was 53.2%. The inhibition rate of 9401 at high dosage combined with radiation had significant difference with nicotinamide combined radiation (t =2.8, P<0.05). Nicotinamide combined with radiation group, 9401 combined with radiation groups could significant inhibit the growth of tumors compared with radiation alone group (t=5.7, 4.0 and 2.2, all P<0.05). Conclusion: 9401 can inhibit the tumor growth and the inhibition effect increases gradually with the drug dose increasing. It also has radiosensitizing effects on mice bearing H22 hepatoma and present broadly

Effect of quercetin on radiosensitivity of human uterine cervix cancer HeLa cells

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Liang Xiaofang; Hong Chengjiao; Zhang Baoguo

2009-01-01

In order to investigate the effects of Quercetin on radiosensitivity of human Uterine Cervix Cancer HeLa cells, MTT assay and clonogenic assay were performed to evaluate the cytotoxicity of Quercetin on the cells. Clonogenic assay was used to observe its effects on the radiosensitivity of the cells. MTT result shows that the inhibition of Quercetin on the cells is in the dose-dependent and time-dependent. And the clonogenic assay result shows that the effect of Quercetin on HeLa cells can be divided into two parts, one for the inhibition of HeLa cells and another for the induction of HeLa cell death. The other clonogenic assay result also shows Quercetin can decrease clonogenic survival rate of HeLa cells exposed to X rays. The study shows Quercetin might enhance the radiosensitivity of the HeLa cell line. And it may provide a useful evaluation to combination of ionizing radiation and Quercetin for cancer patients. (authors)

Normal cellular radiosensitivity in an adult Fanconi anaemia patient with marked clinical radiosensitivity

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Marcou, Yiola; D'Andrea, Andrew; Jeggo, Penelope A.; Plowman, Piers N.

2001-01-01

Background: Fanconi anaemia is a rare disease associated with cellular sensitivity to chemicals (e.g. mitomycin C and diepoxybutane); variable but mild cellular radiosensitivity has also been reported. Materials and methods: A 32-year-old patient with Fanconi anaemia and tonsillar carcinoma, treated by radiotherapy, was found to exhibit profound clinical radiosensitivity. Confluent, ulcerating oropharyngeal mucositis developed after a conventionally fractionated dose of 34 Gy and healing was incomplete by 2 months after cessation of therapy. Results: Cellular radiosensitivity assays and RPLD studies from this patient did not suggest any major detectable radiosensitivity. Conclusion: There is a discrepancy between the observed clinical radiosensitivity and the usual 'predictive' radiosensitivity assays in this patient with Fanconi anaemia

Prostate-Specific Natural Health Products (Dietary Supplements) Radiosensitize Normal Prostate Cells

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Hasan, Yasmin; Schoenherr, Diane; Martinez, Alvaro A.; Wilson, George D.; Marples, Brian

2010-01-01

Purpose: Prostate-specific health products (dietary supplements) are taken by cancer patients to alleviate the symptoms linked with poor prostate health. However, the effect of these agents on evidence-based radiotherapy practice is poorly understood. The present study aimed to determine whether dietary supplements radiosensitized normal prostate or prostate cancer cell lines. Methods and Materials: Three well-known prostate-specific dietary supplements were purchased from commercial sources available to patients (Trinovin, Provelex, and Prostate Rx). The cells used in the study included normal prostate lines (RWPE-1 and PWR-1E), prostate tumor lines (PC3, DU145, and LNCaP), and a normal nonprostate line (HaCaT). Supplement toxicity was assessed using cell proliferation assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and cellular radiosensitivity using conventional clonogenic assays (0.5-4Gy). Cell cycle kinetics were assessed using the bromodeoxyuridine/propidium iodide pulse-labeling technique, apoptosis by scoring caspase-3 activation, and DNA repair by assessing γH2AX. Results: The cell growth and radiosensitivity of the malignant PC3, DU145, and LNcaP cells were not affected by any of the dietary prostate supplements (Provelex [2μg/mL], Trinovin [10μg/mL], and Prostate Rx [50 μg/mL]). However, both Trinovin (10μg/mL) and Prostate Rx (6μg/mL) inhibited the growth rate of the normal prostate cell lines. Prostate Rx increased cellular radiosensitivity of RWPE-1 cells through the inhibition of DNA repair. Conclusion: The use of prostate-specific dietary supplements should be discouraged during radiotherapy owing to the preferential radiosensitization of normal prostate cells.

Effect of allicin on the radiosensitivity of human pancreatic carcinoma BXPC3 cells

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Ma Hongbing; Di Zhengli; He Na; Wen Jiao; Ke Yue

2014-01-01

Objective: To study the effect of allicin on the growth and radiosensitivity of human pancreatic carcinoma BXPC3 cells. Methods: BXPC3 cells were exposed to X-rays in the presence or absence of allicin. Cell proliferation was measured by MTT assay. Cell cycle distribution and apoptosis were detected by flow cytometry assay. Cell radiosensitivity and the influence of allicin on it was evaluated by colony formation assay. The expressions of Bax and Bcl-2 proteins were assayed by RT-PCR and Western blot. Results: IC 50 values of allicin on cell growth were 76.24, 58.34 and 43.58 μmol/L under 12, 24 and 48 h treatment, respectively. Treatment of cells with allicin obviously inhibited cell growth after irradiation and hence increased radiosensitivity (t = 2.74, P < 0.05). This treament also enhanced radiation-induced cell cycle arrest at G 2 /M phase (t = 11.41, P < 0.05), apoptosis induction (t = 12.36, P < 0.05), and Bax expression (t = 4.83, P < 0.05), but it decreased Bcl-2 expression (t = 3.69, P < 0.05). Conclusions: Allicin could inhibit cell growth, induce cell cycle arrest and apoptosis via Bax/Bcl-2 pathway and hence increases radiosensitivity of BXPC3 cells. (authors)

Curcumin enhances the radiosensitivity of renal cancer cells by suppressing NF-κB signaling pathway.

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Li, Gang; Wang, Ziming; Chong, Tie; Yang, Jie; Li, Hongliang; Chen, Haiwen

2017-10-01

The radiation resistance of renal cell carcinoma (RCC) remains the primary obstacle to improve patient survival. This study aimed to investigate the effects of curcumin on the radiosensitivity of RCC cells. Human RCC cell (ACHN) was exposed to irradiation (IR) and/or curcumin treatment. Cell viability, DNA repair, cell cycle, and apoptosis, were evaluated by MTT, immunofluoresence staining and flow cytometry. Moreover, ACHN cells were xenografted into nude mice and subjected to IR and/or curcumin treatment. The expression of NF-κB signaling related proteins in ACHN cells and xenografts was detected by western blot analysis. The results showed that curcumin significantly increased radiosensitivity of ACHN cells by inhibiting the cell proliferation and DNA damage repair, causing cell cycle arrest at G2/M phase, inducing apoptosis in vitro, and suppressing the growth of xenografts in vivo. In addition, curcumin enhanced radiosensitivity was through markedly inhibiting IR-induced NF-κB signaling by modulating the related protein expressions including NF-κBP65, I-κB, VEGF, COX2, and Bcl-2 in ACHN cells, which was further strengthened by NF-κB inhibitor PDTC treatment. Thus, curcumin may confer radiosensitivity on RCC via inhibition of NF-κB activation and its downstream regulars, suggesting the potential application of curcumin as an adjuvant in radiotherapy of RCC. Copyright © 2017. Published by Elsevier Masson SAS.

Radiosensitization of normoxic and hypoxic h1339 lung tumor cells by heat shock protein 90 inhibition is independent of hypoxia inducible factor-1α.

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Schilling, Daniela; Bayer, Christine; Li, Wei; Molls, Michael; Vaupel, Peter; Multhoff, Gabriele

2012-01-01

Ionizing irradiation is a commonly accepted treatment modality for lung cancer patients. However, the clinical outcome is hampered by normal tissue toxicity and tumor hypoxia. Since tumors often have higher levels of active heat shock protein 90 (Hsp90) than normal tissues, targeting of Hsp90 might provide a promising strategy to sensitize tumors towards irradiation. Hsp90 client proteins include oncogenic signaling proteins, cell cycle activators, growth factor receptors and hypoxia inducible factor-1α (HIF-1α). Overexpression of HIF-1α is assumed to promote malignant transformation and tumor progression and thus might reduce the accessibility to radiotherapy. Herein, we describe the effects of the novel Hsp90 inhibitor NVP-AUY922 and 17-allylamino-17-demethoxygeldanamycin (17-AAG), as a control, on HIF-1α levels and radiosensitivity of lung carcinoma cells under normoxic and hypoxic conditions. NVP-AUY922 exhibited a similar biological activity to that of 17-AAG, but at only 1/10 of the dose. As expected, both inhibitors reduced basal and hypoxia-induced HIF-1α levels in EPLC-272H lung carcinoma cells. However, despite a down-regulation of HIF-1α upon Hsp90 inhibition, sensitivity towards irradiation remained unaltered in EPLC-272H cells under normoxic and hypoxic conditions. In contrast, treatment of H1339 lung carcinoma cells with NVP-AUY922 and 17-AAG resulted in a significant up-regulation of their initially high HIF-1α levels and a concomitant increase in radiosensitivity. In summary, our data show a HIF-1α-independent radiosensitization of normoxic and hypoxic H1339 lung cancer cells by Hsp90 inhibition.

Sensing radiosensitivity of human epidermal stem cells

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Rachidi, Walid; Harfourche, Ghida; Lemaitre, Gilles; Amiot, Franck; Vaigot, Pierre; Martin, Michele T.

2007-01-01

Purpose: Radiosensitivity of stem cells is a matter of debate. For mouse somatic stem cells, both radiosensitive and radioresistant stem cells have been described. By contrast, the response of human stem cells to radiation has been poorly studied. As epidermis is a radiosensitive tissue, we evaluated in the present work the radiosensitivity of cell populations enriched for epithelial stem cells of human epidermis. Methods and materials: The total keratinocyte population was enzymatically isolated from normal human skin. We used flow cytometry and antibodies against cell surface markers to isolate basal cell populations from human foreskin. Cell survival was measured after a dose of 2 Gy with the XTT assay at 72 h after exposure and with a clonogenic assay at 2 weeks. Transcriptome analysis using oligonucleotide microarrays was performed to assess the genomic cell responses to radiation. Results: Cell sorting based on two membrane proteins, α6 integrin and the transferrin receptor CD71, allowed isolation of keratinocyte populations enriched for the two types of cells found in the basal layer of epidermis: stem cells and progenitors. Both the XTT assay and the clonogenic assay showed that the stem cells were radioresistant whereas the progenitors were radiosensitive. We made the hypothesis that upstream DNA damage signalling might be different in the stem cells and used microarray technology to test this hypothesis. The stem cells exhibited a much more reduced gene response to a dose of 2 Gy than the progenitors, as we found that 6% of the spotted genes were regulated in the stem cells and 20% in the progenitors. Using Ingenuity Pathway Analysis software, we found that radiation exposure induced very specific pathways in the stem cells. The most striking responses were the repression of a network of genes involved in apoptosis and the induction of a network of cytokines and growth factors. Conclusion: These results show for the first time that keratinocyte

Identification of a radiosensitivity signature using integrative metaanalysis of published microarray data for NCI-60 cancer cells

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Kim Han

2012-07-01

Full Text Available Abstract Background In the postgenome era, a prediction of response to treatment could lead to better dose selection for patients in radiotherapy. To identify a radiosensitive gene signature and elucidate related signaling pathways, four different microarray experiments were reanalyzed before radiotherapy. Results Radiosensitivity profiling data using clonogenic assay and gene expression profiling data from four published microarray platforms applied to NCI-60 cancer cell panel were used. The survival fraction at 2 Gy (SF2, range from 0 to 1 was calculated as a measure of radiosensitivity and a linear regression model was applied to identify genes or a gene set with a correlation between expression and radiosensitivity (SF2. Radiosensitivity signature genes were identified using significant analysis of microarrays (SAM and gene set analysis was performed using a global test using linear regression model. Using the radiation-related signaling pathway and identified genes, a genetic network was generated. According to SAM, 31 genes were identified as common to all the microarray platforms and therefore a common radiosensitivity signature. In gene set analysis, functions in the cell cycle, DNA replication, and cell junction, including adherence and gap junctions were related to radiosensitivity. The integrin, VEGF, MAPK, p53, JAK-STAT and Wnt signaling pathways were overrepresented in radiosensitivity. Significant genes including ACTN1, CCND1, HCLS1, ITGB5, PFN2, PTPRC, RAB13, and WAS, which are adhesion-related molecules that were identified by both SAM and gene set analysis, and showed interaction in the genetic network with the integrin signaling pathway. Conclusions Integration of four different microarray experiments and gene selection using gene set analysis discovered possible target genes and pathways relevant to radiosensitivity. Our results suggested that the identified genes are candidates for radiosensitivity biomarkers and that

The radio-sensitizing effects and mechanisms of artemisinin and its derivates

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Jing, Zeng; Jianping, Cao; Saijun, Fan [School of Radiation Medicine and Public Health, Suzhou Univ., Suzhou (China)

2008-10-15

It has been proved that the antimalarial agent, Artemisinin and its derivates (such as artemether, arteether, artesunate, dihydroartemisinine, etc) boast powerful antitumor effects. Recently, researches have found that Artemisinin and its derivates can also enhance the radio-sensitivity of tumors through regulating cell cycle, creating cytotoxic effects induced by ROS, suppressing GSH activity and inhibiting the reparation of DNA damage etc. Moreover, they can reduce cell survival in a dose-dependent manner. This paper is paying more attention on the radio-sensitizing effects, characteristics and mechanisms of artemisinin and its derivates. (authors)

The radio-sensitizing effects and mechanisms of artemisinin and its derivates

International Nuclear Information System (INIS)

Zeng Jing; Cao Jianping; Fan Saijun

2008-01-01

It has been proved that the antimalarial agent, Artemisinin and its derivates (such as artemether, arteether, artesunate, dihydroartemisinine, etc) boast powerful antitumor effects. Recently, researches have found that Artemisinin and its derivates can also enhance the radio-sensitivity of tumors through regulating cell cycle, creating cytotoxic effects induced by ROS, suppressing GSH activity and inhibiting the reparation of DNA damage etc. Moreover, they can reduce cell survival in a dose-dependent manner. This paper is paying more attention on the radio-sensitizing effects, characteristics and mechanisms of artemisinin and its derivates. (authors)

DNA-Dependent Protein Kinase As Molecular Target for Radiosensitization of Neuroblastoma Cells.

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Dolman, M Emmy M; van der Ploeg, Ida; Koster, Jan; Bate-Eya, Laurel Tabe; Versteeg, Rogier; Caron, Huib N; Molenaar, Jan J

2015-01-01

Tumor cells might resist therapy with ionizing radiation (IR) by non-homologous end-joining (NHEJ) of IR-induced double-strand breaks. One of the key players in NHEJ is DNA-dependent protein kinase (DNA-PK). The catalytic subunit of DNA-PK, i.e. DNA-PKcs, can be inhibited with the small-molecule inhibitor NU7026. In the current study, the in vitro potential of NU7026 to radiosensitize neuroblastoma cells was investigated. DNA-PKcs is encoded by the PRKDC (protein kinase, DNA-activated, catalytic polypeptide) gene. We showed that PRKDC levels were enhanced in neuroblastoma patients and correlated with a more advanced tumor stage and poor prognosis, making DNA-PKcs an interesting target for radiosensitization of neuroblastoma tumors. Optimal dose finding for combination treatment with NU7026 and IR was performed using NGP cells. One hour pre-treatment with 10 μM NU7026 synergistically sensitized NGP cells to 0.63 Gy IR. Radiosensitizing effects of NU7026 increased in time, with maximum effects observed from 96 h after IR-exposure on. Combined treatment of NGP cells with 10 μM NU7026 and 0.63 Gy IR resulted in apoptosis, while no apoptotic response was observed for either of the therapies alone. Inhibition of IR-induced DNA-PK activation by NU7026 confirmed the capability of NGP cells to, at least partially, resist IR by NHEJ. NU7026 also synergistically radiosensitized other neuroblastoma cell lines, while no synergistic effect was observed for low DNA-PKcs-expressing non-cancerous fibroblasts. Results obtained for NU7026 were confirmed by PRKDC knockdown in NGP cells. Taken together, the current study shows that DNA-PKcs is a promising target for neuroblastoma radiosensitization.

The role of propranolol as a radiosensitizer in gastric cancer treatment

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Liao XH

2018-03-01

Full Text Available Xinhua Liao, Prakash Chaudhary, Guanglin Qiu, Xiangming Che, Lin Fan General Surgery Department, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China Purpose: The National Comprehensive Cancer Network guidelines indicate that radiotherapy in gastric cancer shows limited effectiveness at reducing the growth of gastric cancer. Therefore, enhancing the sensitivity and effect of radiotherapy with propranolol, a β-adrenoceptor antagonist, could reduce tumor growth. The role of propranolol as a radiosensitizer has not been adequately studied; therefore, the purpose of the present study is to evaluate the effect of propranolol as a radiosensitizer against gastric cancer in vivo. Methods: Sixty-four male nude mice bearing tumor xenografts were randomly divided into four groups. Cell culture was performed using the human gastric adenocarcinoma cell line SGC-7901. Mice with tumor xenografts were treated with propranolol, isoproterenol, and radiation. The data for tumor weight and volume were obtained for statistical analyses. Furthermore, the expression levels of COX-2, NF-κB, VEGF, and EGFR were examined using immunohistochemical techniques and Western blotting.Results: The growth in the volume and weight of the tumor was lower in mouse models treated with propranolol and radiation therapy compared to the other groups. Decreased expression of NF-κB was also observed in treatment groups where both propranolol and radiation were used, leading to the reduction of COX-2, EGFR, and VEGF expression compared to that in the other groups.Conclusion: The present study indicated that propranolol potentiates the antitumor effects of radiotherapy in gastric cancer by inhibiting NF-κB expression and its downstream genes: VEGF, EGFR, and COX-2. Keywords: propranolol, radiosensitizer, gastric cancer, radiation therapy 

Effect of Quercetin on radio-sensitivity of HeLa cells

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Wu Xiaofen; Hong Chengjiao; Guo Wenxiu; Pan Yanling; Zhang Baoguo

2011-01-01

In order to investigate the mechanism of Quercetin on radio-sensitivity of human Uterine Cervix Cancer HeLa cells, HeLa cells were cultured in different concentrations of Quercetin and different doses of irradiation. The clonogenic assay was used to observe the cell survival rate. The repair of DNA double-strand breaks and effect of Quercetin combination of radiation on the cell cycle were detected by flow cytometry. The results show that the radio-sensitivity of Quercetin on HeLa cells was obvious and the unrepaired DSBs after irradiation increased, but did not decrease G2/M cell cycle arrest. From this it can be inferred that the effect on HeLa cell radio-sensitivity may be related to the inhibition of the repair of DNA double-strand breaks induced by Quercetin, but it dose not reveal a significant relation with the cell cycle and G2/M arrest. (authors)

Radio-sensitization of WRN helicase deficient cancer cells by targeting homologous recombination pathway

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Gupta, Pooja; Saha, Bhaskar; Patro, Birija Sankar; Chattopadhyay, Subrata

2016-01-01

Ionizing radiation (IR) induced DNA double-strand breaks (DSBs) are primarily repaired by non-homologous end joining (NHEJ). However, it is well established that a subset DSBs which are accumulated in IR-induced G2 phase are dependent on homologous recombination (HR). DNA repair deficient tumor cells have been shown to accumulate high levels of DNA damage. Consequently, these cells become hyperdependent on DNA damage response pathways, including the CHK1-kinase-mediated HR-repair. These observations suggest that DNA repair deficient tumors should exhibit increased radio-sensitivity under HR inhibition. Genetic defects leading to functional loss of werner (WRN) protein is associated with genomic instability and increased cancer incidence. WRN function is known to be abrogated in several human cancer cells due to hypermethylation of CpGisland-promoter and transcriptional silencing of WRN gene. In the current investigation, using isogenic pairs of cell lines differing only in the WRN function, we showed that WRN-deficient cell lines were hyper-radiosensitive to CHK1 pharmacologic inhibition. Here, we found that unrepaired DSB was drastically increased in WRN-deficient cells vis-à-vis WRN-proficient cells in response to IR and CHK1 inhibitor (CHK1i). Our results revealed a marginal role of NHEJ pathway accountable for the radio-sensitivity of WRN-deficient cells. Interestingly, silencing CTIP, a HR protein required for RAD51 loading, significantly abrogated the CHK1i-mediated radiosensitivity in WRN-deficient cells. Silencing of WRN or CTIP individually led to no significant difference in the extent of DNA end resection, as required during HR pathway. Imperatively, our results revealed that WRN and CTIP together play a complementary role in executing DNA end resection during HR-mediated repair of IR induced DSBs. Altogether, our data indicated that inhibition of IR-induced HR pathway at RAD51 loading, but not at DSB end resection, make the WRN-deficient cancer cells

Radiosensitization effects of nicotinamide on malignant and normal mouse tissue

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Jonsson, G.G.; Kjellen, E.; Pero, R.W.; Cameron, R.

1985-01-01

Inhibitors of the chromatin-associated enzyme adenosine diphosphate ribosyltransferase have been found to inhibit DNA strand rejoining and to potentiate lethality of DNA-damaging agents both in vivo and in vitro. The authors have in this work examined the radiosensitizing potential of one such inhibitor, nicotinamide, on tumor tissue by using transplanted C3H mouse mammary adenocarcinomas and on normal tissue in a tail-stunting experiment using BALB/cA mice. The data indicate a radiosensitizing effect of nicotinamide on tumor cells as well as on normal tissue. The data indicate a possible role of adenosine diphosphate ribosyltransferase inhibitors as a sensitizing agent in the radiotherapy of malignant tumors

Experimental studies on the radiosensitizing agents against cultured human glioblastoma and human neurinoma

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Sawatari, Yutaka

1976-01-01

The radiosensitivity increasing effect of bromo-2'-deoxyuridine (BUdR) and 5-fluorouracil (5-FU), alone and in combination, was studied comparatively using tissue culture of brain tumor cells (No. 60 cells originating in human glioblastoma and N cells originating in human neurinoma) with colony formation and growth curve as the quantitative indices and the phase contrast microscope and scanning electron microscope for morphological observation. The inhibitive effect of BUdR on growth of the N cells was above 4μg/ml, while 3000μg/ml was required in the case of the No. 60 cells. This indicates that there is a large difference between the sensitivities of these two cell types against BUdR. Increased sensitivity can be anticipated by pretreatment of the No. 60 cells or the N cells with BUdR with a dose of no growth inhibition effect. N cells have a lower radiosensitivity than No. 60 cells; but when both cells are pretreated with BUdR, N cells have a higher radiosensitivity than No. 60 cells. This increasing radiosensitivity of the N cells, which is clinically benign, suggests the possibility of wider application for radiotherapy in the future. A dose of 2μg/ml of 5-FU alone showed no growth inhibiting effect on either the N cells or the No. 60 cells, but it intensified the effect of BUdR. Using a phase contrast microscope and a scanning electron microscope for morphological observation of the No. 60 cells and the N cells which had been exposed to BUdR+5-FU+X-ray, unique findings were observed on the surface structures of these two kinds of cells. (J.P.N.)

Effect of electroporation on radiosensitization with cisplatin in two cell lines with different chemo- and radiosensitivity

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Kranjc, S.; Cemazar, M.; Grosel, A.; Pipan, Z.; Sersa, G.

2003-01-01

Aim. Radiosensitization with cisplatin can be enhanced by electroporation of cells and tumours. The aim of this study was to extend our previous studies on two carcinoma tumour models with different chemo- and radiosensitivity in order to evaluate whether this treatment is effective also on less chemo- and radiosensitive tumour cells. Materials and methods. This in vitro study was performed on carcinoma SCK and EAT-E cells. The cytotoxicity of three-modality treatment consisting of cisplatin, electroporation and irradiation was determined by the clonogenic assay. Results. The radiosensitizing effect of cisplatin on the two cell lines was greatly enhanced by electroporation. By this combined treatment, less chemo and radiosensitive EAT-E cells were rendered as sensitive as more chemo and radiosensitive SCK cells. Conclusion. The enhancement of cisplatin-induced radiosensitization of cells by electroporation could be beneficially used in the treatment of intrinsically less chemo- and radiosensitive tumours. (author)

Influence of the size of garlic propagules on radiosensitivity of clones

International Nuclear Information System (INIS)

Perez Talavera, S.; Acevedo, A.M.; Perez, A.

1989-01-01

The influence of the size of garlic propagules selected to be irradiated on the results of radiosensitivity was studied so as to determine the useful radiation doses for improvement. This was done using radio inhibition of the plant height index as criteria and the mahalanobis distance stadigrapher calculated among defined groups for the behaviour of cloves in reference to six radiation doses. Significative differences were found among dose-effect curves obtained when using big cloves and small cloves, in five garlic clones, as well as different behaviours of clone radiosensitivity when it was investigated using the two proposed variants

DNA-Dependent Protein Kinase As Molecular Target for Radiosensitization of Neuroblastoma Cells.

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M Emmy M Dolman

Full Text Available Tumor cells might resist therapy with ionizing radiation (IR by non-homologous end-joining (NHEJ of IR-induced double-strand breaks. One of the key players in NHEJ is DNA-dependent protein kinase (DNA-PK. The catalytic subunit of DNA-PK, i.e. DNA-PKcs, can be inhibited with the small-molecule inhibitor NU7026. In the current study, the in vitro potential of NU7026 to radiosensitize neuroblastoma cells was investigated. DNA-PKcs is encoded by the PRKDC (protein kinase, DNA-activated, catalytic polypeptide gene. We showed that PRKDC levels were enhanced in neuroblastoma patients and correlated with a more advanced tumor stage and poor prognosis, making DNA-PKcs an interesting target for radiosensitization of neuroblastoma tumors. Optimal dose finding for combination treatment with NU7026 and IR was performed using NGP cells. One hour pre-treatment with 10 μM NU7026 synergistically sensitized NGP cells to 0.63 Gy IR. Radiosensitizing effects of NU7026 increased in time, with maximum effects observed from 96 h after IR-exposure on. Combined treatment of NGP cells with 10 μM NU7026 and 0.63 Gy IR resulted in apoptosis, while no apoptotic response was observed for either of the therapies alone. Inhibition of IR-induced DNA-PK activation by NU7026 confirmed the capability of NGP cells to, at least partially, resist IR by NHEJ. NU7026 also synergistically radiosensitized other neuroblastoma cell lines, while no synergistic effect was observed for low DNA-PKcs-expressing non-cancerous fibroblasts. Results obtained for NU7026 were confirmed by PRKDC knockdown in NGP cells. Taken together, the current study shows that DNA-PKcs is a promising target for neuroblastoma radiosensitization.

Post-irradiation DNA synthesis inhibition and G2 phase delay in radiosensitive body cells from non-Hodgkin's lymphoma patients: An indication of cell cycle defects

International Nuclear Information System (INIS)

Hannan, Mohammed A.; Kunhi, Mohammed; Einspenner, Michael; Khan, Bashir A.; Al-Sedairy, Sultan

1994-01-01

In the present study, both post-irradiation DNA synthesis and G 2 phase accumulation were analyzed in lymphoblastoid cell lines (LCLs) and fibroblast cell strains derived from (Saudi) patients with non-Hodgkin's lymphoma (NHL), ataxia telangiectasia (AT), AT heterozygotes and normal subjects. A comparison of the percent DNA synthesis inhibition (assayed by 3 H-thymidine uptake 30 min after irradiation), and a 24 h post-irradiation G 2 phase accumulation determined by flow cytometry placed the AT heterozygotes and the NHL patients in an intermediate position between the normal subjects (with maximum DNA synthesis inhibition and minimum G 2 phase accumulation) and the AT homozygotes (with minimum DNA synthesis inhibition and maximum G 2 accumulation). The similarity between AT heterozygotes and the NHL patients with respect to the two parameters studied after irradiation was statistically significant. The data indicating a moderate abnormality in the control of cell cycle progression after irradiation in the LCLs and fibroblasts from NHL patients may explain the enhanced cellular and chromosomal radiosensitivity in these patients reported by us earlier. In addition to demonstrating a link between cell cycle abnormality and radiosensitivity as a possible basis for cancer susceptibility, particularly in the NHL patients, the present studies emphasized the usefulness of the assay for 24 h post-irradiation G 2 phase accumulation developed elsewhere in characterizing AT heterozygote-like cell cycle anomaly in cancer patients irrespective of whether they carried the AT gene or any other affecting the cell cycle

Radiosensitizers and protectors

International Nuclear Information System (INIS)

Nori, D.; Kim, J.H.; Hilaris, B.; Chu, F.C.

1987-01-01

Over the past decades, various physical, biological, and clinical strategies have been investigated to improve the therapeutic effectiveness of radiation. One of these efforts has been to develop chemical radiosensitizers and protectors. In the broadest sense, a radiation sensitizer is any agent that enhances the cytolethal effects of radiation. Drugs that selectively protect tissues from radiation injury are under active study. This chapter briefly reviews the present status of chemical radiosensitizers and protectors. The discussion of sensitizers will be limited to the oxic cell and hypoxic cell radiosensitizers and their clinical applications

Thermal radiosensitization in heat- and radiation-sensitive mutants of CHO cells

International Nuclear Information System (INIS)

Kampinga, H.H.; Kanon, B.; Konings, A.W.T.; Stackhouse, M.A.; Bedford, J.S.

1993-01-01

In the current study, the extent of hyperthermic radiosensitization in a new γ-radiation-sensitive cell line, irs-20, recently isolated by Stackhouse and Bedford (1991) and a heat-sensitive mutant hs-36 (Harvey and Bedford 1988) was compared with the radiosensitization of their mutual parent CHO 10B12 cell line. The irs-20 and CHO 10B12 cells have comparable heat (43.5 o C) sensitivities, whereas hs-36 and CHO 10B12 show a similar sensitivity to γ- and X-rays. Radiosensitization due to pre-exposure to 43.5 o C heating of plateau phase cultures was found for all three cell lines, even after relatively mild heat treatment killing <20% of cells. Experiments using CHEF electrophoresis confirmed the dsb repair deficiency of the irs-20 cells (Stackhouse and Bedford 1992) and showed that heat inhibited dsb repair in all three cell lines. (Author)

ATM-mediated Snail Serine 100 phosphorylation regulates cellular radiosensitivity

International Nuclear Information System (INIS)

Boohaker, Rebecca J.; Cui, Xiaoli; Stackhouse, Murray; Xu, Bo

2013-01-01

Purpose: Activation of the DNA damage responsive protein kinase ATM is a critical step for cellular survival in response to ionizing irradiation (IR). Direct targets of ATM regulating radiosensitivity remain to be fully investigated. We have recently reported that ATM phosphorylates the transcriptional repressor Snail on Serine 100. We aimed to further study the functional significance of ATM-mediated Snail phosphorylation in response to IR. Material and methods: We transfected vector-only, wild-type, the Serine 100 to alanine (S100A) or to glutamic acid (S100E) substitution of Snail into various cell lines. We assessed colony formation, γ-H2AX focus formation and the invasion index in the cells treated with or without IR. Results: We found that over-expression of the S100A mutant Snail in HeLa cells significantly increased radiosensitivity. Meanwhile the expression of S100E, a phospho-mimicking mutation, resulted in enhanced radio-resistance. Interestingly, S100E could rescue the radiosensitive phenotype in ATM-deficient cells. We also found that expression of S100E increased γ-H2AX focus formation and compromised inhibition of invasion in response to IR independent of cell survival. Conclusion: ATM-mediated Snail Serine 100 phosphorylation in response to IR plays an important part in the regulation of radiosensitivity

Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

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Meng, Zhen [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China)

2015-05-01

Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocation and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.

Andrographolide radiosensitizes human esophageal cancer cell line ECA109 to radiation in vitro.

Science.gov (United States)

Wang, Z-M; Kang, Y-H; Yang, X; Wang, J-F; Zhang, Q; Yang, B-X; Zhao, K-L; Xu, L-P; Yang, L-P; Ma, J-X; Huang, G-H; Cai, J; Sun, X-C

2016-01-01

To explore the radiosensitivity of andrographolide on esophageal cancer cell line ECA109. The inhibition effects of andrographolide were measured using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) assay. Clonogenic survival assay was used to evaluate the effects of andrographolide on the radiosensitivity of esophageal cancer cells. Immunofluorescence was employed to examine Bax expression. The changes in cell cycle distribution and apoptosis were assayed using flow cytometry. The expression of NF-κb/Cleaved-Caspase3/Bax/Bcl-2 was measured using Western blot analysis. DNA damage was detected via γ-H2AX foci counting. With a clear dose and time effects, andrographolide was found to inhibit the proliferation of esophageal cell line ECA109. The results of the clonogenic survival assay show that andrographolide could markedly enhance radiosensitivity (P Andrographolide caused a dose-dependent increase in Cleaved-Caspase3/Bax protein expression and a decrease in Bcl-2/NF-κb expression. Apoptosis in andrographolide-treated ECA-109 increased significantly compared with the apoptosis in the simple drug and radiation combined with drug groups (P andrographolide combined with radiation group increased the number of DNA double chain breaks. Andrographolide can increase the radiosensitivity of esophageal cell line ECA109. This result may be associated with the decrease in the NF-κb level and the induced apoptosis of esophageal cancer cells. © 2014 International Society for Diseases of the Esophagus.

Radiosensitization and growth inhibition of cancer cells mediated by an scFv antibody gene against DNA-PKcs in vitro and in vivo

International Nuclear Information System (INIS)

Du, Li; Zhou, Ping-Kun; Zhou, Li-Jun; Pan, Xiu-Jie; Wang, Yu-Xiao; Xu, Qin-Zhi; Yang, Zhi-Hua; Wang, Yu; Liu, Xiao-Dan; Zhu, Mao-Xiang

2010-01-01

Overexpression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is commonly occurred in cancers and causes radioresistance and poor prognosis. In present study, the single-chain variable antibody fragments (scFv) targeting DNA-PKcs was developed for the application of radiosensitization in vitro and in vivo. A humanized semisynthetic scFv library and the phage-display antibodies technology were employed to screen DNA-PKcs scFv antibody. DNA-PKcs epitopes were predicted and cloned. A humanized semisynthetic scFv library and the phage-display antibodies technology were employed to screen DNA-PKcs scFv antibody. DNA damage repair was analyzed by comet assay and immunofluorescence detection of γH2AX foci. The radiosensitization in vivo was determined on Balb/c athymic mice transplanted tumours of HeLa cells. Four epitopes of DNA-PKcs have been predicted and expressed as the antigens, and a specific human anti-DNA-PKcs scFv antibody gene, anti-DPK3-scFv, was obtained by screening the phage antibody library using the DNA-PKcs peptide DPK3. The specificity of anti-DPK3-scFv was verified, in vitro. Transfection of HeLa cells with the anti-DPK3-scFv gene resulted in an increased sensitivity to IR, decreased repair capability of DNA double-strand breaks (DSB) detected by comet assay and immunofluorescence detection of γH2AX foci. Moreover, the kinase activity of DNA-PKcs was inhibited by anti-DPK3-scFv, which was displayed by the decreased phosphorylation levels of its target Akt/S473 and the autophosphorylation of DNA-PKcs on S2056 induced by radiation. Measurement of the growth and apoptosis rates showed that anti-DPK3-scFv enhanced the sensitivity of tumours transplanted in Balb/c athymic mice to radiation therapy. The antiproliferation and radiosensitizing effects of anti-DPK3-scFv via targeting DNA-PKcs make it very appealing for the development as a novel biological radiosensitizer for cancer therapeutic potential

Radiosensitivity in plants

International Nuclear Information System (INIS)

Nauman, A.F.

1979-01-01

The report presents a compilation of available data on the sensitivity of plants to ionizing radiation, and provides basic information on methods of determining such sensitivities, or of estimating radiosensitivities by calcuation of the nuclear factors upon which they depend. The scope of the data presented here is necessarily limited to the most generally useful radiobiological end points and to the most commonly-used types of radiation. Many of the factors which influence radiosensitivity, particularly nuclear factors, will be discussed. Emphasis will be upon whole-plant studies done at Brookhaven National Laboratory by A.H. Sparrow and his associates, since these studies are the source of most of the available radiosensitivity data and of all the sensitivity predictions listed here. Data presented here include summaries of experimentally-determined radiosensitivities at various end points for both herbaceous and woody higher plants, and for a few species of ferns and lower plants. The algae and fungi have not been considered here due to space limitations

Radiosensitivity in plants

Energy Technology Data Exchange (ETDEWEB)

Nauman, A F

1979-01-01

The report presents a compilation of available data on the sensitivity of plants to ionizing radiation, and provides basic information on methods of determining such sensitivities, or of estimating radiosensitivities by calcuation of the nuclear factors upon which they depend. The scope of the data presented here is necessarily limited to the most generally useful radiobiological end points and to the most commonly-used types of radiation. Many of the factors which influence radiosensitivity, particularly nuclear factors, will be discussed. Emphasis will be upon whole-plant studies done at Brookhaven National Laboratory by A.H. Sparrow and his associates, since these studies are the source of most of the available radiosensitivity data and of all the sensitivity predictions listed here. Data presented here include summaries of experimentally-determined radiosensitivities at various end points for both herbaceous and woody higher plants, and for a few species of ferns and lower plants. The algae and fungi have not been considered here due to space limitations.

Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma cells

International Nuclear Information System (INIS)

Staab, Adrian; Einsele, Hermann; Flentje, Michael; Vordermark, Dirk; Loeffler, Jürgen; Said, Harun M; Diehlmann, Désirée; Katzer, Astrid; Beyer, Melanie; Fleischer, Markus; Schwab, Franz; Baier, Kurt

2007-01-01

Hypoxia-inducible factor-1 (HIF-1) overexpression has been linked to tumor progression and poor prognosis. We investigated whether targeting of HIF-1 using chetomin, a disrupter of the interaction of HIF-1 with the transcriptional coactivator p300, influences the radiosensitivity of hypoxic HT 1080 human fibrosarcoma cells. Optimal dose of chetomin was determined by EGFP-HRE gene reporter assay in stably transfected HT 1080 cells. Cells were assayed for expression of the hypoxia-inducible genes carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF) by RT-PCR and for clonogenic survival after irradiation with 2, 5 or 10 Gy, under normoxic or hypoxic (0.1% O 2 , 12 h) conditions in the presence or absence of chetomin (150 nM, 12 h, pre-treatment of 4 h). Chetomin treatment significantly reduced CA9 and VEGF mRNA expression in hypoxic cells to 44.4 ± 7.2% and 39.6 ± 16.0%, respectively, of untreated hypoxic controls. Chetomin clearly reduced the modified oxygen enhancement ratio (OER') compared to untreated cells, from 2.02 to 1.27, from 1.86 to 1.22 and from 1.49 to 1.06 at the 50%, 37% and 10% clonogenic survival levels, respectively. HIF-1 inhibition by chetomin effectively reduces hypoxia-dependent transcription and radiosensitizes hypoxic HT 1080 human fibrosarcoma cells in vitro

A ruthenium polypyridyl intercalator stalls DNA replication forks, radiosensitizes human cancer cells and is enhanced by Chk1 inhibition

Science.gov (United States)

Gill, Martin R.; Harun, Siti Norain; Halder, Swagata; Boghozian, Ramon A.; Ramadan, Kristijan; Ahmad, Haslina; Vallis, Katherine A.

2016-08-01

Ruthenium(II) polypyridyl complexes can intercalate DNA with high affinity and prevent cell proliferation; however, the direct impact of ruthenium-based intercalation on cellular DNA replication remains unknown. Here we show the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyridophenazine, PIP = 2-(phenyl)imidazo[4,5-f][1,10]phenanthroline) immediately stalls replication fork progression in HeLa human cervical cancer cells. In response to this replication blockade, the DNA damage response (DDR) cell signalling network is activated, with checkpoint kinase 1 (Chk1) activation indicating prolonged replication-associated DNA damage, and cell proliferation is inhibited by G1-S cell-cycle arrest. Co-incubation with a Chk1 inhibitor achieves synergistic apoptosis in cancer cells, with a significant increase in phospho(Ser139) histone H2AX (γ-H2AX) levels and foci indicating increased conversion of stalled replication forks to double-strand breaks (DSBs). Normal human epithelial cells remain unaffected by this concurrent treatment. Furthermore, pre-treatment of HeLa cells with [Ru(dppz)2(PIP)]2+ before external beam ionising radiation results in a supra-additive decrease in cell survival accompanied by increased γ-H2AX expression, indicating the compound functions as a radiosensitizer. Together, these results indicate ruthenium-based intercalation can block replication fork progression and demonstrate how these DNA-binding agents may be combined with DDR inhibitors or ionising radiation to achieve more efficient cancer cell killing.

Modification of radiation effects on E. coli B/r and a radiosensitive mutant Bsub(s-1) by membrane-binding drugs

International Nuclear Information System (INIS)

Yonei, S.

1979-01-01

In this study, the effects of chlorpromazine, procaine and quinidine on the X-radiation effects on Escherichia coli B/r and its radiosensitive mutant Bsub(s-1) (which is genetically unable to repair radiation damage to DNA) were examined. At chlorpromazine concentrations > = 25 mM, there was loss of colony-forming ability in both strains. Chlorpromazine (0.1 mM) markedly sensitized E. coli B/r under hypoxic conditions of irradiation but not under oxic conditions. There was no significant radiosensitization by chlorpromazine (0.1-1.0mM) in E. coli Bsub(s-1) under either oxic or hypoxic conditions. Similar results were obtained when procaine and quinidine were used as 'membrane-binding radiosensitizers'. Thus these results suggested that radiosensitization by such drugs in E. coli B/r was the result of inhibition of post-irradiation DNA repair in cells. It was concluded that the inhibition of DNA repair could be a secondary consequence of cell membrane alterations or damage caused by the membrane-binding of these drugs. (UK)

Modulation of radiosensitivity by growth factors

International Nuclear Information System (INIS)

Paris, F.

2013-01-01

The full text of the publication follows. For the past 70 years, radiotherapy protocols were defined to target and kill cancer cells. New research developments showed that the tissue or tumor radiosensitivities might be directly modulated by its own microenvironment. Between all the micro-environmental cells, endothelial cells are playing a unique role due to the need of angio-genesis for tumor genesis and to the microvascular endothelial cell apoptosis involved in acute normal tissue and tumor radiosensitivities. Both endothelial behaviours may be controlled by specific growth factors secreted by tumor cells. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two cytokines involved in angio genesis and endothelial cell survival. Because radiation exposure develops opposite molecular and cellular responses by inhibiting proliferation and by enhancing apoptosis, inhibiting these cytokines has been proposed as a relevant strategy to improve radiotherapy efficiency. Drugs or antibody against VEGF, or other growth factors have been used with success to limit endothelial cell resistance, but also to transiently normalize of blood vessels to improve oxygen distribution into the tumor. However, better characterisation of the role of the cytokines will help to better improve the strategy of the use of their antagonists. We demonstrate that bFGF or sphingosin 1 phosphate (S1P), a lipid endothelial growth factor, protects endothelial cells from radiation stress by inhibiting the pre-mitotic apoptosis through enhancement of pro-survival molecular cascade, such as the Pi3K/AKT pathway, but not post-mitotic death. This discrepancy allowed a specific use of S1P as pharmacological drug protecting quiescent endothelial cells, present in normal tissue blood vessels, but not in proliferating angiogenic blood vessels, majority present in tumor blood vessel. In vivo studies are underway. (author)

Inhibition of GRP78 abrogates radioresistance in oropharyngeal carcinoma cells after EGFR inhibition by cetuximab.

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Chaonan Sun

Full Text Available The EGFR-specific mAb cetuximab is one of the most effective treatments for oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone are modest. Combination treatment with radiation can improve the efficacy of treatment through increasing radiosensitivity, while resistance to radiation after administration of cetuximab limits its efficiency. Radiation and drugs can damage the endoplasmic reticulum (ER homeostatic state and result in ER stress (ERS, subsequently causing resistance to radiation and drugs. Whether the ERS pathway is involved in radioresistance after administration of cetuximab has not been reported. Herein, we show that cetuximab could increase the radiosensitivity of FaDu cells but not Detroit562 cells. In addition, cetuximab inhibited the radiation-induced activation of the ERS signalling pathway IRE1α/ATF6-GRP78 in FaDu cells, while this effect was absent in Detroit562 cells. Silencing GRP78 increased the radiosensitivity of oropharyngeal carcinoma cells and inhibited radiation-induced DNA double-strand-break (DSB repair and autophagy. More interestingly, silencing GRP78 abrogated resistance to cetuximab and radiation in Detroit562 cells and had a synergistic effect with cetuximab in increasing the radiosensitivity of FaDu cells. Immunohistochemistry showed that overexpression of both GRP78 and EGFR was associated with a poor prognosis in oropharyngeal carcinoma patients (P<0.05. Overall, the results of this study show that radioresistance after EGFR inhibition by cetuximab is mediated by the ERS signalling pathway IRE1α/ATF6-GRP78. This suppression was consequently unable to inhibit radiation-induced DSB repair and autophagy in oropharyngeal carcinoma cells, which conferred resistance to radiotherapy and cetuximab. These results suggest that the cooperative effects of radiotherapy and cetuximab could be further improved by inhibiting GRP78 in non-responsive oropharyngeal carcinoma patients.

Caffeine inhibits homology-directed repair of I-SceI-induced DNA double-strand breaks.

Science.gov (United States)

Wang, Huichen; Boecker, Wilfried; Wang, Hongyan; Wang, Xiang; Guan, Jun; Thompson, Larry H; Nickoloff, Jac A; Iliakis, George

2004-01-22

We recently reported that two Chinese hamster mutants deficient in the RAD51 paralogs XRCC2 and XRCC3 show reduced radiosensitization after treatment with caffeine, thus implicating homology-directed repair (HDR) of DNA double-strand breaks (DSBs) in the mechanism of caffeine radiosensitization. Here, we investigate directly the effect of caffeine on HDR initiated by DSBs induced by a rare cutting endonuclease (I-SceI) into one of two direct DNA repeats. The results demonstrate a strong inhibition by caffeine of HDR in wild-type cells, and a substantial reduction of this effect in HDR-deficient XRCC3 mutant cells. Inhibition of HDR and cell radiosensitization to killing shows similar dependence on caffeine concentration suggesting a cause-effect relationship between these effects. UCN-01, a kinase inhibitor that effectively abrogates checkpoint activation in irradiated cells, has only a small effect on HDR, indicating that similar to radiosensitization, inhibition of checkpoint signaling is not sufficient for HDR inhibition. Recombination events occurring during treatment with caffeine are characterized by rearrangements reminiscent to those previously reported for the XRCC3 mutant, and immunofluorescence microscopy demonstrates significantly reduced formation of IR-specific RAD51 foci after caffeine treatment. In summary, our results identify inhibition of HDR as a significant contributor to caffeine radiosensitization.

MiR-122 Induces Radiosensitization in Non-Small Cell Lung Cancer Cell Line

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Debin Ma

2015-09-01

Full Text Available MiR-122 is a novel tumor suppresser and its expression induces cell cycle arrest, or apoptosis, and inhibits cell proliferation in multiple cancer cells, including non-small cell lung cancer (NSCLC cells. Radioresistance of cancer cell leads to the major drawback of radiotherapy for NSCLC and the induction of radiosensitization could be a useful strategy to fix this problem. The present work investigates the function of miR-122 in inducing radiosensitization in A549 cell, a type of NSCLC cells. MiR-122 induces the radiosensitization of A549 cells. MiR-122 also boosts the inhibitory activity of ionizing radiation (IR on cancer cell anchor-independent growth and invasion. Moreover, miR-122 reduced the expression of its targeted genes related to tumor-survival or cellular stress response. These results indicate that miR-122 would be a novel strategy for NSCLC radiation-therapy.

Radiosensitization and relative mechanisms of vanillin derivative BVAN08 on human glioma U-251 cells

International Nuclear Information System (INIS)

Wang Shubin; Zhang Bo; Sun Weijian; Wang Yu; Liu Xiaodan; Xu Qinzhi; Zhou Pingkun

2010-01-01

Objective: To provide more convincing evidences and experimental data for exploring vanillin derivative BVAN08, 6-bromine-5-hydroxy-4-methoxy-benzaldehyde, as a new anticancer drug, and to investigate the effect on the growth, radiosensitization of human glioma cell line U-251 and the relative mechanism. Methods: The effect of BVAN08 on cell proliferation of U-251 and radiosensitivity to 60 Co γ-rays (irradiation dose rate 2.3 Gy/min) were analyzed with MTT and colony-forming ability assay. Change in cellular morphology was observed by using light microscope. Change in cell cycle and apoptosis was detected with flow cytometry. The autophagy was observed by using TEM (irradiation dose rate is transmission electron microscope). DNA-PKcs protein level was detected through Western blot analysis. Results: BVAN08 exhibited a dose- and time-dependent inhibition on the proliferation of U-251 cells during the concentration range of 10-100 mol/L (t=1.83-3.07, P 50 at 48 h and 72 h after administration with BVAN08 were 55.3 and 52.7 mol/L, respectively. Obvious G 2 /M arrest was induced in U-251 cells after 4 h administration with BVAN08, and reached peck at 12 h. The G 2 /M population reached 63.3% in U-251 cells after 12 h administration of 60 μmol/L BVAN08 and kept increasing with the time, while both apoptosis and autophagic cell death were induced. The most effective radiosensitization time for BVAN08 treatment was 12 h before irradiation. The enhancement ratio of radiosensitivity was 3.14 for 20 μmol/L of BVAN08 12 h before 2 Gy irradiation. Conclusions: BVAN08 can induce apoptosis as radiosensitizing effect might be associated with the induction of G 2 /M arrest and inhibition of DNA-PKcs expression. BVAN08 seemed to be a promising radiosensitizing anticancer drug. (authors)

53BP1 loss suppresses the radiosensitizing effect of icotinib hydrochloride in colorectal cancer cells.

Science.gov (United States)

Huang, Ai; Yao, Jing; Liu, Tao; Lin, Zhenyu; Zhang, Sheng; Zhang, Tao; Ma, Hong

2018-04-01

This study aimed to investigate the influence of the expression of P53-binding protein 1 (53BP1), a key component in DNA damage repair pathways, on the radiosensitizing effect of icotinib hydrochloride in colorectal cancer and to elucidate the mechanisms underlying this influence. Real-time RT-PCR and Western blotting were performed to verify the gene-knockout effect of 53BP1 small hairpin RNA (ShRNA), and colony formation assay was employed to investigate the influence of 53BP1 downregulation on the radiosensitizing effect of icotinib hydrochloride in HCT116 cells. Cell apoptosis, cell cycle distributions, and histone H2AX (γ-H2AX) fluorescence foci after 53BP1 knockdown were evaluated. Relative protein expression in the ataxia telangiectasia mutated kinase (ATM)-checkpoint kinase-2 (CHK2)-P53 pathway was measured by Western blot analysis to unravel the molecular mechanisms linking the pathway to the above phenomena. Icotinib hydrochloride increased the radiosensitivity of HCT116 cells; however, this effect was suppressed by the downregulation of 53BP1 expression, a change that inhibited cell apoptosis, increased the percentage of HCT116 cells arrested in S-phase and inhibited the protein expression of key molecules in the ATM-CHK2-P53 apoptotic pathway. Our studies confirmed that the loss of 53BP1 serves as a negative regulator of the radiosensitizing effect of icotinib in part by suppressing the ATM-CHK2-P53 apoptotic pathway.

Radiosensitizers: rationale and potential

International Nuclear Information System (INIS)

Brown, J.M.

1981-01-01

This paper briefly reviews agents that are capable of sensitizing hypoxic cells to radiation and chemotherapeutic agents. The first part is a synopsis of the development of hypoxic radiosensitizers, which concludes that misonidazole can be effective against human tumors. Unfortunately, neurotoxicity limits its effectiveness in humans because the dose that can be given in conjunction with daily fractionated radiation is five to ten times lower than is required for full radiosensitization of the hypoxic cells. The second part covers our recent efforts to develop a drug that does not produce such limiting neurotoxicity. The primary rationale of our program was to synthesize a drug with a short plasma half-life that was too hydrophilic to cross the blood-brain barrier but was able to penetrate tumors and radiosensitize hypoxic cells. From this program, a new drug, SR-2508, has been found that is as efficient as misonidazole in its radiosensitizing ability, but is four to ten times less toxic. Finally, the potential of radiosensitizers not only as agents that can sensitize tumor cells to radiation, but also as agents that can specifically sensitize tumors to chemotherapeutic agents, is discussed. In addition, these drugs may be potential cytotoxic agents that produce toxicity only in solid tumors

Development of novel radiosensitizers for cancer therapy

CERN Document Server

Akamatsu, K

2002-01-01

The novel radiosensitizers for cancer therapy, which have some atoms with large X-ray absorption cross sections, were synthesized. The chemical and radiation (X-rays, W target, 100kVp) toxicities and the radiosensitivities to LS-180 human colon adenocarcinoma cells were also evaluated. 2,3,4,5,6-pentabromobenzylalcohol (PBBA) derivatives were not radiosensitive even around the maximum concentration. On the other hand, the hydrophilic sodium 2,4,6-triiodobenzoate (STIB) indicated meaningful radiosensitivity to the cells. Moreover, the membrane-specific radiosensitizers, cetyl fluorescein isthiocyanate (cetyl FITC), cetyl eosin isothiocyanate (cetyl br-FITC), cetyl erythrosin isothiocyanate (cetyl I-FITC), which aim for the membrane damage by X-ray photoabsorption on the target atoms, were localized in the plasma membrane. As the results of the colony formation assay, it was found that both cetyl FITC are similarly radiosensitive. In this report, we demonstrate the synthetic methods of the radiosensitizers, the...

Dimethoxycurcumin, a metabolically stable analogue of curcumin enhances the radiosensitivity of cancer cells: Possible involvement of ROS and thioredoxin reductase

Energy Technology Data Exchange (ETDEWEB)

Jayakumar, Sundarraj; Patwardhan, R.S.; Pal, Debojyoti [Radiation Biology & Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai 400085 (India); Sharma, Deepak [Radiation Biology & Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai 400085 (India); Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094 (India); Sandur, Santosh K., E-mail: sskumar@barc.gov.in [Radiation Biology & Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai 400085 (India); Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094 (India)

2016-09-09

Dimethoxycurcumin (DIMC), a structural analogue of curcumin, has been shown to have more stability, bioavailability, and effectiveness than its parent molecule curcumin. In this paper the radiosensitizing effect of DIMC has been investigated in A549 lung cancer cells. As compared to its parent molecule curcumin, DIMC showed a very potent radiosensitizing effect as seen by clonogenic survival assay. DIMC in combination with radiation significantly increased the apoptosis and mitotic death in A549 cells. This combinatorial treatment also lead to effective elimination of cancer stem cells. Further, there was a significant increase in cellular ROS, decrease in GSH to GSSG ratio and also significant slowdown in DNA repair when DIMC was combined with radiation. In silico docking studies and in vitro studies showed inhibition of thioredoxin reductase enzyme by DIMC. Overexpression of thioredoxin lead to the abrogation of radiosensitizing effect of DIMC underscoring the role of thioredoxin reductase in radiosensitization. Our results clearly demonstrate that DIMC can synergistically enhance the cancer cell killing when combined with radiation by targeting thioredoxin system. - Highlights: • DIMC enhances radiosensitivity of cancer cells by inducing cell death. • DIMC with radiation disrupted the cellular redox and targeted cancer stem cells. • DNA repair is hampered when cells are treated with DIMC. • DIMC inhibited thioredoxin reductase in cancer cells.

Dimethoxycurcumin, a metabolically stable analogue of curcumin enhances the radiosensitivity of cancer cells: Possible involvement of ROS and thioredoxin reductase

International Nuclear Information System (INIS)

Jayakumar, Sundarraj; Patwardhan, R.S.; Pal, Debojyoti; Sharma, Deepak; Sandur, Santosh K.

2016-01-01

Dimethoxycurcumin (DIMC), a structural analogue of curcumin, has been shown to have more stability, bioavailability, and effectiveness than its parent molecule curcumin. In this paper the radiosensitizing effect of DIMC has been investigated in A549 lung cancer cells. As compared to its parent molecule curcumin, DIMC showed a very potent radiosensitizing effect as seen by clonogenic survival assay. DIMC in combination with radiation significantly increased the apoptosis and mitotic death in A549 cells. This combinatorial treatment also lead to effective elimination of cancer stem cells. Further, there was a significant increase in cellular ROS, decrease in GSH to GSSG ratio and also significant slowdown in DNA repair when DIMC was combined with radiation. In silico docking studies and in vitro studies showed inhibition of thioredoxin reductase enzyme by DIMC. Overexpression of thioredoxin lead to the abrogation of radiosensitizing effect of DIMC underscoring the role of thioredoxin reductase in radiosensitization. Our results clearly demonstrate that DIMC can synergistically enhance the cancer cell killing when combined with radiation by targeting thioredoxin system. - Highlights: • DIMC enhances radiosensitivity of cancer cells by inducing cell death. • DIMC with radiation disrupted the cellular redox and targeted cancer stem cells. • DNA repair is hampered when cells are treated with DIMC. • DIMC inhibited thioredoxin reductase in cancer cells.

AZD2014 Radiosensitizes Oral Squamous Cell Carcinoma by Inhibiting AKT/mTOR Axis and Inducing G1/G2/M Cell Cycle Arrest.

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Chih-Chia Yu

Full Text Available Oral squamous cell carcinoma (OSCC is one of the most common malignant neoplasms in Taiwan. Activation of the mTOR signaling pathway has been linked to decreased radiation responsiveness in human oral cancer, thus it limits efficacy of radiotherapy. To address this question, we investigated the effect of AZD2014, a novel small molecular ATP-competitive inhibitor of mTORC1 and mTORC2 kinase, as a radiosensitizer in primary OSCC and OSCC-derived cell line models.We isolated primary tumor cells from OSCC tissues and cell lines. AZD2014 was administered with and without ionizing radiation. The radiosensitizing effect of AZD2014 were then assessed using cell viability assays, clonogenic survival assays, and cell cycle analyses. Western blotting was used to detect protein expression.Combination treatment with AZD2014 and irradiation resulted in significant reduction in OSCC cell line and primary OSCC cell colony formation due to the enhanced inhibition of AKT and both mTORC1 and mTORC2 activity. Pre-treatment with AZD2014 in irradiated oral cancer cells induced tumor cell cycle arrest at the G1 and G2/M phases, which led to disruption of cyclin D1-CDK4 and cyclin B1-CDC2 complexes. Moreover, AZD2014 synergized with radiation to promote both apoptosis and autophagy by increasing caspase-3 and LC3 in primary OSCC cells.These findings suggest that in irradiated OSCC cells, co-treatment with AZD2014, which targets mTORC1 and mTORC2 blockade, is an effective radiosensitizing strategy for oral squamous cell carcinoma.

Radiosensitivity of mouse germ cells

International Nuclear Information System (INIS)

Matsuda, Yoichi; Takeuchi, Toyoko; Maemori, Mamiko; Seki, Naohiko; Tobari, Izuo

1991-01-01

To estimate radiosensitivity of mouse germ cells the analysis of chromosome aberrations was performed at diakinesis-metaphase I of spermatocytes and first-cleavage metaphase of one-cell embryos after exposure to radiations at various stages of primary spermatocytes and spermatids. The result provided evidence that there are two major types of DNA damage in X-irradiated sperm : (1) short-lived DNA lesions ; the lesions are subject to repair inhibition by agents added in G 1 , and are converted into chromosome-type aberrations during G 1 , and (2) long-lived DNA lesions ; the lesions persist until S phase and repair of the lesions is inhibited by caffeine, hydroxyurea and arabinofuranosyl cytosine in G 2 . The characteristic of X-ray damage induced in spermiogenic stage and repair mechanism for the damage in the fertilized egg were discussed comparing with the results with two chemicals, methyl methanesulfonate (MMS) and mitomycin C (MMC). (J.P.N.)

Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous cell carcinoma cells by upregulating IGFBP-3

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Zhao Lei

2012-12-01

Full Text Available Abstract Background Epidermal growth factor receptor (EGFR is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC. The objective of this study was to investigate the efficacy of Nimotuzumab (an anti-EGFR monoclonal antibody on ESCC radiotherapy (RT and underlying mechanisms. Methods Nimotuzumab was administrated to 2 ESCC cell lines KYSE30 and TE-1 treated with RT. Cell growth, colony formation and apoptosis were used to measure anti-proliferation effects. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3 in ESCC cells radiosensitivity treated with Nimotuzumab. In vivo effect of Nimotuzumab on ESCC radiotherapy was done using a mouse xenograft model. Results Nimotuzumab enhanced radiation response of KYSE30 cells (with high EGFR expression in vitro, as evidenced by increased radiation-inhibited cell growth and colony formation and radiation-mediated apoptosis. Mechanism study revealed that Nimotuzumab inhibited phosphorylated EGFR (p-EGFR induced by EGF in KYSE30 cells. In addition, knockdown of IGFBP-3 by short hairpin RNA significantly reduced KYSE30 cells radiosensitivity (PP>0.05. In KYSE30 cell xenografts, Nimotuzumab combined with radiation led to significant tumor growth delay, compared with that of radiation alone (P=0.029, and also with IGFBP-3 up-regulation in tumor tissue. Conclusions Nimotuzumab could enhance the RT effect of ESCC cells with a functional active EGFR pathway. In particular, the increased ESCC radiosensitivity by Nimotuzumab might be dependent on the up-regulation of IGFBP-3 through EGFR-dependent pathway.

Radiosensitivity of grapevines. Empirical modelling of the radiosensitivity of some clones to x-ray irradiation. Pt. 1

International Nuclear Information System (INIS)

Koeroesi, F.; Jezierska-Szabo, E.

1999-01-01

Empirical and formal (Poisson) models were utilized, applying experimental growth data to characterize the radiosensitivity of six grapevine clones to X-ray irradiation. According to the radiosensitivity constants (k), target numbers (n) and volumes, GR 37 doses and energy deposition, the following radiosensitivity order has been found for various vine brands: Chardonnay clone type < Harslevelue K. 9 < Koevidinka K. 8 < Muscat Ottonel clone type < Irsai Oliver K. 11 < Cabernet Sauvignon E. 153. The model can be expanded to describe the radiosensitivity of other plant species and varieties, and also the efficiency of various radioprotecting agents and conditions. (author)

The inherited basis of human radiosensitivity

International Nuclear Information System (INIS)

Gatti, R.A.

2001-01-01

Certain individuals cannot tolerate 'conventional' doses of radiation therapy. This is known to be true of patients with ataxia-telangiectasia and ligase IV deficiency. Although in vitro testing may not correlate completely with clinical radiosensitivity, fibroblasts and lymphoblasts from patients with both of these disorders have been clearly shown to be radiosensitive. Using a colony survival assay (CSA) to test lymphoblastoid cells after irradiation with 1 Gy, a variety of other genetic disorders have been identified as strong candidates for clinical radiosensitivity, such as Nijmegen breakage syndrome, Mre11 deficiency, and Fanconi's anemia. These data are presented and considered as a starting-point for the inherited basis of human radiosensitivity

Autophagy involved in resveratrol increased radiosensitivity in glioma stem cells

International Nuclear Information System (INIS)

Long Linmei; Zhang Qingqing; Yang Neng; Ji Wenjun; Song Yunzhen; Zhao Jianghu; Liang Zhongqin

2012-01-01

Objective: To investigate the effect of Resveratrol combined with X-ray on radiosensitivity in glioma stem cells. Methods: The proliferation inhibition of glioma stem cells induced by X-rays and Resveratrol was assessed with MTT assay. The activation of proapoptotic effect was characterized by Hoechst 33258 stain. MDC stain and Western blot analysis were used to analyze the autophagy mechanism in X-rays-induced death of glioma stem cells. Results: MTT assay indicated that X-rays and Resveratrol decreased the viability of glioma stem cells (P<0.05); we found the proliferative inhibition of glioma stem cells was declined when we used 3-MA to inhibit autophagy(P<0.05). When the cells were treated by the Resveratrol and x-rays, their spherical shape were changed. Apoptosis was induced in glioma stem cells by combined X-rays and Resveratrol as detected by Hoechst 33258 staining. In addition, autophagy was induced in glioma stem cells in the combined treatment group as detected by MDC staining. Western blotting showed that Bcl-2 expression was decreased. in the combined treatment group (P<0.01), and the LC3-Ⅱ expression was increased in the combined treatment group (P<0.01). Conclusion: Resveratrol can increased the radiation sensitivity of glioma stem cells, the apoptosis and autophagy was induced in the glioma stem cells in the combined treatment X-rays and Resveratrol. Our results suggest that autophagy plays an essential role in the regulation of radiosensitization of glioma stem cells. (authors)

Study of radiosensitization of chloroquine on esophageal cancer cell line

International Nuclear Information System (INIS)

Yuan Xiaoli; Li Tao; Huang Jianming; Zha Xiao; Deng Bifang; Lang Jinyi

2014-01-01

Objective: To investigate the possibility of chloroquine radiosensitization of esophageal cancer cell line TE-1 and its further mechanism. Methods: Effect of chloroquine on cell viability of TE-1 cells was determined by MTT method. Expression of LC3, Beclin-1 and formation of acidic vesicular organelles (AVOs) were determined by Western blot, and fluorescence staining with Lyso-Tracker Red DND-99, respectively. Clonogenic survival of TE-1 cells was examined by clonogenic forming assay. Results: Chloroquine showed dose-dependent inhibition of TE-1 cell growth, and its values of IC_5_0 and IC_1_0 were (72.33±5.28) and (15.42±3.33) μmol/L, respectively. The expression of Beclin-1 and LC3-II/I markedly increased in irradiated TE-1 cells. The addition of chloroquine with IC_1_0 concentration significantly reduced the fluorescence and intensity of AVOs accumulation in the cytoplasm of TE-1 cells. Clonogenic survival fraction decreased obviously in TE-1 cells with addition of chloroquine after radiation and the value of SERD0 was 1.439. Conclusions: Chloroquine could radiosensitize esophageal cancer cells by blocking autophagy-lysosomal pathway and be used as a potential radiosensitizing strategy. (authors)

Use of Mitochondria-Specific Dye MKT-077 as a Radiosensitizer to Preoperatively Treat Locally Advanced Breast Cancer

National Research Council Canada - National Science Library

Braun, Rodney D

2007-01-01

The major goal of this project is to determine if the rhodacyanine analog dye, MKT-077, can be used to inhibit breast cancer cell oxygen metabolism and raise tumor oxygen levels, thereby radiosensitizing the tumor...

Use of Mitochondria-Specific Dye MKT-077 as a Radiosensitizer to Preoperatively Treat Locally Advanced Breast Cancer

National Research Council Canada - National Science Library

Braun, Rodney D

2006-01-01

The major goal of this project is to determine if the rhodacyanine analog dye, MKT-077, can be used to inhibit breast cancer cell oxygen metabolism and raise tumor oxygen levels, thereby radiosensitizing the tumor...

Use of Mitochondria-Specific Dye MKT-077 as a Radiosensitizer to Preoperatively Treat Locally Advanced Breast Cancer

National Research Council Canada - National Science Library

Braun, Rodney D

2008-01-01

The major goal of this project is to determine if the rhodacyanine analog dye, MKT-077, can be used to inhibit breast cancer cell oxygen metabolism and raise tumor oxygen levels, thereby radiosensitizing the tumor...

Intranuclear Delivery of a Novel Antibody-Derived Radiosensitizer Targeting the DNA-Dependent Protein Kinase Catalytic Subunit

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Xiong Hairong [Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA (Georgia); State Key Laboratory of Virology, Institute of Medical Virology, Wuhan University School of Medicine, Wuhan (China); Lee, Robert J. [Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, OH (United States); Haura, Eric B. [Thoracic Oncology and Experimental Therapeutics Programs, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States); Edwards, John G. [Apeliotus Technologies, Inc., Atlanta, GA (United States); Dynan, William S. [Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA (Georgia); Li Shuyi, E-mail: sli@georgiahealth.edu [Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, GA (Georgia); Apeliotus Technologies, Inc., Atlanta, GA (United States)

2012-07-01

Purpose: To inhibit DNA double-strand break repair in tumor cells by delivery of a single-chain antibody variable region fragment (ScFv 18-2) to the cell nucleus. ScFv 18-2 binds to a regulatory region of the DNA-dependent protein kinase (DNA-PK), an essential enzyme in the nonhomologous end-joining pathway, and inhibits DNA end-joining in a cell-free system and when microinjected into single cells. Development as a radiosensitizer has been limited by the lack of a method for intranuclear delivery to target cells. We investigated a delivery method based on folate receptor-mediated endocytosis. Methods and Materials: A recombinant ScFv 18-2 derivative was conjugated to folate via a scissile disulfide linker. Folate-ScFv 18-2 was characterized for its ability to be internalized by tumor cells and to influence the behavior of ionizing radiation-induced repair foci. Radiosensitization was measured in a clonogenic survival assay. Survival curves were fitted to a linear-quadratic model, and between-group differences were evaluated by an F test. Sensitization ratios were determined based on mean inhibitory dose. Results: Human KB and NCI-H292 lung cancer cells treated with folate-conjugated ScFv 18-2 showed significant radiosensitization (p < 0.001). Sensitization enhancement ratios were 1.92 {+-} 0.42 for KB cells and 1.63 {+-} 0.13 for NCI-H292 cells. Studies suggest that treatment inhibits repair of radiation-induced DSBs, as evidenced by the persistence of {gamma}-H2AX-stained foci and by inhibition of staining with anti-DNA-PKcs phosphoserine 2056. Conclusions: Folate-mediated endocytosis is an effective method for intranuclear delivery of an antibody-derived DNA repair inhibitor.

The inherited basis of human radiosensitivity

Energy Technology Data Exchange (ETDEWEB)

Gatti, R.A. [Univ. of California, School of Medicine, Los Angeles, CA (United States). Experimental Pathology

2001-11-01

Certain individuals cannot tolerate 'conventional' doses of radiation therapy. This is known to be true of patients with ataxia-telangiectasia and ligase IV deficiency. Although in vitro testing may not correlate completely with clinical radiosensitivity, fibroblasts and lymphoblasts from patients with both of these disorders have been clearly shown to be radiosensitive. Using a colony survival assay (CSA) to test lymphoblastoid cells after irradiation with 1 Gy, a variety of other genetic disorders have been identified as strong candidates for clinical radiosensitivity, such as Nijmegen breakage syndrome, Mre11 deficiency, and Fanconi's anemia. These data are presented and considered as a starting-point for the inherited basis of human radiosensitivity.

In vitro and in vivo study of a nanoliposomal cisplatin as a radiosensitizer

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Xiaomeng Zhang

2011-02-01

Full Text Available Xiaomeng Zhang1*, Huanjun Yang1*, Ke Gu1, Jian Chen2, Mengjie Rui2, Guo-Liang Jiang11Departments of Radiation Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College,Fudan University,Shanghai, People’s Republic of China; 2School of Pharmacy, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; *Xiaomeng Zhang and Huanjun Yang share the first authorshipObjective: To investigate the in vitro and in vivo radiosensitization effect of an institutionally designed nanoliposome encapsulated cisplatin (NLE-CDDP.Materials and methods: NLE-CDDP was developed by our institute. In vitro radiosensitization of NLE-CDDP was evaluated by colony forming assay in A549 cells. In vivo radiosensitization was studied with tumor growth delay (TGD in Lewis lung carcinoma. The radiosensitization for normal tissue was investigated by jejunal crypt survival. The radiosensitization studies were carried out with a 72 h interval between drug administration and irradiation. The mice were treated with 6 mg/kg of NLE-CDDP or CDDP followed by single doses of 2 Gy, 6 Gy, 16 Gy, and 28 Gy. Sensitization enhancement ratio (SER was calculated by D0s of cell survival curves for A549 cells, doses needed to yield TGD of 20 days in Lewis lung carcinoma, or D0s of survival curves in crypt cells in radiation alone and radiation plus drug groups.Results: Our NLE-CDDP could inhibit A549 cells in vitro with half maximal inhibitory concentration of 1.12 µg/mL, and its toxicity was 2.35 times that observed in CDDP. For in vitro studies of A549 cells, SERs of NLE-CDDP and CDDP were 1.40 and 1.14, respectively, when combined with irradiation. For in vivo studies of Lewis lung carcinoma, the strongest radiosensitization was found in the 72 h interval between NLE-CDDP and irradiation. When given 72 h prior to irradiation, NLE-CDDP yielded higher radiosensitization than CDDP (SER of 4.92 vs 3.21 and slightly increased injury in jejunal

Integrin inhibitor (Cilengitide) as radiosensitization strategy for malignant tumors

International Nuclear Information System (INIS)

Silva, Felipe Henrique de Souza

2017-01-01

Radiotherapy is effective in tumor control, but several tumors have molecular characteristics that lead to radioresistance and possible posttreatment recurrence. Many tumors have overexpression of integrin receptors. Integrins play a central role in growth, motility, regulation of adhesion and survival, leading to increased proliferation, invasion and metastasis of tumors, making these receptors excellent targets for the development of new therapies. Studies have shown that inhibiting the interaction of matrix proteins with integrin receptors may increase the cytotoxic effect of ionizing radiation by demonstrating the radiosensitizing potential of combination therapy in tumoral lines. Cilengitide an inhibitor of integrins receptors α Vβ3 and αVβ5 stands out for its great antitumor potential against gliomas. Thus, the combination of ionizing radiation with cilengitide is an alternative therapeutic strategy. However, the effect of this combination is little studied in Glioblastomas (U87 and T98) and not studied in melanoma (UACC). The objective of this study was to evaluate the radiosensitising potential of the RGD molecule cilengitida by means of the combined treatment with gamma radiation in different tumor lines, as well as to compare the effect of this combination therapy with cisplatin, a molecule already used in clinical practice. Our panel of tumor cell lines was composed of U87 (wild-type p53 malignant glioblastoma) T98 (malignant glioblastoma mutant p53), MCF7 (mammary carcinoma) and UACC (melanoma). The radiosensitizer effect of cilengitide was evaluated by the quantification of metabolic cell viability through the MTT assay. Inhibition of colony formation was investigated in clonogenicity assays. The flow cytometer was used to investigate cell cycle distribution and the type of cell death induced. We observed that in all cell lines examined, cilengitida promoted detachment, metabolic alterations and reduction of proliferation, as well as alteration of

Radiosensitivities of sensitized lymphocytes

International Nuclear Information System (INIS)

Taniguchi, Kazuto

1979-01-01

Immunization of mice with cell antigens such as allogeneic tumor cells or xenogeneic erythrocytes raises a variety of immune reactions mediated by T lymphocytes: i.e. delayed type hypersensitivity (DTH), cytotoxicity, and antibody production. The radiosensitivities of these reactions were examined in mice exposed to 600 R x-irradiation a few hours before or after immunization. 1) DTH to xenogeneic erythrocytes, as demonstrated by footpad reaction, was not suppressed by irradiation 3 h before or after immunization. DTH to allogeneic tumor cells, as demonstrated by a migration inhibition test, hardly developed in mice that had been irradiated before or after immunization. It may have belonged to distinct types of delayed reactions which were mediated by distinct subpopulations of T lymphocytes. 2) Cytotoxicity against allogeneic cells and xenogeneic erythrocytes showed almost the same radiosensitivity. It was scarcely detected in mice that had been irradiated before immunization. However, a low but definite degree of cytotoxicity was detected in mice that had been irradiated only a few hours after immunization. Solubilized allogeneic cells instead of native cells were used as immunizing antigens. It was also possible for precursor cells with cytotoxicity to acquire a radioresistant nature by immunization of solubilized antigens, but native cells were required as stimulation for radioresistant precursor cells to differentiated into nature cytotoxic effector cells. 3) Antibody production against xenogeneic erythrocytes or allogeneic cells was almost completely depleted in mice that had been irradiated before or after immunization. It is possible that antibody production essentially requires cell division and clonal expansion of B lymphocytes. (Bell, E.)

Comparative radiosensitivity in the class insecta

International Nuclear Information System (INIS)

Willard, W.K.; Cherry, D.S.

1975-01-01

A 'radiosensitivity index' (LT 50 /mean longevity) was correlated with the mean longevity and dry weight of 37 insect species (both sexes of 12 species) representing eight orders. Curvilinear regression analysis relating radiosensitivity to mean longevity and mean dry weight indicated that 46.3% of the observed variation could be attributed to longevity and 32.6% to the dry weight of the species. In general, large long-lived adults were more radiosensitive than small short-lived adults. Correlation of the phylogeny of insect orders and order groupings with the radio-sensitivity index was found to be poor. However, when the index was related to longevity, there was a tendency for species comprising the major orders investigated to occur in groups along the predicted curve. (author)

Inhibition of autophagy induced by TSA sensitizes colon cancer cell to radiation.

Science.gov (United States)

He, Gang; Wang, Yan; Pang, Xueli; Zhang, Bo

2014-02-01

Radiotherapy is one of the main treatments for clinical cancer therapy. However, its application was limited due to lack of radiosensitivity in some cancers. Trichostatin A (TSA) is a classic histone deacetylases inhibitor (HDACi) that specifically inhibits the biochemical functions of HDAC and is demonstrated to be an active anticancer drug. However, whether it could sensitize colon cancer to radiation is not clear. Our results showed that TSA enhanced the radiosensitivity of colon cancer cells as determined by CCK-8 and clonogenic survival assay. Moreover, apoptotic cell death induced by radiation was enhanced by TSA treatment. Additionally, TSA also induced autophagic response in colon cancer cells, while autophagy inhibition led to cell apoptosis and enhanced the radiosensitivity of colon cancer cells. Our data suggested that inhibition of cytoprotective autophagy sensitizes cancer cell to radiation, which might be further investigated for clinical cancer radiotherapy.

Insulin-like growth factor stimulation increases radiosensitivity of a pancreatic cancer cell line through endoplasmic reticulum stress under hypoxic conditions

International Nuclear Information System (INIS)

Isohashi, Fumiaki; Endo, Hiroko; Mukai, Mutsuko; Inoue, Masahiro; Inoue, Takehiro

2008-01-01

Tumor hypoxia is an obstacle to radiotherapy. Radiosensitivity under hypoxic conditions is determined by molecular oxygen levels, as well as by various biological cellular responses. The insulin-like growth factor (IGF) signaling pathway is a widely recognized survival signal that confers radioresistance. However, under hypoxic conditions the role of IGF signaling in radiosensitivity is still poorly understood. Here, we demonstrate that IGF-II stimulation decreases clonogenic survival under hypoxic conditions in the pancreatic cancer cell lines AsPC-1 and Panc-1, and in the human breast cancer cell line MCF-7. IGF treatment under hypoxic conditions suppressed increased radiation sensitivity in these cell lines by pharmacologically inhibiting the phosphoinositide 3-kinase-mammalian target of rapamycin pathway, a major IGF signal-transduction pathway. Meanwhile, IGF-II induced the endoplasmic reticulum stress response under hypoxia, including increased protein levels of CHOP and ATF4, mRNA levels of CHOP, GADD34, and BiP as well as splicing levels of XBP-1. The response was suppressed by inhibiting phosphoinositide 3-kinase and mammalian target of rapamycin activity. Overexpression of CHOP in AsPC-1 cells increased radiation sensitivity by IGF-II simulation under hypoxic conditions, whereas suppression of CHOP expression levels with small hairpin RNA or a dominant negative form of a proline-rich extensin-like receptor protein kinase in hypoxia decreased IGF-induced radiosensitivity. IGF-induced endoplasmic reticulum stress contributed to radiosensitization independent of cell cycle status. Taken together, IGF stimulation increased radiosensitivity through the endoplasmic reticulum stress response under hypoxic conditions. (author)

Stattic Enhances Radiosensitivity and Reduces Radio-Induced Migration and Invasion in HCC Cell Lines through an Apoptosis Pathway

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Gang Xu

2017-01-01

Full Text Available Purpose. Signal transducer and activator of transcription factor 3 (STAT3 is involved in tumorigenesis, development, and radioresistance of many solid tumors. The aim of this study is to investigate the effects of stattic (an inhibitor of STAT3 on the radiosensitivity and radio-induced migration and invasion ability in hepatocellular carcinoma (HCC cell lines. Methods. HCC cells were treated with stattic, and cell survival rate was analyzed through CCK-8 assay. Radiosensitivity was evaluated using cloning formation analysis; STAT3, p-STAT3, and apoptosis related proteins were detected by western blot. Radio-induced migration and invasion ability in HCC cells were analyzed by wound-healing assay and transwell test. Results. Stattic inhibits the expression of p-STAT3 and reduces cell survival in a dose-dependent manner in HCC cell lines, and the IC50 values for Hep G2, Bel-7402, and SMMC-7721 are 2.94 μM, 2.5 μM, and 5.1 μM, respectively. Cloning formation analysis shows that stattic enhances the radiosensitivity of HCC cells. Wound-healing assay and transwell test show that stattic inhibits radio-induced migration and invasion. Further study indicates that stattic promotes radio-induce apoptosis through regulating the expression of apoptosis related proteins in HCC cells. Conclusion. Stattic enhances radiosensitivity and reduces radio-induced migration and invasion ability in HCC cells probably through apoptosis pathway.

The toxic effects, GSH depletion and radiosensitivity by BSO on retinoblastoma

International Nuclear Information System (INIS)

Yi Xianjin; Ni Chuo; Wang Wengi; Li Ding; Jin Yizun

1993-01-01

Retinoblastoma is the most common intraocular malignant tumor in children. Previous investigations have reported that buthionine sulfoximine (BSO) can deplete intracellular glutathione (GSH) by the specific inhibition and increase cellular radiosensitivity. The toxic effects, GSH depletion and radiosensitivity of BSO on retinoblastoma were reported. GSH content of retinoblastoma cell lines Y-79, So-Rb50 and retinoblastoma xenograft is (2.7 +- 1.3) x 10 -12 mmol/cell, (1.4 +- 0.2) x 10 -12 mmol/cell, and 2.8 +- 1.2 μmol/g respectively. The ID50 of BSO on Y-79 and So-Rb50 in air for 3h exposure is 2.5 mM and 0.2 mM respectively. GSH depletion by 0.1 mM BSO for 24h on Y-79 cells and 0.01 mM BSO for 24 h on So-Rb50 cells is 16.35%, and 4.7% of control. GSH depletion in tumor and other organ tissues in retinoblastoma bearing nude mice after BSO administration is differential. BSH depletion after BSO exposure in Y-79 cells in vitro decrease the D 0 value of retinoblastoma cells. The SER of 0.01 mM and 0.05 mM BSO for 24 h under the hypoxic condition is 1.21 and 1.36 respectively. Based on these observations, the authors conclude that BSO toxicity on retinoblastoma cells depends on the characteristics of cell line and BSO can increase hypoxic retinoblastoma cells radiosensitivity in vitro. Further study of BSO radiosensitization on retinoblastoma in vivo using nude mouse xenograft is needed

Radiosensitivity of amphibia

Energy Technology Data Exchange (ETDEWEB)

Muramatsu, S [National Inst. of Radiological Sciences, Chiba (Japan)

1975-04-01

Radiosensitivity (semi-lethal dose) and the damages of radiation in the amphibia were studied by /sup 3/H-TdR from the standpoint of cellular kinetics. The cell mitosis cycle of the amphibia required a long time. The functional cell regeneration and the physiological function of the cell were slower than in mice. The reason for the low radiosensitivity of the amphibia was discussed relative to the environmental factor of temperature. Because the amphibia change body temperature according to environmental temperature, the danger of radiation damage, the actual lethal dose and the period of survival were influenced by the environmental temperature. Acute radiation danger to amphibia was essentially the same as the danger to mammalia, both young and old. LD/sub 50/ irradiation effects varied among the species. The cell regeneration, turn over, and the mitosis in the amphibia, were affected by environmental temperature, however, the courses proceeded slower than those of the mammalia. Therefore, the question remains, whether the comparison of the radiosensitivities of amphibia with other classes of animal by LDsub(50/30) irradiation was appropriate.

Targeting Phosphatidylinositol 4-Kinase IIIα for Radiosensitization: A Potential Model of Drug Repositioning Using an Anti-Hepatitis C Viral Agent

Energy Technology Data Exchange (ETDEWEB)

Kwon, Jeanny [Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul (Korea, Republic of); Kim, Dan Hyo; Park, Ji Min [Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam (Korea, Republic of); Park, Young Hee [Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul (Korea, Republic of); Hwang, Yeo Hyun [Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam (Korea, Republic of); Wu, Hong-Gyun [Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul (Korea, Republic of); Institute of Radiation Medicine, Seoul National University, Seoul (Korea, Republic of); Shin, Kyung Hwan [Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul (Korea, Republic of); Kim, In Ah, E-mail: inah228@snu.ac.kr [Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul (Korea, Republic of); Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam (Korea, Republic of); Institute of Radiation Medicine, Seoul National University, Seoul (Korea, Republic of); Cancer Research Institute, Seoul National University, Seoul (Korea, Republic of)

2016-11-15

Purpose: To investigate which isotype of phosphatidylinositol 4-kinase (PI4K) may affect radiosensitivity and examine whether anti–hepatitis C viral (HCV) agents, some of which have been shown to inhibit PI4K IIIα activity, could be repositioned as a radiosensitizer in human cancer cells. Methods and Materials: U251, BT474, and HepG2 cell lines and normal human astrocyte were used. Ribonucleic acid interference, clonogenic assays, Western blotting, immunofluorescence, annexin V assay, lysotracker staining, and β-galactosidase assay were performed. Results: Of the 4 PI4K isotypes, specific inhibition of IIIα increased radiosensitivity. For pharmacologic inhibition of PI4K IIIα, we screened 9 anti-HCV agents by half-maximal inhibitory concentration assay. Simeprevir was selected, and its inhibition of PI4K IIIα activity was confirmed. Combination of simeprevir treatment and radiation significantly attenuated expression of phospho-phospho-PKC and phospho-Akt and increased radiation-induced cell death in tested cell lines. Pretreatment with simeprevir prolonged γH2AX foci formation and down-regulation of phospho-DNA-PKcs, indicating impairment of nonhomologous end-joining repair. Cells pretreated with simeprevir exhibited mixed modes of cell death, including apoptosis and autophagy. Conclusion: These data demonstrate that targeting PI4K IIIα using an anti-HCV agent is a viable approach to enhance the therapeutic efficacy of radiation therapy in various human cancers, such as glioma, breast, and hepatocellular carcinoma.

The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells

Directory of Open Access Journals (Sweden)

Roberto Gomez-Casal

2015-05-01

Full Text Available The molecular chaperone HSP90 is involved in stabilization and function of multiple client proteins, many of which represent important oncogenic drivers in NSCLC. Utilization of HSP90 inhibitors as radiosensitizing agents is a promising approach. The antitumor activity of ganetespib, HSP90 inhibitor, was evaluated in human lung adenocarcinoma (AC cells for its ability to potentiate the effects of IR treatment in both in vitro and in vivo. The cytotoxic effects of ganetespib included; G2/M cell cycle arrest, inhibition of DNA repair, apoptosis induction, and promotion of senescence. All of these antitumor effects were both concentration- and time-dependent. Both pretreatment and post-radiation treatment with ganetespib at low nanomolar concentrations induced radiosensitization in lung AC cells in vitro. Ganetespib may impart radiosensitization through multiple mechanisms: such as down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and promotion of cellular senescence. In vivo, ganetespib reduced growth of T2821 tumor xenografts in mice and sensitized tumors to IR. Tumor irradiation led to dramatic upregulation of β-catenin expression in tumor tissues, an effect that was mitigated in T2821 xenografts when ganetespib was combined with IR treatments. These data highlight the promise of combining ganetespib with IR therapies in the treatment of AC lung tumors.

Resveratrol enhances radiosensitivity of human non-small cell lung cancer NCI-H838 cells accompanied by inhibition of nuclear factor-kappa B activation

International Nuclear Information System (INIS)

Liao, Hui-Fen; Kuo Cheng-Deng; Yang, Yuh-Cheng; Lin, Chin-Ping; Tai, Hung-Chi; Chen, Yu-Jen; Chen, Yu-Yawn

2005-01-01

Resveratrol, a polyphenol in red wine, possesses many pharmacological activities including cardio-protection, chemoprevention, anti-tumor effects, and nuclear factor-kappa B (NF-κB) inactivation. The present study was designed to evaluate the effects and possible mechanism of resveratrol in enhancing radiosensitivity of lung cancer cells. Human non-small cell lung cancer NCI-H838 cells were irradiated with or without resveratrol pretreatment. The surviving fraction and sensitizer enhancement ratio (SER) were estimated by using a colony formation assay and linear-quadratic model. The cell-cycle distribution was evaluated by using prospidium iodide staining and flow cytometry. An enzyme-linked immunosorbent assay (ELISA)-based assay with immobilized oligonucleotide was performed to assess the DNA binding activity of NF-κB. Resveratrol had no direct growth-inhibitory effect on NCI-H838 cells treated for 24 hours with doses up to 25 μM. Pretreatment with resveratrol significantly enhanced cell killing by radiation, with an SER up to 2.2. Radiation activated NF-κB, an effect reversed by resveratrol pretreatment. Resveratrol resulted in a decrease of cells in the G 0 /G 1 phase and an increase in the S phase. Our results demonstrate that resveratrol enhances the radiosensitivity of NCI-H838 cells accompanied by NF-κB inhibition and S-phase arrest. (author)

Radiogenomics: predicting clinical normal tissue radiosensitivity

DEFF Research Database (Denmark)

Alsner, Jan

2006-01-01

Studies on the genetic basis of normal tissue radiosensitivity, or  'radiogenomics', aims at predicting clinical radiosensitivity and optimize treatment from individual genetic profiles. Several studies have now reported links between variations in certain genes related to the biological response...... to radiation injury and risk of normal tissue morbidity in cancer patients treated with radiotherapy. However, after these initial association studies including few genes, we are still far from being able to predict clinical radiosensitivity on an individual level. Recent data from our own studies on risk...

DNMT (DNA methyltransferase) inhibitors radiosensitize human cancer cells by suppressing DNA repair activity

International Nuclear Information System (INIS)

Kim, Hak Jae; Kim, Jin Ho; Chie, Eui Kyu; Da Young, Park; Kim, In Ah; Kim, Il Han

2012-01-01

Histone modifications and DNA methylation are two major factors in epigenetic phenomenon. Unlike the histone deacetylase inhibitors, which are known to exert radiosensitizing effects, there have only been a few studies thus far concerning the role of DNA methyltransferase (DNMT) inhibitors as radiosensitizers. The principal objective of this study was to evaluate the effects of DNMT inhibitors on the radiosensitivity of human cancer cell lines, and to elucidate the mechanisms relevant to that process. A549 (lung cancer) and U373MG (glioblastoma) cells were exposed to radiation with or without six DNMT inhibitors (5-azacytidine, 5-aza-2'-deoxycytidine, zebularine, hydralazine, epigallocatechin gallate, and psammaplin A) for 18 hours prior to radiation, after which cell survival was evaluated via clonogenic assays. Cell cycle and apoptosis were analyzed via flow cytometry. Expressions of DNMT1, 3A/3B, and cleaved caspase-3 were detected via Western blotting. Expression of γH2AX, a marker of radiation-induced DNA double-strand break, was examined by immunocytochemistry. Pretreatment with psammaplin A, 5-aza-2'-deoxycytidine, and zebularine radiosensitized both A549 and U373MG cells. Pretreatment with psammaplin A increased the sub-G1 fraction of A549 cells, as compared to cells exposed to radiation alone. Prolongation of γH2AX expression was observed in the cells treated with DNMT inhibitors prior to radiation as compared with those treated by radiation alone. Psammaplin A, 5-aza-2'-deoxycytidine, and zebularine induce radiosensitivity in both A549 and U373MG cell lines, and suggest that this effect might be associated with the inhibition of DNA repair

Modification of the radiosensitizing effect of metronidazole by 5-fluorouracil and caffeine

International Nuclear Information System (INIS)

Esel'baeva, G.O.; Ermekova, S.A.

1986-01-01

A study was made of the combined effect of 5-fluorouracil, metronidazole, caffeine and radiation on radiosensitivity of Pliss lymphosarcoma and protein synthesis rate during the first few hours following irradiation. A complete regression of the tumor was noted in 100% of animals after a 3-fold exposure. Effective postirradiation inhibition of protein synthesis was achieved by injection of metronidazole and caffeine together with 5-fluorouracil

Differential radiosensitivity of seeds, seedlings and callus cultures of Petunia inflata

International Nuclear Information System (INIS)

Bapat, V.A.; Rao, P.S.

1976-01-01

A comparative study of the effects of γ-irradiation on seeds, seedlings and callus cultures of Petunia inflata showed striking differences in radiosensitivity as reflected in differences in mean fresh and dry weights, seedling height and morphology. Seeds subjected to low doses (4-6 kR) of irradiation showed stimulation of seedling height. Direct exposure of seedlings to high doses (10 kR) of irradiation caused inhibition in their development. Callus cultures, however, were more radioresistant compared to seeds and seedlings. Tissues grown on either an irradiated nutrient medium or on a medium in which sucrose alone had been irradiated, showed a marked inhibition in their growth potential

Downregulation of miR-210 expression inhibits proliferation, induces apoptosis and enhances radiosensitivity in hypoxic human hepatoma cells in vitro

International Nuclear Information System (INIS)

Yang, Wei; Sun, Ting; Cao, Jianping; Liu, Fenju; Tian, Ye; Zhu, Wei

2012-01-01

Hypoxia is a common feature of solid tumors and an important contributor to tumor radioresistance. miR-210 is the most consistently and robustly induced microRNA under hypoxia in different types of tumor cells and normal cells. In the present study, to explore the feasibility of miR-210 as an effective therapeutic target, lentiviral-mediated anti-sense miR-210 gene transfer technique was employed to downregulate miR-210 expression in hypoxic human hepatoma SMMC-7721, HepG2 and HuH7 cells, and phenotypic changes of which were analyzed. Hypoxia led to an increased hypoxia inducible factor-1α (HIF-1α) and miR-210 expression and cell arrest in the G 0 /G 1 phase in all cell lines. miR-210 downregulation significantly suppressed cell viability, induced cell arrest in the G 0 /G 1 phase, increased apoptotic rate and enhanced radiosensitivity in hypoxic human hepatoma cells. Moreover, apoptosis-inducing factor, mitochondrion-associated, 3 (AIFM3) was identified as a direct target gene of miR-210. AIFM3 downregulation by siRNA attenuated radiation induced apoptosis in miR-210 downregulated hypoxic human hepatoma cells. Taken together, these data suggest that miR-210 might be a potential therapeutic target and specific inhibition of miR-210 expression in combination with radiotherapy might be expected to exert strong anti-tumor effect on hypoxic human hepatoma cells. -- Highlights: ► miR-210 downregulation radiosensitized hypoxic hepatoma. ► AIFM3 was identified as a direct target gene of miR-210. ► miR-210 might be a therapeutic target to hypoxic hepatoma.

Radiosensitivity and genes

Energy Technology Data Exchange (ETDEWEB)

Qiyue, Hu; Mingyue, Lun [Suzhou Medical Coll., JS (China)

1995-07-01

Reported effects of some oncogenes, tumour suppressor genes and DNA repair genes on sensitivity of cells to ionizing radiation are reviewed. The role of oncogenes in cellular response to irradiation is discussed, especially the extensively studied oncogenes such as the ras gene family. For tumour suppressor genes, mainly the p53, which is increasingly implicated as a gene affecting radiosensitivity, is reviewed. It is considered that there is a cell cycle checkpoint determinant which is postulated to be able to arrest the irradiated cells in G{sub 1} phase to allow them to repair damage before they undergo DNA synthesis. So far there are six DNA repair genes which have been cloned in mammalian cells, but only one, XRCC1, appears to be involved in repair of human X-ray damage. XRCC1 can correct high sisterchromatid exchange levels when transferred into EM{sub 9} cells, but its expression seems to have no correlation with radiosensitivity of human neck and head tumour cells. Radiosensitivity is an intricate issue which may involve many factors. A scheme of cellular reactions after exposure to irradiation is proposed to indicate a possible sequence of events initiated by ionizing radiation.

Radiosensitivity and genes

International Nuclear Information System (INIS)

Hu Qiyue; Lun Mingyue

1995-07-01

Reported effects of some oncogenes, tumour suppressor genes and DNA repair genes on sensitivity of cells to ionizing radiation are reviewed. The role of oncogenes in cellular response to irradiation is discussed, especially the extensively studied oncogenes such as the ras gene family. For tumour suppressor genes, mainly the p53, which is increasingly implicated as a gene affecting radiosensitivity, is reviewed. It is considered that there is a cell cycle checkpoint determinant which is postulated to be able to arrest the irradiated cells in G 1 phase to allow them to repair damage before they undergo DNA synthesis. So far there are six DNA repair genes which have been cloned in mammalian cells, but only one, XRCC1, appears to be involved in repair of human X-ray damage. XRCC1 can correct high sisterchromatid exchange levels when transferred into EM 9 cells, but its expression seems to have no correlation with radiosensitivity of human neck and head tumour cells. Radiosensitivity is an intricate issue which may involve many factors. A scheme of cellular reactions after exposure to irradiation is proposed to indicate a possible sequence of events initiated by ionizing radiation

Triolimus: A Multi-Drug Loaded Polymeric Micelle Containing Paclitaxel, 17-AAG, and Rapamycin as a Novel Radiosensitizer.

Science.gov (United States)

Tomoda, Keishiro; Tam, Yu Tong; Cho, Hyunah; Buehler, Darya; Kozak, Kevin R; Kwon, Glen S

2017-01-01

Triolimus is a multi-drug loaded polymeric micelle containing paclitaxel (PTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin (RAP). This study examines the radiosensitizing effect of Triolimus in vitro and in vivo. Radiosensitizing effects of Triolimus on A549 cells are dose dependent and at 2 × 10 -9 m, Triolimus shows significant radiosensitization even at low radiation doses (2 Gy). By sensitivity enhancement ratio, PTX alone, dual drug combinations, and Triolimus treatment at 2 × 10 -9 m have radiosensitizing effects with potency as follows: PTX alone (PTX) > PTX and RAP (P/R) > Triolimus (TRIO) > PTX and 17-AAG (P/17) >17-AAG and RAP (17/R). In vivo, fractionated radiation of 15 Gy preceded by infusion of PTX alone, dual drug combinations, or an intermediate dose of Triolimus (Int. TRIO: PTX/17-AAG/RAP at 15/15/7.5 mg kg -1 ) strongly inhibits A549 tumor growth. Notably, pretreatment with high dose of Triolimus (High TRIO: PTX/17-AAG/RAP at 60/60/30 mg kg -1 ) before the fractionated radiation leads to tumor control for up to 24 weeks. An enhanced radiosensitizing effect is observed without an increase in acute toxicity compared to PTX alone or radiation alone. These results suggest that further investigations of Triolimus in combination with radiation therapy are merited. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Radiosensitization by SAHA in Experimental Colorectal Carcinoma Models-In Vivo Effects and Relevance of Histone Acetylation Status

International Nuclear Information System (INIS)

Folkvord, Sigurd; Ree, Anne Hansen; Furre, Torbjorn; Halvorsen, Thomas; Flatmark, Kjersti

2009-01-01

Purpose: Histone deacetylase inhibitors are being evaluated as antitumor agents in ongoing clinical trials, and promising preclinical results, combined with favorable toxicity profiles, have rendered the drugs as interesting candidates for combination with other treatment modalities, such as radiotherapy. The aim of the present study was to evaluate the radiosensitizing properties of suberoylanilide hydroxamic acid (SAHA) and the possible requirement of histone hyperacetylation at radiation exposure. Methods and materials: Radiosensitization by SAHA was assessed in a colorectal carcinoma cell line and in two colorectal xenograft models by analysis of clonogenic survival and tumor growth delay, respectively. Histone acetylation status at radiation exposure was evaluated by Western blot. Results: In vitro, radiosensitization was demonstrated when cells were preincubated with SAHA, and, in the xenografts, tumor growth was delayed when the mice were treated with fractionated radiation combined with daily SAHA injections compared with radiation alone. Surprisingly, the SAHA-dependent growth delay was still present when radiation was delivered at restored baseline acetylation levels compared with maximal histone hyperacetylation. Conclusion: SAHA was an effective radiosensitizer in experimental colorectal carcinoma models, suggesting that histone deacetylase inhibition might constitute a valuable supplement to current multimodal treatment strategies in rectal cancer. The presence of histone hyperacetylation at radiation was not required to obtain an increased radiation response, questioning the validity of using histone hyperacetylation as a molecular marker for radiosensitivity.

The toxic effects, GSH depletion and radiosensitivity by BSO on retinoblastoma

International Nuclear Information System (INIS)

Xianjin Yi; Li Ding; Yizun Jin; Chuo Ni; Wenji Wang

1994-01-01

Retinoblastoma is the most common intraocular malignant tumor in children. Previous investigations have reported that buthionine sulfoximine (BSO) can deplete intracellular glutathione (GSH) by specific inhibition and increase cellular radiosensitivity. The toxic effects, GSH depletion and radiosensitivity effects of BSO on retinoblastoma cells are reported in this paper. GSH content of retinoblastoma cell lines Y-79, So-Rb50 and retinoblastoma xenograft is 2.7 ± 1.3 X 1.0 -12 mmol/cell, 1.4 ± 0.2 X 1.0 -12 mmol/cell, and 2.8 ± 1.2 μmol/g, respectively. The ID 50 of BSO on Y-79 and So-Rb50 in air for 3 h exposure is 2.5 mM and 0.2 mM, respectively. GSH depletion by 0.1 mM BSO for 24 h on Y-79 cells and 0.01 mM BSO for 24 h on So-Rb50 cells is 16.35%, and 4.7% of control. GSH depletion in tumor and other organ tissues in retinoblastoma-bearing nude mice after BSO administration is differential. GSH depletion after BSO exposure in Y-79 cells in vitro decreases the Do value of retinoblastoma cells. The SER of 0.01 mM and 0.05 mM BSO for 24 h under hypoxic conditions is 1.21 and 1.36, respectively. Based on these observations, the authors conclude that BSO toxicity on retinoblastoma cells depends on the characteristics of the cell line and that BSO can increase hypoxic retinoblastoma cells' radiosensitivity in vitro. Further study of BSO radiosensitization on retinoblastoma in vivo using nude mouse xenografts is needed. 25 refs., 3 figs., 3 tabs

Increased chromosome radiosensitivity during pregnancy

International Nuclear Information System (INIS)

Ricoul, Michelle; Sabatier, Laure; Dutrillaux, Bernard

1997-01-01

It was necessary to consider the risks of exposure of pregnant women, not only in relation to the child, but also in relation to their own hypersensitivity. We have demonstrated that pregnancy increases radiosensitivity of chromosome in the mouse at the end of gestation. This is of importance since it may have implications on radioprotection of pregnant women and give experimental guidelines to the problems of hypersensitivity to drugs and cancer aggravation during pregnancy. Blood obtained from women at various times of pregnancy was exposed to ionizing radiations. By comparison to non-pregnant women, an increase in chromosome breakage was observed in metaphases from lymphocytes, after short-term culture in the presence of the serum of the same donor. Immediately after delivery, this increase in radiosensitivity disappeared. In a prospective study, serial analyses showed a very strong correlation between the amount of pregnancy hormones, progesterone in particular, and the increase in radiosensitivity. Pregnant women may have an increased sensitivity to ionizing radiation during the second half of their pregnancy. This study provides the first evidence in human that radiosensitivity may vary in relation to physiological conditions

Hyperthermia radiosensitization in human glioma cells comparison of recovery of polymerase activity, survival, and potentially lethal damage repair

International Nuclear Information System (INIS)

Raaphorst, G.P.; Feeley, M.M.

1994-01-01

DNA polymerase inactivation is compared to thermal radiosensitization and inhibition of damage recovery in human glioma cells. Two human glioma cell lines (U87MG and U373MG) were exposed to hyperthermia and irradiation. Hyperthermia was given at 43 degrees C and 45 degrees C and DNA polymerase α + δ + ε and β activities were measured. Hyperthermia was given at various times before irradiation and the degree of radiosensitization and polymerase activity was assessed at various times after heating. In addition the ability of cells to undergo repair of potentially lethal radiation damage was assessed for cells irradiated at various times after heating. Polymerase α + δ + ε and polymerase β both recovered after heating but polymerase β was faster and was complete in U373MG but not in the U87MG cell lines after 48 h incubation after heating (45 degrees C, 60 min). Incubation, between hyperthermia and irradiation resulted in a loss of radiosensitization and a loss of inhibition of repair of potentially lethal damage. These changes correlated well with recovery of polymerase β but not with polymerase α + δ + ε. The correlation of polymerase β activity and thermoradiosensitization and its recovery indicate that polymerase β may be one of the mechanisms involved in thermoradiosensitization. 35 refs., 7 figs

Radiosensitivity and cell kinetics of the human solid cancer transplanted to nude mouse

International Nuclear Information System (INIS)

Ikeuchi, Shunji

1983-01-01

This study was undertaken to analyse the relationship between radiosensitivity and cell kinetics of human solid cancer in experimental nude mouse system. Four strains of tumors used for the experiment were poorly differentiated squamous cell carcinoma of the lung (Lu-9), oat cell carcinoma of the lung (Lu-24), well differentiated squamous cell carcinoma of the tongue (To-1) and moderately differentiated squamous cell carcinoma of the esophagus (Es-4) which were serially transplantable to BALB/c nude mice. Radiosensitivity was evaluated by tumor growth in terms of inhibition rate, histological change and host reaction after irradiation. Cell kinetics were studied by autoradiography with pulse administration of 3 H-thymidine to mice. Although Lu-24 was most radiosensitive, followed by To-1, Es-4 and Lu-9 in the order of sensitivity, it was suggested that they might be more radioresistant in nude mice without T-cell function than in human. Regarding squamous cell carcinomas, well differentiated type was more radiosensitive than poorly differentiated one. All of these tumors in nude mouse revealed distinct percent labeled mitosis curves with two clear peaks which were quite different from those in human body. Lu-24 showed a characteristic pattern with a long time lag before visible growth, short G 1 , and low growth fraction, compared to other three tumors. Three strains of squamous cell carcinoma demonstrated similar cell kinetic factors which were almost the same as those in human body reported previously. The differences in volume doubling time of tumor, growth fraction and cell loss factor were partially related to those of radiosensitivities among tumors except for Lu-24. The theoretical volume doubling time was proved to be most reliable for estimation of effectiveness of irradiation, but the labeling index was not a valuable indicator for it. (author)

Hormonal status can modify radiosensitivity

International Nuclear Information System (INIS)

Ricoul, M.; Sabatier, L.; Dutrillaux, B.

1997-01-01

In preliminary experiments, we have demonstrated that pregnancy increases chromosome radiosensitivity in the mouse at the end of gestation. Blood obtained from women at various times of pregnancy was then exposed to ionizing radiations in vitro. By comparison to non pregnant women, an increase in chromosome breakages was observed in metaphases from lymphocytes. Immediately after delivery, this increase of radiosensitivity disappeared. In a prospective study, serial analyses showed a very strong correlation between the amount of pregnancy hormones, progesterone in particular, and the increase of radiosensitivity. Thus, pregnant women may have an increased sensitivity to ionizing radiation during the second half of their pregnancy and the risks of radiation exposure of pregnant women have to be considered not only n relation to the child, but also to their own hypersensitivity. (authors)

Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase, inhibits the early step in homologous recombination

International Nuclear Information System (INIS)

Sakata, Koh-ichi; Someya, Masanori; Matsumoto, Yoshihisa; Takagi, Masaru; Hareyama, Masato; Tauchi, Hiroshi; Kai, Masahiro; Toyota, Minoru; Fukushima, Masakazu

2011-01-01

Gimeracil (5-chloro-2, 4-dihydroxypyridine) is an inhibitor of dihydropyrimidine dehydrogenase (DPYD), which degrades pyrimidine including 5-fluorouracil in the blood. Gimeracil was originally added to an oral fluoropyrimidine derivative S-1 to yield prolonged 5-fluorouracil concentrations in serum and tumor tissues. We have already reported that gimeracil had radiosensitizing effects by partially inhibiting homologous recombination (HR) in the repair of DNA double strand breaks. We investigated the mechanisms of gimeracil radiosensitization. Comet assay and radiation-induced focus formation of various kinds of proteins involved in HR was carried out. Small interfering RNA (siRNA) for DPYD were transfected to HeLa cells to investigate the target protein for radiosensitization with gimeracil. SCneo assay was carried out to examine whether DPYD depletion by siRNA inhibited HR repair of DNA double strand breaks. Tail moments in neutral comet assay increased in gimeracil-treated cells. Gimeracil restrained the formation of foci of Rad51 and replication protein A (RPA), whereas it increased the number of foci of Nbs1, Mre11, Rad50, and FancD2. When HeLa cells were transfected with the DPYD siRNA before irradiation, the cells became more radiosensitive. The degree of radiosensitization by transfection of DPYD siRNA was similar to that of gimeracil. Gimeracil did not sensitize DPYD-depleted cells. Depletion of DPYD by siRNA significantly reduced the frequency of neopositive clones in SCneo assay. Gimeracil partially inhibits the early step in HR. It was found that DPYD is the target protein for radiosensitization by gimeracil. The inhibitors of DPYD, such as gimeracil, could enhance the efficacy of radiotherapy through partial suppression of HR-mediated DNA repair. (author)

Studies on Drosophila radiosensitive strains

International Nuclear Information System (INIS)

Varentsova, E.P.; Zakharov, I.A.

1976-01-01

45 of radiosensitive strains of Drosophila melanogaster were isolated by Curly/Lobe technique after EMS treatment of Livadia population males. The lethality of non-Curly late larvae after gamma-irradiation (4000r) characterized radiosensitivity strains. Most of them exhibited higher frequency of the spontaneous dominant lethals (up to 69%). The males of 6 strains were semi-sterile. 5 of these strains exhibited higher frequency of X-chromosome non-disjunction

Silencing the Girdin gene enhances radio-sensitivity of hepatocellular carcinoma via suppression of glycolytic metabolism.

Science.gov (United States)

Yu, Li; Sun, Yifan; Li, Jingjing; Wang, Yan; Zhu, Yuxing; Shi, Yong; Fan, Xiaojun; Zhou, Jianda; Bao, Ying; Xiao, Jie; Cao, Ke; Cao, Peiguo

2017-08-15

Radiotherapy has been used increasingly to treat primary hepatocellular carcinoma. Clinically, the main cause of radiotherapy failure is cellular radioresistance, conferred via glycolytic metabolism. Our previous study demonstrated that Girdin is upregulated in primary hepatocellular carcinoma and promotes the invasion and metastasis of tumor cells. However, whether Girdin underlies the radio-sensitivity of hepatocellular carcinoma remains unclear. A short hairpin RNA (shRNA) was used to silence CCDC88A (encoding Girdin), and real-time PCR was performed to determine CCDC88A mRNA expression. Then, cell proliferation, colony formation, flow cytometric, scratch, and transwell assays were to examine the influence of Girdin silencing on cellular radiosensitivity. Glycolysis assays were conducted to exam cell glycolysis process. Western blotting was performed to explore the signaling pathway downstream of Girdin. Finally, animal experiments were performed to demonstrate the effect of CCDC88A silencing on the radiosensitivity of hepatoma in vivo. shRNA-induced Girdin silencing suppressed glycolysis and enhanced the radio-sensitivity of hepatic cell lines, HepG2 and Huh-7. Furthermore, silencing of Girdin inhibited the PI3K/AKT/HIF-1α signaling pathway, which is a central regulator of glycolysis. Girdin can regulate glycolysis in hepatocellular carcinoma cells through the PI3K/AKT/HIF-1α signaling pathway, which decreases the sensitivity of tumor cells to radiotherapy.

Anti-EGFR therapy radiosensitizes human lung adenocarcinoma xenograft in nude mouse

International Nuclear Information System (INIS)

Wang Hui; Li Tianran; Tian Jiahe; Qu Baolin; Zhu Hui

2008-01-01

Objective: To investigate the effect of Gefitinib on radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. Methods: Human lung adenocarcinoma cell line A549 was used to establish nude mouse xenograft tumor model. The mice were derided into 4 groups: control, irradiation alone, Gefinitib alone and radiation combined with Genifitib. Radiation schedule was 3 fractions of 5 Gy, once daily. Gefitinib was daily administered by gavage at 100 mg/(kg·day -1 ) for 14 days. In the combination group, radiotherapy was performed 2 hours after Gefitinib administration. Tumor diameter was measured every other day. Percentage of tumor growth inhibition, growth delay time and regrowth delay time were evaluated. Results: For A549 xenografts in radiation alone, gefitinib alone and combination therapy groups, the percentage of tumor growth inhibition was 22.7%, 12.4% and 38.2%, respectively (F=25.75, P=0.000). Tumor growth delay time was 6.0, 7.8 and 21.6 days, respectively (F=70.49, P=0.000). Tumor regrowth delay time in combination therapy and irradiation alone groups was 23.4 and 10.2 days. (F=174.24, P= 0.000). Sensitizing enhancement ratio of combination group was 1.5 in growth and 1.7 in regrowth. Conclusions: Anti-EGFR therapy enhances the radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. (authors)

Downregulation of miR-210 expression inhibits proliferation, induces apoptosis and enhances radiosensitivity in hypoxic human hepatoma cells in vitro

Energy Technology Data Exchange (ETDEWEB)

Yang, Wei, E-mail: detachedy@yahoo.com.cn [Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Suzhou (China); Sun, Ting [Brain and Nerve Research Laboratory, The First Affiliated Hospital, Soochow University, Suzhou (China); Cao, Jianping; Liu, Fenju [Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Suzhou (China); Tian, Ye [Department of Radiotherapy and Oncology, The Second Affiliated Hospital, Soochow University, Suzhou (China); Zhu, Wei [Department of Radiobiology, School of Radiological Medicine and Protection, Soochow University, Suzhou (China)

2012-05-01

Hypoxia is a common feature of solid tumors and an important contributor to tumor radioresistance. miR-210 is the most consistently and robustly induced microRNA under hypoxia in different types of tumor cells and normal cells. In the present study, to explore the feasibility of miR-210 as an effective therapeutic target, lentiviral-mediated anti-sense miR-210 gene transfer technique was employed to downregulate miR-210 expression in hypoxic human hepatoma SMMC-7721, HepG2 and HuH7 cells, and phenotypic changes of which were analyzed. Hypoxia led to an increased hypoxia inducible factor-1{alpha} (HIF-1{alpha}) and miR-210 expression and cell arrest in the G{sub 0}/G{sub 1} phase in all cell lines. miR-210 downregulation significantly suppressed cell viability, induced cell arrest in the G{sub 0}/G{sub 1} phase, increased apoptotic rate and enhanced radiosensitivity in hypoxic human hepatoma cells. Moreover, apoptosis-inducing factor, mitochondrion-associated, 3 (AIFM3) was identified as a direct target gene of miR-210. AIFM3 downregulation by siRNA attenuated radiation induced apoptosis in miR-210 downregulated hypoxic human hepatoma cells. Taken together, these data suggest that miR-210 might be a potential therapeutic target and specific inhibition of miR-210 expression in combination with radiotherapy might be expected to exert strong anti-tumor effect on hypoxic human hepatoma cells. -- Highlights: Black-Right-Pointing-Pointer miR-210 downregulation radiosensitized hypoxic hepatoma. Black-Right-Pointing-Pointer AIFM3 was identified as a direct target gene of miR-210. Black-Right-Pointing-Pointer miR-210 might be a therapeutic target to hypoxic hepatoma.

Increased catalase activity by all-trans retinoic acid and its effect on radiosensitivity in rat glioma cells

International Nuclear Information System (INIS)

Jin, Hua; Jeon, Ha Yeun; Park, Woo Yoon; Kim, Won Dong; Ahn, Hee Yul; Yu, Jae Ran

2005-01-01

It has been reported that all-trans retinoic acid (ATRA) can inhibit glioma growing in vitro. However, clinical trials with ATRA alone in gliomas revealed modest results. ATRA has been shown to increase radiosensitivity in other tumor types, so combining radiation and ATRA would be one of alternatives to increase therapeutic efficacy in malignant gliomas. Thus, we intended to know the role of catalase, which is induced by ATRA, for radiosensitivity. If radiation-reduced reactive oxygen species (ROS) is removed by catalase, the effect of radiation will be reduced. A rat glioma cell line (36B10) was used for this study. The change of catalase activity and radiosensitivity by ATRA, with or without 3-amino-1, 2, 4-triazole (ATZ), a chemical inhibitor of catalase were measured. Catalase activity was measured by the decomposition of H 2 O 2 spectrophotometrically. Radiosensitivity was measured with clonogenic assay. Also ROS was measured using a 2, 7-dichlorofluores-cein diacetate spectrophotometrically. When 36B10 cells were exposed to 10, 25 and 50 μ M of ATRA for 48 h, the expression of catalase activity were increased with increasing concentration and incubation time of ATRA. Catalase activity was decreased with increasing the concentration of AT (1, 10 mM) dose-dependently. ROS was increased with ATRA and it was augmented with the combination of ATRA and radiation. ATZ decreased ROS production and increased cell survival in combination of ATRA and radiation despite the reduction of catalase. The increase of ROS is one of the reasons for the increased radiosensitivity in combination with ATRA. The catalase that is induced by ATRA doesn't decrease ROS production and radiosensitivity

The HSP90 inhibitor NVP-AUY922 radiosensitizes by abrogation of homologous recombination resulting in mitotic entry with unresolved DNA damage.

Directory of Open Access Journals (Sweden)

Shane Zaidi

Full Text Available Heat shock protein 90 (HSP90 is a molecular chaperone responsible for the conformational maintenance of a number of client proteins that play key roles in cell cycle arrest, DNA damage repair and apoptosis following radiation. HSP90 inhibitors exhibit antitumor activity by modulating the stabilisation and activation of HSP90 client proteins. We sought to evaluate NVP-AUY922, the most potent HSP90 inhibitor yet reported, in preclinical radiosensitization studies.NVP-AUY922 potently radiosensitized cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. Radiosensitization by NVP-AUY922 was verified for the first time in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice, as measured by delayed tumor growth and increased surrogate end-point survival (p = <0.0001. NVP-AUY922 was shown to ubiquitously inhibit resolution of dsDNA damage repair correlating to delayed Rad51 foci formation in all cell lines tested. Additionally, NVP-AUY922 induced a stalled mitotic phenotype, in a cell line-dependent manner, in HeLa and HN5 cell lines irrespective of radiation exposure. Cell cycle analysis indicated that NVP-AUY922 induced aberrant mitotic entry in all cell lines tested in the presence of radiation-induced DNA damage due to ubiquitous CHK1 depletion, but resultant downstream cell cycle effects were cell line dependent.These results identify NVP-AUY922 as the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validate it in a clinically relevant in vivo model. Mechanistic analysis at clinically achievable concentrations demonstrated that radiosensitization is mediated by the combinatorial inhibition of cell growth and survival pathways, ubiquitous delay in Rad51-mediated homologous recombination and CHK1-mediated G(2/M arrest, but that the contribution of cell cycle perturbation to radiosensitization may be cell line

Catecholamines of the body tissues and radiosensitivity of rodents

International Nuclear Information System (INIS)

Grayevskaya, V.M.; Zolotariova, N.N.

1975-01-01

Various species of rodents are distinguished by their radiosensitivity (increasing): bank vole 57 Br mouse < golden hamster < BALB mouse < guinea pig. There is a positive correlation between radiosensitivity of these species and catecholamines content in the adrenals, urea and blood; and negative correlation between radiosensitivity and adrenaline and noradrenaline concentrations in liver and spleen cells. Presumable causes of this correlation, and the possibility of application of the index under study for predicting the organism radiosensitivity and forecasting the outcome of radiation damage are discussed

Radiosensitivity of peripheral blood lymphocytes in autoimmune disease

Energy Technology Data Exchange (ETDEWEB)

Harris, G [Kennedy Inst. of Rheumatology, London (UK). Div. of Experimental Pathology; Cramp, W A; Edwards, J C; George, A M; Sabovljev, S A; Hart, L; Hughes, G R.V. [Hammersmith Hospital, London (UK); Denman, A M [Northwich Park Hospital, Harrow (UK); Yatvin, M B [Wisconsin Clinical Cancer Center, Madison (USA)

1985-06-01

The proliferation of peripheral blood lymphocytes, cultured with Con A, can be inhibited by ionizing radiation. Lymphocytes from patients with conditions associated with autoimmunity, such as rheumatoid arthritis, systemic lupus erythematosus and polymyositis, are more radiosensitive than those from healthy volunteers or patients with conditions not associated with autoimmunity. Nuclear material isolated from the lymphocytes of patients with autoimmune diseases is, on average, lighter in density than the nuclear material from most healthy controls. This difference in density is not related to increased sensitivity to ionizing radiation but the degree of post-irradiation change in density (lightening) is proportional to the initial density, i.e. more dense nuclear material always shows a greater upward shift after radiation. The recovery of pre-irradiation density of nuclear material, 1 h after radiation exposure, taken as an indication of DNA repair, correlates with the radiosensitivity of lymphocyte proliferation (Con A response); failure to return to pre-irradiation density being associated with increased sensitivity of proliferative response. These results require extension but, taken with previously reported studied of the effects of DNA methylating agents, support the idea that DNA damage and its defective repair could be important in the aetio-pathogenesis of autoimmune disease.

Radiosensitivity of cells

International Nuclear Information System (INIS)

Alexander, P.

1960-01-01

The mechanism by which radiation kills cells must be investigated with the goal to make possible to devise means to alter the radiosensitivity of cells. The object of our investigation, supported by IAEA, is to try and find the reasons for the variation in sensitivity between different cells. Once we know the reason for the differences in radiosensitivity of different micro-organisms we can begin to look rationally for ways of enhancing the radiation response of the more sensitive organisms. An investigation of this type has implications far beyond food sterilization, as it cannot fail to provide fundamental facts about radiation injury to cells in general. Cancer researchers have looked for many years for means of sensitizing cancer cells to radiation

Radiosensitivity of cells

Energy Technology Data Exchange (ETDEWEB)

Alexander, P [Radiation Biology Section, Chester Beatty Research Institute, Royal Cancer Hospital, London (United Kingdom)

1960-07-15

The mechanism by which radiation kills cells must be investigated with the goal to make possible to devise means to alter the radiosensitivity of cells. The object of our investigation, supported by IAEA, is to try and find the reasons for the variation in sensitivity between different cells. Once we know the reason for the differences in radiosensitivity of different micro-organisms we can begin to look rationally for ways of enhancing the radiation response of the more sensitive organisms. An investigation of this type has implications far beyond food sterilization, as it cannot fail to provide fundamental facts about radiation injury to cells in general. Cancer researchers have looked for many years for means of sensitizing cancer cells to radiation

Radio-sensitization of esophageal cancer EC9706 cells to X ray by histone deacetylase inhibiter Trichostatin A

International Nuclear Information System (INIS)

Lin Xiaoli; Qin Guangyong; Fang Huasheng; Zhang Fengqiu; Ya Huiyuan

2009-01-01

Cell apoptosis and the expression of DNA damage repair-related genes XRCC2, ATM and Lig4 were detected separately by flow cytometry analysis and real-time fluorescence quantitative (RT-PCR), in order to investigate the effect of Trichostatin A (TSA) pre-treatment on the radiosensitivity of esophageal cancer EC9706 cells to X ray in vitro. The results indicate that pre-irradiation exposure to TSA enhances cell apoptotic rate by X ray markedly (P<0.05) and the mRNA levels of XRCC2, ATM and Lig4 (except 8Gy) are up-regulated by X ray individually (P<0.05). TSA alone and TSA in combination with X ray all reduce mRNA levels of XRCC2, ATM and Lig4. In conclusions, TSA may radio-sensitize EC9706 cells to X ray by reducing mRNA levels of XRCC2, ATM and Lig4. (authors)

Clinical studies on radiosensitization of cervical cancer by cisplatinum

International Nuclear Information System (INIS)

Yu Shiying; Chen Yuan; Xu Zhiqiang

1993-01-01

A prospective randomized clinical trial on the radiosensitizing effect of cisplatinum was carried out in 60 patients with cervical cancer, of whom 30 were given cisplatinum in combination with radiotherapy (radiosensitizing group) and the remaining 30 radiotherapy alone (control group). The results showed that the length of time of immediate CR and PR was shorter in the radiosensitizing group than in the control group. The sensitive enhancement ratio was 1.846. No toxicity was observed in the radiosensitizing group, and the treatment was well tolerated by the patients

Catecholamines of the body tissues and radiosensitivity of rodents

Energy Technology Data Exchange (ETDEWEB)

Grayevskaya, V M; Zolotariova, N N [AN SSSR, Moscow. Inst. Morfologii Zhivotnykh

1975-01-01

Various species of rodents are distinguished by their radiosensitivity (increasing): bank vole < Wistar rat < wild mouse < CC/sub 57/Br mouse < golden hamster < BALB mouse < guinea pig. There is a positive correlation between radiosensitivity of these species and catecholamines content in the adrenals, urea and blood; and negative correlation between radiosensitivity and adrenaline and noradrenaline concentrations in liver and spleen cells. Presumable causes of this correlation, and the possibility of application of the index under study for predicting the organism radiosensitivity and forecasting the outcome of radiation damage are discussed.

AT-406, an IAP inhibitor, activates apoptosis and induces radiosensitization of normoxic and hypoxic cervical cancer cells.

Science.gov (United States)

Lu, Jing; Qin, Qin; Zhan, Liang-Liang; Liu, Jia; Zhu, Hong-Cheng; Yang, Xi; Zhang, Chi; Xu, Li-Ping; Liu, Zhe-Ming; Wang, Di; Cui, He-Qing; Meng, Ciu-Ciu; Cai, Jing; Cheng, Hong-Yan; Sun, Xin-Chen

2014-01-01

IAP antagonists increased the antitumor efficacy of X-irradiation in some types of cancers, but their effects on hypoxic cancer cells remain unclarified. We aims to investigate the radiosensitizing effect of an IAP inhibitor AT-406 on cervical cancer cell lines under both normoxia and hypoxia conditions. Hela and Siha cells were treated to investigate the effects of drug administration on cell proliferation, apoptosis, and radiosensitivity. Western blot analysis was used to determine the role of AT-406 in inhibition of IAPs. The pathway of apoptosis was characterized by caspases activity assay. AT-406 potently sensitized Hela cells but not Siha cells to radiation under normoxia. Notably, the radiosensitizing effect of AT-406 on hypoxic cells was more evident than on normoxic cells in both cell lines. Further mechanism studies by western blot showed that under normoxia AT-406 decreased the level of cIAP1 in Hela cells in a dose-dependent manner; while additional downregulation of XIAP expression was induced by AT-406 treatment under hypoxia in both cell lines. Finally, AT-406 works on both extrinsic death receptor and intrinsic mitochondrial apoptosis pathways to activate apoptosis. Totally, AT-406 acts as a strong radiosensitizer in human cervical cancer cells, especially in hypoxic condition.

Induction of thermal shock proteins and changes in radiosensitivity after heat treatment of Bombyx mori L. embryos

International Nuclear Information System (INIS)

Agaev, F.A.

1993-01-01

The method of gel-electrophoresis was used to study thermal shock protein synthesis in Bombyx mori embryos exposed to a mixture of heat and gamma-radiation. Induction of thermal shock protein synthesis was not inhibited by gamma-radiation. It is suggested that thermal shock proteins are involved embryo radiosensitivity modification

Evaluation of a MTT assay in measurement of radiosensitizing effect

International Nuclear Information System (INIS)

Higuchi, Keiko; Mitsuhashi, Norio; Saitoh, Jun-ichi; Maebayashi, Katsuya; Sakurai, Hideyuki; Akimoto, Tetsuo; Niibe, Hideo

1999-01-01

The usefulness of a MTT assay by measuring the radiosensitizing effect of caffeine on rat yolk sac tumor cell line with a mutant-type p53 in vitro was evaluated. A rat yolk sac tumor cell line with a mutant-type p53, NMT-1R, was used in this study. The radiosensitivity of NMT-1R with or without caffeine was measured with a MTT assay. The results were compared with those by a clonogenic assay. Caffeine at a concentration of 2.0 mM which released radiation-induced G 2 block demonstrated a radiosensitizing effect, but caffeine at a concentration of 0.5 mM did not. The radiosensitizing effect of caffeine measured by a MTT assay correlated with that measured by a clonogenic assay. A MTT assay was useful to measure radiosensitivity and/or a radiosensitizing effect in vitro. (author)

Effect of sanguinarine on the growth and radiosensitivity of human ovarian cancer cells

International Nuclear Information System (INIS)

Xu Jiaying; Ji Junmin; Jiao Yang; Wu Li; Fan Sanjun

2012-01-01

Objective: To study the effect of sanguinarine on the growth and radiosensitivity of ovarian cancer SK-OV-3 cells. Methods: Cell growth was determined by MTT and clonogenic assay. Cell cycle analysis was performed by flow cytometry assay. The cell apoptosis was analyzed by Annexin V/PI assay. Results: Sanguinarine inhibited SK-OV-3 cell growth in a dose-and time-dependent fashion and its IC 50 values were 3.02 and 1.11 μmol/L at 24 and 48 h, respectively. Sanguinarine also significantly triggered a sub-G 1 peak, an indicator of apoptosis,and caused a G 0 /G 1 arrest. Furthermore, the cell apoptosis induced by X-irradiation was significantly increased at 6 Gy when the cells were pre-treated with sanguinarine, in which the early apoptotic population increased from 10.28% to 43.28% (t=19.41, P<0.01) and the late apoptotic population increased from 20.26% to 30.80% (t=8.78, P<0.01). The multi-target click model was used to fit survival curves and the SER of sanguinarine treatment approached to 1.625 at the dose of D 0 . Conclusions: Sanguinarine could inhibit SK-OV-3 cell growth by inducing apoptosis and cell cycle arrest and enhance cell radiosensitivity at low doses. (authors)

Coculture with astrocytes reduces the radiosensitivity of glioblastoma stem-like cells and identifies additional targets for radiosensitization

International Nuclear Information System (INIS)

Rath, Barbara H; Wahba, Amy; Camphausen, Kevin; Tofilon, Philip J

2015-01-01

Toward developing a model system for investigating the role of the microenvironment in the radioresistance of glioblastoma (GBM), human glioblastoma stem-like cells (GSCs) were grown in coculture with human astrocytes. Using a trans-well assay, survival analyses showed that astrocytes significantly decreased the radiosensitivity of GSCs compared to standard culture conditions. In addition, when irradiated in coculture, the initial level of radiation-induced γH2AX foci in GSCs was reduced and foci dispersal was enhanced suggesting that the presence of astrocytes influenced the induction and repair of DNA double-strand breaks. These data indicate that astrocytes can decrease the radiosensitivity of GSCs in vitro via a paracrine-based mechanism and further support a role for the microenvironment as a determinant of GBM radioresponse. Chemokine profiling of coculture media identified a number of bioactive molecules not present under standard culture conditions. The gene expression profiles of GSCs grown in coculture were significantly different as compared to GSCs grown alone. These analyses were consistent with an astrocyte-mediated modification in GSC phenotype and, moreover, suggested a number of potential targets for GSC radiosensitization that were unique to coculture conditions. Along these lines, STAT3 was activated in GSCs grown with astrocytes; the JAK/STAT3 inhibitor WP1066 enhanced the radiosensitivity of GSCs under coculture conditions and when grown as orthotopic xenografts. Further, this coculture system may also provide an approach for identifying additional targets for GBM radiosensitization

Predisposition to cancer and radiosensitivity

International Nuclear Information System (INIS)

Pichierri, P.; Franchitto, A.; Palitti, F.

2000-01-01

Many cancer-prone diseases have been shown to be radiosensitive. The radiosensitivity has been attributed to pitfalls in the mechanisms of repair of induced DNA lesions or to an impaired cell cycle checkpoint response. Although discrepancies exist in the results obtained by various authors on the radiosensitivity of individuals affected by the same disease, these can be attributed to the large variability observed already in the response to radiation of normal individuals. To date three test are commonly used to assess radiosensitivity in human cells: survival, micronucleus and G 2 chromosomal assay. The three tests may be performed using either fibroblasts or peripheral blood lymphocytes and all the three tests share large interindividual variability. In this regard a new approach to the G 2 chromosomal assay which takes into account the eventual differences in cell cycle progression among individuals has been developed. This new approach is based on the analysis of G 2 homogeneous cell populations. Cells irradiated are immediately challenged with medium containing bromodeoxyuridine (BrdU rd). Then cells are sampled at different post-irradiation times and BrdU rd incorporation detected on metaphases spread and the scoring is done only at time points showing similar incidence of labelled cells among the different donors. Using this approach it has been possible to reduce the interindividual variability of the G 2 chromosomal assay. (author)

The effect of anaesthesia on the radiosensitivity of rat intestine, foot skin and R-1 tumours

International Nuclear Information System (INIS)

Kal, H.B.; Gaiser, J.F.

1980-01-01

A comparison has been made of the effects of Nembutal (sodium pentobarbital) and Ethrane (2-chloro-1,1,2-trifluoroethyldifluoromethyl ether) anaesthesia on the radiation responses of rat intestine, foot skin and R-1 rhabdomyosarcoma. Single-dose experiments under Nembutal or short-lasting Ethrane anaesthesia resulted in equivalent radiosensitivities for the R-1 sarcoma and foot skin, whereas Ethrane induced radiosensitization in the intestine. In the Ethrane anaesthesia lasting 3 hours, and in the split-dose experiments, Ethrane inhibited repair of radiation-induced damage in the R-1 sarcoma and in the foot skin. It is therefore recommended that the use of Ethrane as an anaesthetic should be avoided in experiments designed to investigate repair of damage in fractionated studies or during protracted irradiation treatments. (UK)

Application of bio-marker to study on tumor radiosensitivity

International Nuclear Information System (INIS)

Guo Wanfeng; Ding Guirong; Han Liangfu

2001-01-01

To definite tumor radiosensitivity is important for applying the schedules of individualization of patient radiotherapy. Many laboratories were carrying on the research which predict the tumor radiosensitivity with one bio-marker or/and multi-bio-marker in various levels. At present has not witnessed the specific bio-marker, but it provides an excellent model for predicting tumor radiosensitivity

Spike propagation in driven chain networks with dominant global inhibition

International Nuclear Information System (INIS)

Chang Wonil; Jin, Dezhe Z.

2009-01-01

Spike propagation in chain networks is usually studied in the synfire regime, in which successive groups of neurons are synaptically activated sequentially through the unidirectional excitatory connections. Here we study the dynamics of chain networks with dominant global feedback inhibition that prevents the synfire activity. Neural activity is driven by suprathreshold external inputs. We analytically and numerically demonstrate that spike propagation along the chain is a unique dynamical attractor in a wide parameter regime. The strong inhibition permits a robust winner-take-all propagation in the case of multiple chains competing via the inhibition.

Inhibition delay increases neural network capacity through Stirling transform

Science.gov (United States)

Nogaret, Alain; King, Alastair

2018-03-01

Inhibitory neural networks are found to encode high volumes of information through delayed inhibition. We show that inhibition delay increases storage capacity through a Stirling transform of the minimum capacity which stabilizes locally coherent oscillations. We obtain both the exact and asymptotic formulas for the total number of dynamic attractors. Our results predict a (ln2) -N-fold increase in capacity for an N -neuron network and demonstrate high-density associative memories which host a maximum number of oscillations in analog neural devices.

Photosensitizers and radiosensitizers in dermatology and oncology

International Nuclear Information System (INIS)

Bruckner, V.

1979-01-01

Two therapeutic modalities are currently of great interest, namely photo- and radiosensitization. Whereas photosensitizers only function in combination with ultraviolet (UV) light, radiosensitizers act only in combination with ionizing radiation. Because of the small UV penetration, up to a maximum of 0,5 mm, photosensitization can take place only at the surface of the body, i.e. the skin. Photosensitizers are applied in dermatology in order to optimize and improve the UV therapy of certain diseases (mainly psoriasis, mycosis fungoides and vitiligo). Radiosensitizers lead to an increase in sensitivity of the hypoxic and therefore radioresistant parts of tumours against X- and gamma-radiation. With sufficient concentration within the tumour, they can act where the radiation can reach, even in the deeper parts of the body. They represent a modern and useful aid to radiation oncology. Because of neurotoxic effects, however, their practical use is limited. A short review of the history, mechanisms of action, application and side-effects of these photo- and radiosensitizers is presented

Photosensitizers and radiosensitizers in dermatology and oncology

Energy Technology Data Exchange (ETDEWEB)

Bruckner, V [Stellenbosch University, Parowvallei (South Africa). Departments of Medical Physics and Radiology

1979-09-22

Two therapeutic modalities are currently of great interest, namely photo- and radiosensitization. Whereas photosensitizers only function in combination with ultraviolet (UV) light, radiosensitizers act only in combination with ionizing radiation. Because of the small UV penetration, up to a maximum of 0,5 mm, photosensitization can take place only at the surface of the body, i.e. the skin. Photosensitizers are applied in dermatology in order to optimize and improve the UV therapy of certain diseases (mainly psoriasis, mycosis fungoides and vitiligo). Radiosensitizers lead to an increase in sensitivity of the hypoxic and therefore radioresistant parts of tumours against X- and gamma-radiation. With sufficient concentration within the tumour, they can act where the radiation can reach, even in the deeper parts of the body. They represent a modern and useful aid to radiation oncology. Because of neurotoxic effects, however, their practical use is limited. A short review of the history, mechanisms of action, application and side-effects of these photo- and radiosensitizers is presented.

Hereditary syndromes with enhanced radiosensitivity

International Nuclear Information System (INIS)

Lohmann, D.

2000-01-01

Sensitivity to ionizing radiation is modified by heritable genetic factors. This is exemplified by heritable disorders that are characterized by predisposition to the development of neoplasms. Cells derived from patients with ataxia telangiectasia, Nijmegen breakage syndrome and ataxia telangiektasia-like disorder show a markedly changed reaction to exposure to ionizing radiation. Correspondingly, at least in patients with ataxia telangiectasia, an enhanced radiosensitivity that is of clinical importance has been observed. In addition to these recessive disorders, some autosomal dominant cancer predisposition syndromes are associated with increased radiosensitivity. As cells from these patients still have a normal allele (that is dominant over the mutant allele), the cellular phenotype is most often normal. Specifically, there is no overtly altered reaction in response to ionizing radiation. Nevertheless, two dominant cancer predisposition syndromes, namely hereditary retinoblastoma and naevoid basal cell carcinoma syndrome, are associated with a enhanced radiosensitivity as indicated by increased development of tumors following radiation therapy. (orig.) [de

Radiosensitivity study of cultured barley (hordeum vulgare)

International Nuclear Information System (INIS)

Wang Cailian; Shen Mei; Xu Gang; Zhao Kongnan; Chen Qiufang

1991-07-01

For studying the radioactivity, forty seven varieties of dormant barley seeds were irradiated with various doses (0 ∼ 400 Gy) of 137 Cs γ-rays. The results showed that the dose-effects relations of seedling growth inhibition could be fitted by an equation of F(D) = 1 - (1 - e -a 1 D ) N , and the dose-effects of cell-nucleus, the frequency of root tip cell with chromosome aberations and peroxidase isoenzyme band could be expressed by a linear regression equation Y = A + B · X. The radioactivity of naked barley was much higher than of covered barley. According to different radiosensitivities the varieties studied could be divided into five types i.e. extreme resistant, resistant, intermediate, sensitive, and extreme sensitive. The results also showed that there was close relationship between the DNA content of cell-nucleus, peroxidase isoenzyme zymogram and radioactivity. The radiosensitivty was proportional to the DNA content. The volume of cell-nucleus varied inversly as D 50 of nucleus volume and no obvious correlation with the D 50 of seedling growth inhibition

Isolation and characterization of a radiosensitive Chinese hamster ovary cell line

International Nuclear Information System (INIS)

Fuller, L.F.

1987-01-01

A x-ray sensitive Chinese hamster ovary cell line was isolated using a semi-automated procedure in which mutagenized CHO cells were allowed to form colonies on top of agar, x-irradiated, then photographed at two later times. Comparison of the photographs allowed the identification of colonies which displayed significant growth arrest. One of the colonies identified in this manner produced a stable, radiosensitive line. This cell line is normal in x-ray induced inhibition of DNA synthesis, and single- and double-strand break repair, and is moderately sensitive to ethyl methane sulfonate and UV light. The sensitive line performs only half as much x-ray-induced repair replication as the parental line and this deficiency is believed to be the primary cause of its radiosensitivity. The sensitive line produces significantly higher numbers of x-ray-induced chromosome and chromatid aberrations including chromatid aberrations following exposure during the G 1 phase of the cell cycle. The line is hypomutable compared to the parental line with x-ray exposure inducing only one-third as many 6-thioguanine resistant colonies

Expression of hPNAS-4 Radiosensitizes Lewis Lung Cancer

International Nuclear Information System (INIS)

Zeng Hui; Yuan Zhu; Zhu Hong; Li Lei; Shi Huashan; Wang Zi; Fan Yu; Deng Qian; Zeng Jianshuang; He Yinbo; Xiao Jianghong; Li Zhiping

2012-01-01

Purpose: This study aimed to transfer the hPNAS-4 gene, a novel apoptosis-related human gene, into Lewis lung cancer (LL2) and observe its radiosensitive effect on radiation therapy in vitro and in vivo. Methods and Materials: The hPNAS-4 gene was transfected into LL2 cells, and its expression was detected via western blot. Colony formation assay and flow cytometry were used to detect the growth and apoptosis of cells treated with irradiation/PNAS-4 in vitro. The hPNAS-4 gene was transferred into LL2-bearing mice through tail vein injection of the liposome/gene complex. The tumor volumes were recorded after radiation therapy. Proliferating cell nuclear antigen (PCNA) immunohistochemistry staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed to detect the tumor cell growth and apoptosis in vivo. Results: The hPNAS-4 gene was successfully transferred into LL2 cells and tumor tissue, and its overexpressions were confirmed via western blot analysis. Compared with the control, empty plasmid, hPNAS-4, radiation, and empty plasmid plus radiation groups, the hPNAS-4 plus radiation group more significantly inhibited growth and enhanced apoptosis of LL2 cells in vitro and in vivo (P<.05). Conclusions: The hPNAS-4 gene was successfully transferred into LL2 cells and tumor tissue and was expressed in both LL2 cell and tumor tissue. The hPNAS-4 gene therapy significantly enhanced growth inhibition and apoptosis of LL2 tumor cells by radiation therapy in vitro and in vivo. Therefore, it may be a potential radiosensitive treatment of radiation therapy for lung cancer.

Functional neural networks underlying response inhibition in adolescents and adults.

Science.gov (United States)

Stevens, Michael C; Kiehl, Kent A; Pearlson, Godfrey D; Calhoun, Vince D

2007-07-19

This study provides the first description of neural network dynamics associated with response inhibition in healthy adolescents and adults. Functional and effective connectivity analyses of whole brain hemodynamic activity elicited during performance of a Go/No-Go task were used to identify functionally integrated neural networks and characterize their causal interactions. Three response inhibition circuits formed a hierarchical, inter-dependent system wherein thalamic modulation of input to premotor cortex by fronto-striatal regions led to response suppression. Adolescents differed from adults in the degree of network engagement, regional fronto-striatal-thalamic connectivity, and network dynamics. We identify and characterize several age-related differences in the function of neural circuits that are associated with behavioral performance changes across adolescent development.

The Effect of VPA on Increasing Radiosensitivity in Osteosarcoma Cells and Primary-Culture Cells from Chemical Carcinogen-Induced Breast Cancer in Rats.

Science.gov (United States)

Liu, Guochao; Wang, Hui; Zhang, Fengmei; Tian, Youjia; Tian, Zhujun; Cai, Zuchao; Lim, David; Feng, Zhihui

2017-05-10

This study explored whether valproic acid (VPA, a histone deacetylase inhibitor) could radiosensitize osteosarcoma and primary-culture tumor cells, and determined the mechanism of VPA-induced radiosensitization. The working system included osteosarcoma cells (U2OS) and primary-culture cells from chemical carcinogen (DMBA)-induced breast cancer in rats; and clonogenic survival, immunofluorescence, fluorescent in situ hybridization (FISH) for chromosome aberrations, and comet assays were used in this study. It was found that VPA at the safe or critical safe concentration of 0.5 or 1.0 mM VPA could result in the accumulation of more ionizing radiation (IR)-induced DNA double strand breaks, and increase the cell radiosensitivity. VPA-induced radiosensitivity was associated with the inhibition of DNA repair activity in the working systems. In addition, the chromosome aberrations including chromosome breaks, chromatid breaks, and radial structures significantly increased after the combination treatment of VPA and IR. Importantly, the results obtained by primary-culture cells from the tissue of chemical carcinogen-induced breast cancer in rats further confirmed our findings. The data in this study demonstrated that VPA at a safe dose was a radiosensitizer for osteosarcoma and primary-culture tumor cells through suppressing DNA-double strand breaks repair function.

Enhanced Radiosensitization Effect of Curcumin Delivered by PVP-PCL Nanoparticle in Lung Cancer

Directory of Open Access Journals (Sweden)

Cuixia Wen

2017-01-01

Full Text Available Curcumin, the principal polyphenolic curcuminoid, has been reported in numerous studies for its antitumor effect in a series of cancers. It is also reported that curcumin possesses radiosensitization effect in some cancers. However, the poor solubility and unsatisfied bioavailability of curcumin significantly undermine its potential application. Here we prepared curcumin loaded nanoparticles by employing PVP-PCL as drug carrier. Characterization studies indicated the satisfied drug loading efficiency and a sustained in vitro release pattern. Quantification uptake study showed that the uptake efficiency of Cum-NPs by lung cancer cells was time- and dose-dependent. In vitro anticancer study demonstrated the superior cytotoxic effect of Cum-NPs with stronger apoptotic induction over free Cum. Most importantly, there is almost no report on the radiosensitization effect of curcumin loaded nanoparticles. Here, Cum-NPs led to more inhibition of the colony forming ability of A549 cells as compared to the equivalent concentration of free Cum as shown in clonogenic assay. Furthermore, Cum-NPs are much more effective in enhancing the tumor growth inhibitory effect of radiation therapy in a A549 xenograft model. Therefore, results from the current study seem to be the first report on the radiosensitization effect of Cum-NPs and paved the way for a curcumin nanodrug delivery system as a potential radiation adjuvant.

Radiosensitivity of hepatocellular carcinoma

International Nuclear Information System (INIS)

Hennequin, C.; Quero, L.; Rivera, S.

2011-01-01

The frequency of hepatocellular carcinoma (HCC) is increasing in the western world and the role of radiotherapy is more and more discussed. Classically, hepatocellular carcinoma was considered as a radioresistant tumour: in fact, modern radio-biologic studies, performed on cell lines directly established from patients, showed that hepatocellular carcinoma has the same radiosensitivity than the other epithelial tumours. From clinical studies, its α/β ratio has been estimated to be around 15 Gy. Radiosensitivity of normal hepatic parenchyma is now well evaluated and some accurate NTCP models are available to guide hepatic irradiation. The biology of hepatocellular carcinoma is also better described: the combination of radiotherapy and targeted therapies will be a promising approach in the near future. (authors)

Radiosensitivity of human lymphocytes and thymocytes

International Nuclear Information System (INIS)

Kwan, D.K.; Norman, A.

1977-01-01

The in vitro survival of human peripheral blood lymphocytes and thymocytes was measured 4 days following graded doses of γ radiation. Results indicate considerable heterogeneity among lymphocyte subpopulations with respect to radiosensitivity. Total T lymphocytes were characterized by rosette formation with neuraminidase-treated sheep red blood cells (nSRBC); early T (T/sub E/) cells, by early rosettes; and B cells, by their inability to form nSRBC rosettes. Late T (T/sub L/) cells were defined as T -- T/sub E/. Survival curves of T, T/sub E/, and B cells are biphasic. The radiosensitive and radioresistant components of T, T/sub E/, and B cells all have a D 0 of about 50 and 550 rad, respectively. B cells appeared to be slightly more radiosensitive than T cells. T/sub L/ cells and thymocytes, however, appeared to be homogeneous with respect to radiosensitivity, both having D 0 values of about 135 rad. The survival of T cells in mixed T and B cell cultures resembled that of separated T cells, suggesting that ionizing radiation has no significant effect on rosette formation. It also indicates that interactions of T and B cells do not significantly affect their radiation responses

Review of our histological criteria for the radiosensitivity of uterine cervical cancer

International Nuclear Information System (INIS)

Tsukahara, Yoshiharu; Shiozawa, Kyuyo; Tsukamoto, Takashi; Sonehara, Morio; Noguchi, Hiroshi

1975-01-01

The determination of radiosensitiveness based on 111 operated specimens after test irradiation of 1000R was compared with that based on 64 specimens which had received biopsies seven days after irradiation. It was concluded that the determination of radiosensitiveness by local biopsy could be applied to practical use. The results of this study are listed as follows: (1) Radiosensitivity exists within tumor cells themselves before irradiation, while radiosensitiveness is a complicated change in which some reaction on the host side added to degenerated tumor cells. (2) In the determination of radio-sensitiveness, there was a good accordance of 85% between biopsies and removed specimens. (3) The followings are findings of favorable radiosensitiveness based on the removed specimens; (a) neutrocyte infiltration within cancer nests, (b) lysis of cancer nests, (c) destruction of fundus of cancer nests, (d) damages of advanced sites of cancer infiltration, (e) damages of chromatin. As unfavorable findings, (f) mitosis, (g) abundant viable cells. (4) Various histological findings within cancer nests and variation of radiosensitiveness according to various regions of the tumor often cause a discord with biopsies. (5) Many specimens which show the intermediate histological type in maturation before irradiation indicate favorable radiosensitiveness. Even if they belong to the intermediate type, the specimens in which the issued histological findings are mixed show mostly unfavorable radiosensitiveness. (6) Removed specimens can be expressed in indices of radiosensitiveness. (Ichikawa, K.)

Hyperthermic radiosensitization : mode of action and clinical relevance

NARCIS (Netherlands)

Kampinga, HH; Dikomey, E

Purpose: To provide an update on the recent knowledge about the molecular mechanisms of thermal radiosensitization and its possible relevance to thermoradiotherapy. Summary: Hyperthermia is probably the most potent cellular radiosensitizer known to date. Heat interacts with radiation and potentiates

Studies on Drosophila radiosensitivity strains

International Nuclear Information System (INIS)

Varentsova, E.R.; Sharygin, V.I.; Khromykh, Yu.U.

1985-01-01

Fertility of radiosensitive mutant drosophila female strain rad (2) 201 61 after irradiation and frequency of dominant lethal mutations (DLM), induced by γ-radiation for 0-5 h and 5-7 days, are investigated. It is shown, that oocytes of the mutant strain are more radiosensitive as compared with cells of mongrel flies as to criterion of DLM appearance over the period of maturing. Early oocytes of stages 2-7 are the most sensitive, i.e. at the stages, corresponding to the manifestation of previously established recombination-defective properties of mutations rad (2) 201 61 . It is also sown, that doses of γ-rays, exceeding 10 Gy produce a strong sterilizing effect on mutant females due to destruction and resorption of egg chambers, irradiated at the stages of previtellogenetic growth of oocytes. In females, carrying mutation of radiosensitivity there is no direct correlation betwen sensitivity of oocytes proper to DLM induction and sensitivity of egg folleicles to resorbing effect of γ-rays. The ways of possible involvement of mutant locus studied into genetic processes in various specialized cells of drosophila

Radiosensitivity of primary cultured fish cells with different ploidy

International Nuclear Information System (INIS)

Mitani, Hiroshi; Egami, Nobuo; Kobayashi, Hiromu.

1986-01-01

The radiosensitivity of primary cultured goldfish cells (Carassius auratus) was investigated by colony formation assay. The radiosensitivity of cells from two varieties of goldfish, which show different sensitivity to lethal effect of ionizing radiation in vivo, was almost identical. Primary cultured cells from diploid, triploid and tetraploid fish retained their DNA content as measured by microfluorometry, and the nuclear size increases as ploidy increases. However, radiosensitivity was not related to ploidy. (author)

TNF-α inhibits trophoblast integration into endothelial cellular networks.

Science.gov (United States)

Xu, B; Nakhla, S; Makris, A; Hennessy, A

2011-03-01

Preeclampsia has been linked to shallow trophoblast invasion and failure of uterine spiral artery transformation. Interaction between trophoblast cells and maternal uterine endothelium is critically important for this remodelling. The aim of our study was to investigate the effect of TNF-α on the interactions of trophoblast-derived JEG-3 cells into capillary-like cellular networks. We have employed an in vitro trophoblast-endothelial cell co-culture model to quantify trophoblast integration into endothelial cellular networks and to investigate the effects of TNF-α. Controlled co-cultures were also treated with anti-TNF-α antibody (5 μg/ml) to specifically block the effect of TNF-α. The invasion was evaluated by performing quantitative PCR (Q-PCR) to analyse gene expression of matrix metalloproteinases-2 (MMP-2), MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, integrins (α(1)β(1) and α(6)β(4)), plasminogen activator inhibitor (PAI)-1, E-cadherin and VE-cadherin. JEG-3 cell integration into endothelial networks was significantly inhibited by exogenous TNF-α. The inhibition was observed in the range of 0.2-5 ng/ml, to a maximum 56% inhibition at the highest concentration. This inhibition was reversed by anti-TNF-α antibody. Q-PCR analysis showed that mRNA expression of integrins α(1)β(1) and MMP-2 was significantly decreased. VE-cadherin mRNA expression was significantly up-regulated (32-80%, p integration into maternal endothelial cellular networks, and this process involves the inhibition of MMP-2 and a failure of integrins switch from α(6)β(4) to α(1)β(1.) These molecular correlations reflect the changes identified in human preeclampsia. Copyright © 2011 Elsevier Ltd. All rights reserved.

Radiosensitization of head and neck cancer cells by the phytochemical agent sulforaphane

International Nuclear Information System (INIS)

Kotowski, Ulana; Heiduschka, Gregor; Brunner, Markus; Fahim, Tammer; Thurnher, Dietmar; Czembirek, Cornelia; Eder-Czembirek, Christina; Schmidt, Rainer

2011-01-01

Sulforaphane is a naturally occurring compound found in broccoli and other cruciferous vegetables. Recently it gained attention because of its antiproliferative properties in many cancer cell lines. The aim of this study was to investigate whether sulforaphane could act as a radiosensitizer in head and neck squamous cell carcinoma cell lines. Four head and neck squamous cell carcinoma cell lines (i.e., (HNSCC) SCC9, SCC25, CAL27, and FADU) were treated with sulforaphane and subsequently irradiated. Then proliferation and clonogenic assays were performed. Apoptosis was detected by flow cytometry. Possible regulation of Akt and Mcl-1 was investigated by western blotting. Sulforaphane and radiation in combination leads to stronger inhibition of cell proliferation and of clonogenic survival than each treatment method alone. Western blot analysis of Akt and Mcl-1 showed no changed expression. Sulforaphane is a promising agent in the treatment of head and neck cancer due to its antiproliferative and radio-sensitizing properties. A combination of sulforaphane and radiation decreases clonogenic survival. Apoptosis is not regulated through Akt or the Mcl-1 protein. (orig.)

Radiosensitization of head and neck cancer cells by the phytochemical agent sulforaphane

Energy Technology Data Exchange (ETDEWEB)

Kotowski, Ulana; Heiduschka, Gregor; Brunner, Markus; Fahim, Tammer; Thurnher, Dietmar [Medical University of Vienna (Austria). Dept. of Otorhinolaryngology, Head and Neck Surgery; Czembirek, Cornelia; Eder-Czembirek, Christina [Medical University of Vienna (Austria). Dept. of Cranio-, Maxillofacial and Oral Surgery; Schmidt, Rainer [Medical University of Vienna (Austria). Dept. of Radiotherapy and -biology

2011-09-15

Sulforaphane is a naturally occurring compound found in broccoli and other cruciferous vegetables. Recently it gained attention because of its antiproliferative properties in many cancer cell lines. The aim of this study was to investigate whether sulforaphane could act as a radiosensitizer in head and neck squamous cell carcinoma cell lines. Four head and neck squamous cell carcinoma cell lines (i.e., (HNSCC) SCC9, SCC25, CAL27, and FADU) were treated with sulforaphane and subsequently irradiated. Then proliferation and clonogenic assays were performed. Apoptosis was detected by flow cytometry. Possible regulation of Akt and Mcl-1 was investigated by western blotting. Sulforaphane and radiation in combination leads to stronger inhibition of cell proliferation and of clonogenic survival than each treatment method alone. Western blot analysis of Akt and Mcl-1 showed no changed expression. Sulforaphane is a promising agent in the treatment of head and neck cancer due to its antiproliferative and radio-sensitizing properties. A combination of sulforaphane and radiation decreases clonogenic survival. Apoptosis is not regulated through Akt or the Mcl-1 protein. (orig.)

Inhibition of phosphatidylinositol-3-kinase causes increased sensitivity to radiation through a PKB-dependent mechanism

International Nuclear Information System (INIS)

Gottschalk, Alexander R.; Doan, Albert; Nakamura, Jean L.; Stokoe, David; Haas-Kogan, Daphne A.

2005-01-01

Purpose: To identify whether inhibition of phosphatidylinositol-3-kinase (PI3K) causes increased radiosensitivity through inhibition of protein kinase B (PKB), implicating PKB as an important therapeutic target in prostate cancer. Methods and Materials: The prostate cancer cell line LNCaP was treated with the PI3K inhibitor LY294002, radiation, and combinations of the two therapies. Apoptosis and survival were measured by cell cycle analysis, Western blot analysis for cleaved poly (ADP-ribose) polymerase, and clonogenic survival. To test the hypothesis that inhibition of PKB is responsible for LY294002-induced radiosensitivity, LNCaP cells expressing a constitutively active form of PKB were used. Results: The combination of PI3K inhibition and radiation caused an increase in apoptosis and a decrease in clonogenic survival when compared to either modality alone. The expression of constitutively activated PKB blocked apoptosis induced by combination of PI3K inhibition and radiation and prevented radiosensitization by LY294002. Conclusion: These data indicate that PI3K inhibition increases sensitivity of prostate cancer cell lines to ionizing radiation through inactivation of PKB. Therefore, PTEN mutations, which lead to PKB activation, may play an important role in the resistance of prostate cancer to radiation therapy. Targeted therapy against PKB could be beneficial in the management of prostate cancer patients

Tumour-specific radiosensitizers for radiation therapy

International Nuclear Information System (INIS)

Denekamp, J.

1977-01-01

Recently Adams and coworkers at the Gray Laboratory have developed a new class of radiosensitizers which act specifically on hypoxic cells by abolishing the protection afforded by low oxygen concentrations. Since most experimental tumours contain a high proportion of oxygen-deprived cells, and most normal tissues are well oxygenated, these drugs are tumour specific radiosensitizers. Based on the hypothesis that sensitization increases with increasing electron affinity, the two nitroimidazoles, metronidazole (Flagyl) and Ro-07/0582 were identified as potent radiosensitizers with low toxicity. These drugs are effective only in the absence of oxygen, and only if the drug is present at the time of irradiation. The degree of sensitization increases with drug concentration rapidly over the range 0.1 to 1.0mg/g body weight for Ro-07-0582, and more gradually for Flagyl. Tumour studies have been performed on at least 12 different experimental tumours, using a variety of end points. Significant sensitization has been observed in every tumour studied, often corresponding to a dose reduction factor of 2.0 for high but non-toxic drug doses. Fractionated studies have also been performed on a few tumour lines. In most cases a useful therapeutic advantage was observed, although the sensitization was smaller. Ro-07-0582 used with X-rays gives a therapeutic gain comparable with that from cyclotron-produced fast neutrons. Neutrons used together with Ro-07-0582 are even more effective. In addition to the radiosensitization there is a specific cytotoxicity to hypoxic cells after prolonged exposure to Ro-07-0582. This cytotoxicity can be greatly enhanced in vitro by moderate hyperthermia. Flagyl and Ro-07-0582 have been used clinically as radiosensitizers, with promising early results. The clinical application is limited to certain dose fractionation patterns because of neurotoxicity. (author)

Radiosensitivity of lymphocytes among Filipinos: final report

International Nuclear Information System (INIS)

Medina, F.I.S.; Gregorio, J.S.; Aguilar, C.P.; Poblete, E.E.

1996-01-01

This report is about the studies on the radiosensitivity of Filipino lymphocytes to radiation that can elucidate on the potential of blood chromosomes as biological dosimeters. The objective of this study is to determine the radiosensitivity of lymphocytes among Filipinos and to establish the radiation-induced chromosome anomaly standard curve in lymphocytes for radiological dosimetry. 47 refs., 9 figs., 1 tab

Cellular radiosensitivity in human severe-combined-immunodeficiency (SCID) syndromes

International Nuclear Information System (INIS)

Sproston, Anthony R.M.; West, Catharine M.L.; Hendry, Jolyon H.

1997-01-01

Purpose: The aim of the work was to establish to what extent a variety of human severe-combined-immunodeficiency (SCID) disorders are associated with in vitro cellular hypersensitivity to ionizing radiation. Materials and methods: A study was made of fibroblast strains established from individuals with adenosine deaminase deficiency, T(-)B(-) SCID, Omenn's syndrome and a SCID heterozygote. For comparison, an assessment was also made of the radiosensitivity of a series of fibroblast strains derived from: normal donors, a patient with ataxia-telangiectasia (A-T) and an A-T heterozygote. Radiosensitivity was determined using a clonogenic assay following both high (HDR) and low (LDR) dose-rate irradiation. Results: Following HDR irradiation, the fibroblast strains derived from the different human SCID disorders displayed a wide range of radiosensitivity: the adenosine deaminase deficiency cells were similar in radiosensitivity to normal fibroblasts, T(-)B(-) cells were as hypersensitive to radiation as A-T cells and the Omenn's syndrome cells showed intermediate radiosensitivity. However, whereas all four normal cell strains studied showed significant LDR sparing, none of the SCID fibroblasts did. Conclusions: These data indicate that human SCID is variable in terms of radiosensitivity depending on the particular defect. In addition, the lack of LDR sparing of radiation-induced damage suggests the involvement of some form(s) of DNA repair defect in all the human SCID syndromes

Identification and Characterization of a Small Inhibitory Peptide That Can Target DNA-PKcs Autophosphorylation and Increase Tumor Radiosensitivity

Energy Technology Data Exchange (ETDEWEB)

Sun Xiaonan [Department of Radiation Oncology, Sir Run Run Shaw Hospital, Sir Run Run Shaw Institute of Clinical Medicine of Zhejiang University, Hangzhou (China); Yang Chunying [Department of Radiation Oncology, Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX (United States); Liu Hai; Wang Qi [Department of Radiation Oncology, Sir Run Run Shaw Hospital, Sir Run Run Shaw Institute of Clinical Medicine of Zhejiang University, Hangzhou (China); Wu Shixiu [Department of Radiation Oncology, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou (China); Li Xia; Xie Tian [Research Center of Biomedicine and Health, Hangzhou Normal University, Hangzhou (China); Brinkman, Kathryn L.; Teh, Bin S.; Butler, E. Brian [Department of Radiation Oncology, Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX (United States); Xu Bo, E-mail: bxu@tmhs.org [Department of Radiation Oncology, Methodist Hospital Research Institute, Weill Cornell Medical College, Houston, TX (United States); Zheng, Shu, E-mail: zhengshu@zju.edu.cn [Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou (China)

2012-12-01

Purpose: The DNA protein kinase catalytic subunit (DNA-PKcs) is one of the critical elements involved in the DNA damage repair process. Inhibition of DNA-PKcs results in hypersensitivity to ionizing radiation (IR); therefore, this approach has been explored to develop molecular targeted radiosensitizers. Here, we aimed to develop small inhibitory peptides that could specifically target DNA-PKcs autophosphorylation, a critical step for the enzymatic activation of the kinase in response to IR. Methods and Materials: We generated several small fusion peptides consisting of 2 functional domains, 1 an internalization domain and the other a DNA-PKcs autophosphorylation inhibitory domain. We characterized the internalization, toxicity, and radiosensitization activities of the fusion peptides. Furthermore, we studied the mechanisms of the inhibitory peptides on DNA-PKcs autophosphorylation and DNA repair. Results: We found that among several peptides, the biotin-labeled peptide 3 (BTW3) peptide, which targets DNA-PKcs threonine 2647 autophosphorylation, can abrogate IR-induced DNA-PKcs activation and cause prolonged {gamma}-H2AX focus formation. We demonstrated that BTW3 exposure led to hypersensitivity to IR in DNA-PKcs-proficient cells but not in DNA-PKcs-deficient cells. Conclusions: The small inhibitory peptide BTW3 can specifically target DNA-PKcs autophosphorylation and enhance radiosensitivity; therefore, it can be further developed as a novel class of radiosensitizer.

Identification and Characterization of a Small Inhibitory Peptide That Can Target DNA-PKcs Autophosphorylation and Increase Tumor Radiosensitivity

International Nuclear Information System (INIS)

Sun Xiaonan; Yang Chunying; Liu Hai; Wang Qi; Wu Shixiu; Li Xia; Xie Tian; Brinkman, Kathryn L.; Teh, Bin S.; Butler, E. Brian; Xu Bo; Zheng, Shu

2012-01-01

Purpose: The DNA protein kinase catalytic subunit (DNA-PKcs) is one of the critical elements involved in the DNA damage repair process. Inhibition of DNA-PKcs results in hypersensitivity to ionizing radiation (IR); therefore, this approach has been explored to develop molecular targeted radiosensitizers. Here, we aimed to develop small inhibitory peptides that could specifically target DNA-PKcs autophosphorylation, a critical step for the enzymatic activation of the kinase in response to IR. Methods and Materials: We generated several small fusion peptides consisting of 2 functional domains, 1 an internalization domain and the other a DNA-PKcs autophosphorylation inhibitory domain. We characterized the internalization, toxicity, and radiosensitization activities of the fusion peptides. Furthermore, we studied the mechanisms of the inhibitory peptides on DNA-PKcs autophosphorylation and DNA repair. Results: We found that among several peptides, the biotin-labeled peptide 3 (BTW3) peptide, which targets DNA-PKcs threonine 2647 autophosphorylation, can abrogate IR-induced DNA-PKcs activation and cause prolonged γ-H2AX focus formation. We demonstrated that BTW3 exposure led to hypersensitivity to IR in DNA-PKcs-proficient cells but not in DNA-PKcs-deficient cells. Conclusions: The small inhibitory peptide BTW3 can specifically target DNA-PKcs autophosphorylation and enhance radiosensitivity; therefore, it can be further developed as a novel class of radiosensitizer.

Radiosensitizing effect of RHOB protein in melanoma cells

International Nuclear Information System (INIS)

Notcovich, C.; Grissi, C.; Sánchez Crespo, R.; Delgado, D.C.; Molinari, B.; Ibañez, I.L.; Durán, H.

2015-01-01

Melanoma cells are highly resistant to chemo or radiotherapy. DNA damage agents such as ionizing radiation induce apoptosis involving RhoB protein. In a great variety of tumors the levels of this protein decrease along tumor progression. RhoB is considered a tumor suppressor gene due to its antiproliferative and proapoptotic effect. Considering the aforementioned, the aim of this study was to characterize the radiobiological response of different human melanoma cell lines, and to evaluate the possible correlation between RhoB expression and radiosensitivity. The human melanoma cell lines A375, MELJ and SB2 were gamma-irradiated ( 137 Cs). Survival curves were obtained by clonogenic assay and fitted to the Linear-Quadratic (LQ) model. Radiosensitivity was evaluated by surviving fraction at 2 Gy (SF2). Results showed that MELJ was significantly more radioresistant (SF2=0.71) than A375 and SB2 (0.29 and 0.21 respectively. Expression levels of RhoB, evaluated by western blot, increased in all lines vs. non-irradiated control. SB2, the most radiosensitive cells, showed a greater induction (p<0.05) of RhoB. Finally, to study whether RhoB has a radiosensitizing effect, these cell lines were stably transfected with a wild type RhoB construction, a constitutively active RhoB mutant V14, or with the empty plasmid as control. For all cell lines higher expression level of this protein was found in RhoB or V14 transfected cells (p<0.05). Sensitization was evaluated by SF2. Significant radiosensitization was demonstrated in clones derived from A375 and SB2 ((p<0.05), while for MELJ cells, radio-sensitization was only found in clones overexpressing V14. In conclusion, the increase of RhoB in melanoma cell lines, either by radiation or transfection has a radiosensitizing effect. Thus, we propose RhoB modulation as a potential therapeutic tool to improve the radiation response of radioresistant melanoma. (authors)

Inhibition of X-ray-induced potentially lethal damage (PLD) repair in aerobic plateau-phase Chinese hamster cells by misonidazole

International Nuclear Information System (INIS)

Brown, D.M.

1984-01-01

The effect of the 2-nitroimidazole radiosensitizer misonidazole (MISO) and the hydrophilic analog SR-2508 on the repair of X-ray-induced potentially lethal damage (PLD) was studied in plateau-phase Chinese Hamster ovary (HA-1) cells. It was found that although MISO does not radiosensitize aerobic cells, it inhibits the repair of PLD. However, under hypoxic conditions, MISO has no effect on PLD repair. The major portion of the inhibition of PLD repair in aerobic cells requires the presence of MISO only during irradiation; little or no additional inhibition occurs when MISO is present during the postirradiation repair period. Also, treatment of aerobic cells with 5 mM MISO for either 5 or 30 min prior to irradiation is equally inhibitory. This suggests that the presence of MISO in some way modifies the initial lesion under aerobic conditions since it does not increase cell killing as determined by immediate plating but inhibits subsequent repair. The inhibition is concentration dependent; 0.5 mM MISO inhibits PLD repair by one-half while 5-10 mM totally inhibits the repair measured 6 hr postirradiation. This phenomenon suggests that radiosensitization of tissue in vivo by MISO and other 2-nitroimidazoles may not be unequivocal proof of the presence of hypoxic cells

Age-dependent radiosensitivity of mouse oocytes

International Nuclear Information System (INIS)

Koehler, C.

1976-01-01

It has been shown that there are three distinct phases of radiosensitivity in oocytes of prepubertal mice: a period of rapidly increasing sensitivity between 0 and 4 days of age; a period of consistent, high sensitivity between 5 and 18 days of age; and a period of decreasing sensitivity from 19 to at least 21 days of age. Two distinct phases have been demonstrated for the rate of population decline of the oocytes of primary follicles: an initial period of rapid loss from 0 to 4 days of age; and a period of much slower loss from 5 through 23 days of age. Correlations have been drawn between the first two phases of radiosensitivity and morphological changes in the oocyte, and between the third phase of radiosensitivity and endocrinological changes in the maturing animal. The reaction of oocytes to radiation has been separated into two categories: immediate death (within 24 hours); and delayed death (over the entire lifespan of the animal)

Heat shock protein 90 (Hsp90) chaperone complex. A molecular target for enhancement of thermosensitivity and radiosensitivity

International Nuclear Information System (INIS)

Akimoto, Tetsuo; Nonaka, Tetsuo; Kitamoto, Yoshizumi; Sakurai, Hideyuki

2002-01-01

Heat shock protein 90 (Hsp90) is a highly conserved heat shock protein in animal and plants, and exists abundantly in the cytoplasm in unstressed condition, accounting for 1-2% in cytoplasmic proteins. Main difference of Hsp90 from other Hsps are its substrate that Hsp90 binds to. These substrates include various signal transduction proteins, kinase, steroid receptors and transcription factors, therefore, Hsp90 plays a key role in maintaining cellular signal transduction networks. Many chaperoned proteins (client proteins) of Hsp90 are associated with cellular proliferation or malignant transformation, thus Hsp90 chaperone complex has been focused as targets for cancer therapy. Among the client proteins, there are several molecules that have been defined as targets or factors for determination or enhancement of radiosensitivity or thermosensitivity. Thus, it is easily speculated that Hsp90 chaperone complex inhibitors that disrupt association of Hsp90 and client protein in combination with radiation or/and heat has potential effect on enhancement of radiosensitivity or thermosensitivity. In this paper, possible mechanisms in enhancing radiosensitivity or thermosensitivity according to the client proteins will be summarized. (author)

Radiation and chemical interactions producing cellular and subcellular damage and their repair. Coordinated programme on improvement in radiotherapy of cancer using modifiers of radiosensitivity of cells

International Nuclear Information System (INIS)

Kada, T.

1982-01-01

As a result of biochemical studies on the DNA repair of damages induced by ionizing radiation as well as on the radiosensitization with chemicals containing halogen atoms, it was suggested that inhibition of the post-irradiation repair by chemical factors may be useful in improving the radiotherapy. It was possbile to prepare an in vitro repair system in combination with transforming DNA of Bacillus subtilis as well as human placenta extracts; it was shown that certain radiosensitizers worked actually as repair inhibitors in this in vitro system

Radiosensitivity in ataxia-telangiectasia

International Nuclear Information System (INIS)

Lavin, M.F.; Khanna, K.K.; Watters, D.

1998-01-01

Full text: Radiosensitivity is a major hallmark of the human genetic disorder ataxia-telangiectasia. This hypersensitivity to ionizing radiation has been demonstrated in vitro after exposure of patients to therapeutic thought to be the major factor contculture. Clearly an understanding of the nature of the molecular defect in ataxia-telangiectasia will be of considerable assistance in delineating additional pathways that determine cellular radiosensitivity/radioresistance. Furthermore, since patients with this syndrome are also predisposed to developing a number of leukaemias and lymphomas the possible connection between radiosensitivity and cancer predisposition is of interest. Now that the gene (ATM) responsible for this genetic disease has been cloned and identified, progress is being made in determining the role of the ATM protein in mediating the effects of cellular exposure to ionizing radiation and other forms of redox stress. Proteins such as the product of the tumour suppressor gene p53 and the proto-oncogene c-Abl (a protein tyrosine kinase) have been shown to interact with ATM. Since several intermediate steps in both the p53 and c-Abl pathways, activated by ionizing radiation, are known it will be possible to map the position of ATM in these pathways and describe its mechanism of action. What are the clinical implications of understanding the molecular basis of the defect in ataxia-telangiectasia? As outlined above since radiosensitivity is a universal characteristic of A-T understanding the mechanism of action of ATM will provide additional information or radiation signalling in human cells. With this information it may be possible to sensitize tumour cells to radiation and thus increase the therapeutic benefit of radiotherapy. This might involve the use of small molecules that would interfere with the normal ATM controlled pathways and thus sensitize cells to radiation or alternatively it might involve the efficient introduction of ATM anti-sense c

Radiosensitivity in ataxia-telangiectasia

Energy Technology Data Exchange (ETDEWEB)

Lavin, M.F. [Royal Brisbane Hospital, QLD (Australia). Queensland Institute of Medical Research and The Department of Surgery; Khanna, K.K.; Watters, D. [Royal Brisbane Hospital, QLD (Australia). Queensland Institute of Medical Research

1998-12-31

Full text: Radiosensitivity is a major hallmark of the human genetic disorder ataxia-telangiectasia. This hypersensitivity to ionizing radiation has been demonstrated in vitro after exposure of patients to therapeutic thought to be the major factor contculture. Clearly an understanding of the nature of the molecular defect in ataxia-telangiectasia will be of considerable assistance in delineating additional pathways that determine cellular radiosensitivity/radioresistance. Furthermore, since patients with this syndrome are also predisposed to developing a number of leukaemias and lymphomas the possible connection between radiosensitivity and cancer predisposition is of interest. Now that the gene (ATM) responsible for this genetic disease has been cloned and identified, progress is being made in determining the role of the ATM protein in mediating the effects of cellular exposure to ionizing radiation and other forms of redox stress. Proteins such as the product of the tumour suppressor gene p53 and the proto-oncogene c-Abl (a protein tyrosine kinase) have been shown to interact with ATM. Since several intermediate steps in both the p53 and c-Abl pathways, activated by ionizing radiation, are known it will be possible to map the position of ATM in these pathways and describe its mechanism of action. What are the clinical implications of understanding the molecular basis of the defect in ataxia-telangiectasia? As outlined above since radiosensitivity is a universal characteristic of A-T understanding the mechanism of action of ATM will provide additional information or radiation signalling in human cells. With this information it may be possible to sensitize tumour cells to radiation and thus increase the therapeutic benefit of radiotherapy. This might involve the use of small molecules that would interfere with the normal ATM controlled pathways and thus sensitize cells to radiation or alternatively it might involve the efficient introduction of ATM anti-sense c

Contributions concerning radiosensitivity proffered by the basic sciences to clinical radiation therapy

International Nuclear Information System (INIS)

Caputo, A.

1974-01-01

Basic concepts of radiosensitivity are reviewed. Some topics discussed are: probability of lethal injury as a dose dependent function; mutations resulting from radiation damage to DNA; relation of cell radiosensitivity to chromosome volume; relation of molecular structure of DNA to relative radiosensitivity of the organism; repair replication of DNA following uv and x irradiation of Escherichia coli and mammalian cells; and relation of the cell cycle to radiosensitivity. (U.S.)

Proteasome inhibitors block DNA repair and radiosensitize non-small cell lung cancer.

Directory of Open Access Journals (Sweden)

Kyle R Cron

Full Text Available Despite optimal radiation therapy (RT, chemotherapy and/or surgery, a majority of patients with locally advanced non-small cell lung cancer (NSCLC fail treatment. To identify novel gene targets for improved tumor control, we performed whole genome RNAi screens to identify knockdowns that most reproducibly increase NSCLC cytotoxicity. These screens identified several proteasome subunits among top hits, including the topmost hit PSMA1, a component of the core 20 S proteasome. Radiation and proteasome inhibition showed synergistic effects. Proteasome inhibition resulted in an 80-90% decrease in homologous recombination (HR, a 50% decrease in expression of NF-κB-inducible HR genes BRCA1 and FANCD2, and a reduction of BRCA1, FANCD2 and RAD51 ionizing radiation-induced foci. IκBα RNAi knockdown rescued NSCLC radioresistance. Irradiation of mice with NCI-H460 xenografts after inducible PSMA1 shRNA knockdown markedly increased murine survival compared to either treatment alone. Proteasome inhibition is a promising strategy for NSCLC radiosensitization via inhibition of NF-κB-mediated expression of Fanconi Anemia/HR DNA repair genes.

Radiosensitivity of fingermillet genotypes

Energy Technology Data Exchange (ETDEWEB)

Raveendran, T S; Nagarajan, C; Appadurai, R; Prasad, M N; Sundaresan, N [Tamil Nadu Agricultural Univ., Coimbatore (India)

1984-07-01

Varietal differences in radiosensitivity were observed in a study involving 4 genotypes of fingermillet (Eleusine coracana (Linn.) Gaertn.) subjected to gamma-irradiation. Harder seeds were found to tolerate a higher dose of the mutagen.

Modern concepts for basic radiobiological factors characterizing tumor tissue radiosensitivity

International Nuclear Information System (INIS)

Gocheva, L.; Sergieva, K.

2002-01-01

Traditionally radiotherapy is prescribed at doses consistent with the expected therapeutic response and tolerance of tumor and normal tissues without consideration to individual differences in radiosensitivity. However, the basic radiobiological knowledge and clinical experience along this line point to significant variations in the observed therapeutic results. It has been established that cells and tissues under experimental and clinical conditions manifest a wide spectrum of individual radiosensitivity. The aim of this survey is to outline the current concepts for the basic radiobiological factors influencing tumor radiosensitivity. A thorough discussion is done of the essence, mechanisms of action, methods of determination and measurement, and effect on the prognosis in patients with malignant diseases of a number of radiobiological factors, such as: tumor-cell proliferation, apoptosis, tumor hypoxia and neovascularization. Although the knowledge of the mechanisms of radiosensitivity is constantly expanding, its clinical implementation is still rather limited. The true role of radiosensitivity in predicting the therapeutic response should be more accurately defined. (authors)

A review of human cell radiosensitivity in vitro

International Nuclear Information System (INIS)

Deschavanne, Patrick J.; Fertil, Bernard

1996-01-01

The survival curves of 694 human cell lines irradiated in exponentially growing phase in vitro were collected from the literature. Among them, 271 were derived from tumors, 423 were nontransformed fibroblasts and other normal cell strains from healthy people or people with some genetic disorders. Seventy-six different cell types are identified, and a specific radiosensitivity could be associated with each, using D-bar and surviving fraction at 2 Gy. Technical factors such as culture medium, feeder cells, and scoring method were found to affect intrinsic radiosensitivity. In particular, the cell type is not a discriminating factor when cells are studied in agar. Results obtained with cells irradiated in agar must be used cautiously, depending on how the cells were prepared for the experiments. The use of feeder cells narrows the range of radiosensitivity of human cells. For cells irradiated as monolayer, it was possible to build a scale of radiosensitivity according to cell type, ranging, in terms of D-bar from 0.6 Gy for the most sensitive cell lines to more than 4 Gy for the most resistant. Considering that, in most cases, we could estimate the variation of radiosensitivity within each cell type, our classification among cell types can be used by researchers to place their results in the context of the literature

Impact of homologous recombination on individual cellular radiosensitivity

International Nuclear Information System (INIS)

Koch, Kerstin; Wrona, Agnieszka; Dikomey, Ekkehard; Borgmann, Kerstin

2009-01-01

Purpose: Individual radiosensitivity as measured with in vitro irradiated lymphocytes using metaphase analysis can predict the risk of normal tissue effects after radiotherapy. This parameter is considered to be primarily determined by the cellular repair capacity of DNA double-strand breaks (DSBs). It is now tested to which extent this capacity also depends on homologous recombination (HR), which is a pathway available when cells are in S/G2 phase. Methods: Experiments were performed with CHO K1 cells, in which HR was suppressed via knock-down of RAD51 using RNA interference (RNAi). RAD51 was measured via western and foci formation, cell survival by colony forming, DSBs by γH2AX foci formation, and chromosomal damage using PCC, G0 or G2 assay. Results: In quiescent G1 cells DSB repair is completed 6 h after irradiation. But there is still a substantial fraction of non-repaired DSBs. Most of these DSBs are repaired when G1 cells are stimulated into cell cycle. Suppression of HR by down-regulation of RAD51 did not affect this repair. In contrast, repair was inhibited when cells were irradiated in late S/G2. In line with these data down-regulation of HR did affect survival of cells irradiated in late S/G2, but not in G1. Conclusions: Individual radiosensitivity as measured for G0/1 cells using metaphase analysis does not depend on homologous recombination

Radiosensitization of mouse skin by oxygen and depletion of glutathione

International Nuclear Information System (INIS)

Stevens, Graham; Joiner, Michael; Joiner, Barbara; Johns, Helen; Denekamp, Juliana

1995-01-01

Purpose: To determine the oxygen enhancement ratio (OER) and shape of the oxygen sensitization curve of mouse foot skin, the extent to which glutathione (GSH) depletion radiosensitized skin, and the dependence of such sensitization on the ambient oxygen tension. Methods and Materials: The feet of WHT mice were irradiated with single doses of 240 kVp x-rays while mice were exposed to carbogen or gases with oxygen/nitrogen mixtures containing 8-100% O 2 . The anoxic response was obtained by occluding the blood supply to the leg of anesthetized mice with a tourniquet, surrounding the foot with nitrogen, and allowing the mice to breathe 10% O 2 . Further experiments were performed to assess the efficacy of this method to obtain an anoxic response. Radiosensitivity of skin was assessed using the acute skin-reaction assay. Glutathione levels were modified using two schedules of dl-buthionine sulphoximine (BSO) and diethylmaleate (DEM), which were considered to produce extensive and intermediate levels of GSH depletion in the skin of the foot during irradiation. Results: Carbogen caused the greatest radiosensitization of skin, with a reproducible enhancement of 2.2 relative to the anoxic response. The OER of 2.2 is lower than other reports for mouse skin. This may indicate that the extremes of oxygenation were not produced, although there was no direct evidence for this. When skin radiosensitivity was plotted against the logarithm of the oxygen tension in the ambient gas, a sigmoid curve with a K value of 17-21% O 2 in the ambient gas was obtained. Depletion of GSH caused minimal radiosensitization when skin was irradiated under anoxic or well-oxygenated conditions. Radiosensitization by GSH depletion was maximal at intermediate oxygen tensions of 10-21% O 2 in the ambient gas. Increasing the extent of GSH depletion led to increasing radiosensitization, with sensitization enhancement ratios of 1.2 and 1.1, respectively, for extensive and intermediate levels of GSH

Targeted radiosensitization of cells expressing truncated DNA polymerase {beta}.

NARCIS (Netherlands)

Neijenhuis, S.; Verwijs-Janssen, M.; Broek, Bart van den; Begg, A.C.; Vens, C.

2010-01-01

Ionizing radiation (IR) is an effective anticancer treatment, although failures still occur. To improve radiotherapy, tumor-targeted strategies are needed to increase radiosensitivity of tumor cells, without influencing normal tissue radiosensitivity. Base excision repair (BER) and single-strand

HLA‐G modulates the radiosensitivity of human neoplastic cells

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Michelin, Severino; Gallegos, Cristina; Baffa Trasci, Sofía; Dubner, Diana; Favier, B.; Carosella, E.D.

2011-01-01

Tumor cells show a very broad range of radiosensitivities. The differential radiosensitivity may depend on many factors, being the efficiency to recognize and/or repair the DNA lesion, and the cell cycle control mechanisms, the most important (Jeggo and Lavin, 2009; Kumala et al., 2003). Human leukocyte antigen‐G (HLA‐G) is a non‐classical HLA class I molecule involved in fetus protection form the maternal immune system, transplant tolerance, and viral and tumoral immune escape (Carosella et al., 2008). It has been determined that gamma radiation modulates HLA‐G expression at the plasma membrane of human melanoma cells. However, its role in tumoral radiosensitivity has not been demonstrated yet. The objective of this work was to determine if the radiosensitivity of human neoplastic cell lines cultured in vitro was mediated by HLA‐G expression. (authors)

Mesoscopic segregation of excitation and inhibition in a brain network model.

Directory of Open Access Journals (Sweden)

Daniel Malagarriga

2015-02-01

Full Text Available Neurons in the brain are known to operate under a careful balance of excitation and inhibition, which maintains neural microcircuits within the proper operational range. How this balance is played out at the mesoscopic level of neuronal populations is, however, less clear. In order to address this issue, here we use a coupled neural mass model to study computationally the dynamics of a network of cortical macrocolumns operating in a partially synchronized, irregular regime. The topology of the network is heterogeneous, with a few of the nodes acting as connector hubs while the rest are relatively poorly connected. Our results show that in this type of mesoscopic network excitation and inhibition spontaneously segregate, with some columns acting mainly in an excitatory manner while some others have predominantly an inhibitory effect on their neighbors. We characterize the conditions under which this segregation arises, and relate the character of the different columns with their topological role within the network. In particular, we show that the connector hubs are preferentially inhibitory, the more so the larger the node's connectivity. These results suggest a potential mesoscale organization of the excitation-inhibition balance in brain networks.

Effect of Gamma Radiation on Amino Acid Based Vesicle Carrying Radiosensitizer

International Nuclear Information System (INIS)

Nur Ratasha Alia Mohd Rosli; Faizal Mohamed; Muhammad Amir Syafiq Mohd Sah; Irman Abdul Rahman

2014-01-01

Vesicles has been developed and studied to be used as a medium to transport radiosensitizer in treating cancer cells by increasing its sensitivity effectively towards the radiation given during radiotherapy. This study was conducted to investigate the effect of gamma radiation on amino acid-based vesicle carrying radiosensitizer. Amino acid based vesicles carrying radiosensitizer were synthesized using sonication method with sodium N-lauroylsarcosinate hydrate and decanol being the primary surfactant, while hydrogen peroxide and sodium hyaluronate as the encapsulated radiosensitizer. The synthesized vesicle was then irradiated at radiation doses equivalent to those given during radiotherapy. Irradiated vesicle carrying radiosensitizer were then characterized using Transmission Electron Microscopy (TEM), Fourier Transform Infrared Spectroscopy (FTIR) and Polarized Light Microscope. Results obtained shows that there were no significant changes in morphology and molecular conformation of the synthesized vesicle after irradiation. Even at higher radiation dose of 100 Gray and 200 Gray, the results remained unchanged. This indicates that the synthesized vesicle carrying radiosensitizer is morphologically and spectroscopically stable even at high radiation doses. (author)

Radiosensitizing effect of PSMC5, a 19S proteasome ATPase, in H460 lung cancer cells

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Yim, Ji-Hye; Yun, Hong Shik; Lee, Su-Jae; Baek, Jeong-Hwa; Lee, Chang-Woo; Song, Ji-Young; Um, Hong-Duck; Park, Jong Kuk; Kim, Jae-Sung; Park, In-Chul; Hwang, Sang-Gu

2016-01-01

The function of PSMC5 (proteasome 26S subunit, ATPase 5) in tumors, particularly with respect to cancer radioresistance, is not known. Here, we identified PSMC5 as a novel radiosensitivity biomarker, demonstrating that radiosensitive H460 cells were converted to a radioresistance phenotype by PSMC5 depletion. Exposure of H460 cells to radiation induced a marked accumulation of cell death-promoting reactive oxygen species, but this effect was blocked in radiation-treated H460 PSMC5-knockdown cells through downregulation of the p53-p21 pathway. Interestingly, PSMC5 depletion in H460 cells enhanced both AKT activation and MDM2 transcription, thereby promoting the degradation of p53 and p21 proteins. Furthermore, specific inhibition of AKT with triciribine or knockdown of MDM2 with small interfering RNA largely restored p21 expression in PSMC5-knockdown H460 cells. Our data suggest that PSMC5 facilitates the damaging effects of radiation in radiation-responsive H460 cancer cells and therefore may serve as a prognostic indicator for radiotherapy and molecular targeted therapy in lung cancer patients. - Highlights: • PSMC5 is a radiation-sensitive biomarker in H460 cells. • PSMC5 depletion inhibits radiation-induced apoptosis in H460 cells. • PSMC5 knockdown blocks ROS generation through inhibition of the p53-p21 pathway. • PSMC5 knockdown enhances p21 degradation via AKT-dependent MDM2 stabilization.

Validation of a radiosensitivity molecular signature in breast cancer

NARCIS (Netherlands)

S.A. Eschrich (Steven); C. Fulp (Carl); Y. Pawitan (Yudi); J.A. Foekens (John); M. Smid (Marcel); J.W.M. Martens (John); M. Echevarria (Michelle); P.S. Kamath (Patrick); J.-H. Lee (Ji-Hyun); E.E. Harris (Eleanor); J. Bergh (Jonas); J.F. Torres-Roca (Javier)

2012-01-01

textabstractPurpose: Previously, we developed a radiosensitivity molecular signature [radiosensitivity index (RSI)] that was clinically validated in 3 independent datasets (rectal, esophageal, and head and neck) in 118 patients. Here, we test RSI in radiotherapy (RT)-treated breast cancer patients.

Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in human esophageal cancer cell lines in vitro: Possible involvement of inhibition of survival signal transduction pathways

International Nuclear Information System (INIS)

Akimoto, Tetsuo; Nonaka, Tetsuo; Ishikawa, Hitoshi; Sakurai, Hideyuki; Saitoh, Jun-ichi; Takahashi, Takeo; Mitsuhashi, Norio

2001-01-01

Purpose: The effect of genistein, a tyrosine kinase inhibitor, on radiosensitivity was examined, especially focusing on 'survival signal transduction pathways'. Methods and Materials: Two human esophageal squamous cell cancer cell lines, TE-1 (p53, mutant) and TE-2 (p53, wild), were used. Radiosensitivity was determined by clonogenic assay, and activation of survival signals was examined by Western blot. Results: Genistein (30 μM) greatly enhanced radiosensitivity in these cell lines by suppressing radiation-induced activation of survival signals, p42/p44 extracellular signal-regulated kinase and AKT/PKB. Significant increase in the percentage of apoptotic cells and increased poly[ADP-ribose] polymerase cleavage were observed in TE-2, but not in TE-1 even after combination of genistein with irradiation. In terms of changes in expression of p53-related proteins, increase in expression of Bax and decrease in that of Bcl-2 were observed in TE-2 but not in TE-1, suggesting that the main mode of cell death induced by genistein in a cell line with wild type p53 differed from that with mutant p53. Conclusions: This study suggested that survival signals, including p42/p44 ERK and AKT/PKB, may be involved in determining radiosensitivity, and genistein would be a potent therapeutic agent that has an enhancing effect on radiation

Radiosensitivity in seeds of Coix lachryma-jobi TOURN

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Gabrielli, A C [Universidade Estadual de Campinas (Brazil). Inst. de Biologia; Medina Filho, H P [Instituto Agronomico de Campinas (Brazil)

1979-04-01

Radiosensitivity in seeds of Coix lachryma-jobi Tourn. Seeds of Coix lachryma-jobi Tourn., containing 9% humidity were irradiated with 0 to 70 Krad doses of gama-radiation from a /sup 60/Co source. The zero-time was set to be the time of sowing. At high doses of radiation, germination after 15 days was little affected, but after 21 days survival rate decreased. Our results show that the LD/sub 50/ is about 60 Krad and the GR/sub 50/ is approximately 30 Krad. The morphological alterations which were observed in some plants, as well as the effects of gama-radiation on growth inhibition and survival rate of the seedlings, suggest that doses between 30 and 50 Krad could be useful to obtain genetic variability in adapted cultivars of this species.

Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer

International Nuclear Information System (INIS)

Brooks, Colin; Sheu, Tommy; Bridges, Kathleen; Mason, Kathy; Kuban, Deborah; Mathew, Paul; Meyn, Raymond

2012-01-01

Many prostate cancers demonstrate an increased expression of growth factor receptors such as vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) which have been correlated with increased resistance to radiotherapy and poor prognosis in other tumors. Therefore, response to radiation could potentially be improved by using inhibitors of these abnormally activated pathways. We have investigated the radiosensitizing effects of sunitinib, a potent, multi-tyrosine kinase inhibitor of the VEGFR and PDGFR receptors, on human prostate cancer cells. The radiosensitizing effects of sunitinib were assessed on human prostate cancer cell lines DU145, PC3 and LNCaP by clonogenic assay. Sunitinib’s ability to inhibit the activities of its key targets was determined by immunoblot analysis. The radiosensitizing effects of sunitinib in vivo were tested on human tumor xenografts growing in nude mice where response was assessed by tumor growth delay. Clonogenic survival curve assays for both DU145 and PC3 cells showed that the surviving fraction at 2 Gy was reduced from 0.70 and 0.52 in controls to 0.44 and 0.38, respectively, by a 24 hr pretreatment with 100 nM sunitinib. LNCaP cells were not radiosensitized by sunitinib. Dose dependent decreases in VEGFR and PDGFR activation were also observed following sunitinib in both DU145 and PC3 cells. We assessed the ability of sunitinib to radiosensitize PC3 xenograft tumors growing in the hind limb of nude mice. Sunitinib given concurrently with radiation did not prolong tumor growth delay. However, when animals were treated with sunitinib commencing the day after fractionated radiation was complete, tumor growth delay was enhanced compared to radiation alone. We conclude, based on the in vivo results, that sunitinib and radiation do not interact directly to radiosensitize the PC3 tumor cells in vivo as they did in vitro. The fact that tumor growth delay was enhanced when sunitinib was

Chromosomal radiosensitivity of prostate cancer patients

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McRobbie, M.L.; Riches, A.; Baxby, K.

2003-01-01

Full text: Radiosensitivity of peripheral blood lymphocytes from prostate cancer patients is being investigated using the G2 assay and the Cytokinesis Block Micronucleus(CBMN)assay. The G2 assay evaluates chromosomal damage caused by irradiating cells in the G2 phase of the cell cycle. The CBMN assay quantifies the post mitotic micronuclei, which are the expression of damage incurred during G0. An association between hypersensitivity to the chromosome damaging effects of ionising radiation and cancer predispostion has been demonstrated in a number of heritable conditions by using the aforementioned techniques. Recently, increased chromosomal radiosensitivity has been demonstrated in a significant proportion of patients with no obvious family history of malignancy. The aim of this study is to establish whether a group of prostatic carcinoma patients exists and if so whether there are any correlations between their G2 and G0 sensitivities. The study has shown there is no correlation between G2 and G0 sensitivity, confirming the general trend that individuals exhibiting chromosomal radiosensitivity are defective in only one mechanism and G2 and G0 sensitivity are largely independent. Current data indicates that there is an identifiable group of men within the prostate cancer population with increased chromosomal radiosensitivity. Using the G2 assay and the 90th percentile of the controls as a cut off point for sensitivity, no significant difference between the controls and the patient population has been found. However, using the CBMN assay and again the 90th percentile, approximately 11% of the control group are sensitive compared with approximately 40% of the carcinoma cases. The implications of this increased radiosensitivity are as yet unclear, but it is indicative of increased chromosomal fragility and therefore, possibly associated with malignant transformation. Hence, it may prove a useful tool in identifying individuals at increased risk of developing

Predictive radiosensitivity tests in human lymphocytes

International Nuclear Information System (INIS)

Di Giorgio, Marina; Vallerga, Maria B.; Taja, Maria R.; Sardi, M.; Busto, E.; Mairal, L.; Roth, B.; Menendez, P.; Bonomi, M.

2004-01-01

Individual radiosensitivity is an inherent characteristic, associated with an abnormally increased reaction to ionising radiation of both the whole body and cells derived from body tissues. Human population is not uniform in its radiation sensitivity. Radiosensitive sub-groups exist, which would suffer an increased incidence of both deterministic and stochastic effects. Clinical studies have suggested that a large part of the spectrum of normal tissue reaction may be due to differences in individual radiosensitivity. The identification of such sub-groups should be relevant for radiation therapy and radiation protection purposes. It is suggested that DNA repair mechanisms are involved. Consequently, the characterization of DNA repair in lymphocytes through cytokinesis blocked micronucleus (MN) and alkaline single-cell microgel electrophoresis (comet) assays could be a suitable approache to evaluate individual radiosensitivity in vitro. The aims of this study were: 1) To assess the in vitro radiosensitivity of peripheral blood lymphocytes from two groups of cancer patients (prospectively and retrospectively studied), using MN and comet assays, in comparison with the clinical radiation reaction and 2) To test the predictive potential of both techniques for the identification of radiosensitivity sub-groups. 38 cancer patients receiving radiation therapy were enrolled in this study. 19 patients were evaluated prior, mid-way and on completion of treatment (prospective group) and 19 patients were evaluated about 6-18 month after radiotherapy (retrospective group). Cytogenetic data from the prospective group were analysed using a mathematical model to evaluate the attenuation of the cytogenetic effect as a function of the time between a single exposure and blood sampling, estimating a cytogenetic recovery factor k. In the retrospective group, blood samples were irradiated in vitro with 0 (control) or 2 Gy and evaluated using MN test. Cytogenetic data were analysed

The effect of intra- and extracellular GSH depletion on aerobic radiosensitization in three cell lines

International Nuclear Information System (INIS)

Clark, E.P.; Epp, E.R.; Morse-Gaudio, M.; Biaglow, J.E.

1985-01-01

The effect of changes in the intra- and extracellular glutathione (GSH) concentrations on aerobic radiosensitization was studied in thee cell lines: CHO, V79 and A549. Intracellular GSH was metabolically depleted after the inhibition of GSH synthesis by buthionine sulfoximine (BSO) treatment of attached cell cultures. Extracellular GSH was controlled through the replacement of growth medium with a thiol-free salt solution and, where desired, by the exogenous addition of GSH. Each of the cell lines examined exhibited an enhanced aerobic radioresponse when the intracellular GSH was extensively depleted (GSH < 5% of control after 1.0 mM BSO/24 hr treatment) and the extracellular GSH concentration was zero. However, this enhanced radiosensitivity was eliminated by the addition of exogenous GSH, albeit at a high concentration (5 mM). Most interesting and as yet unexplained is the observation that GSH appears to affect restoration of the control radioresponse without increasing the intracellular GSH concentration

Comparison of the radiosensitivity of three goldfish cell lines using short term endpoints

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Mitani, H. (Tokyo Univ. (Japan). Faculty of Science)

1984-06-01

The induction and rejoining of DNA strand breaks after ..gamma..-irradiation in three goldfish (Carassius auratus) cell lines with different sensitivities to the lethal effect of ..gamma..-rays has been studied by the DNA strand separation method using hydroxylapatite chromatography. The induction and rejoining of DNA strand breaks was similar in all cell lines. There was also little difference in the degree of inhibition of DNA synthesis immediately after irradiation. However, the rank orders of the durations of division delay and the radiosensitivities of the three cell lines were the same.

Expression of p210 BCR/ABl increases hematopoietic progenitor cell radiosensitivity

International Nuclear Information System (INIS)

Santucci, M.A.; Anklesaria, P.; Das, I.J.; Sakakeeny, M.A.; FitzGerald, T.J.; Greenberger, J.S.; Laneuville, P.

1993-01-01

The cytogenetic finding of the Ph1+ chromosome and its molecular biologic marker bcr/abl gene rearrangement in cells from patients with chronic myeloid leukemia are associated with a proliferative advantage of the Ph1+ clone in vivo. Although the transition to the acute terminal phase or blastic crisis is often associated with additional cytogenetic abnormalities, the molecular events which correlate the initial cytogenetic lesion with the terminal phase are poorly understood. Defective cellular DNA repair capacity is often associated with chromosomal instability, increased mutation frequency, and biologic alterations. The authors tested whether the protein product of the bcr/abl translocation (p210) could alter DNA repair after gamma-irradiation of murine cell lines expressing the bcr/abl cDNA. The 32D cl 3 parent, 32D cl 3 pYN (containing the control vector plasmid) and each of two sources of 32D cl 3 cells expressing p210 cDNA (32D-PC1 cell line and 32D-LG7 subclone) showed a D 0 of 1.62, 1.57, 1.16, and 1.27 Gy, respectively. Thus, expression of the p210 product induced a significant increase in radiosensitivity at the clinically relevant radiation therapy dose-rate. The increased radiosensitivity of p210-expressing cells persisted if cells were held before plating in a density-inhibited state for 8 hr after gamma-irradiation, indicating little effect on the repair of potentially lethal gamma-irradiation damage. The IL-3 dependent parent 32D cl 3 cells demonstrated programmed cell death in the absence of growth factor or following gamma-irradiation to 200 cGy. Expression of p210 cDNA in the 32D-PC1 and 32D-LG7 subclones abrogated IL-3 requirement of these cell lines and inhibited gamma-irradiation induced programmed cell death. These data suggest a role for p210 in amplifying gamma-irradiation DNA damage or broadly inhibiting DNA repair, conditions that may stimulate further cytogenetic alterations in hematopoietic cells. 43 refs., 3 figs., 1 tab

Activating and inhibiting connections in biological network dynamics

Directory of Open Access Journals (Sweden)

Knight Rob

2008-12-01

Full Text Available Abstract Background Many studies of biochemical networks have analyzed network topology. Such work has suggested that specific types of network wiring may increase network robustness and therefore confer a selective advantage. However, knowledge of network topology does not allow one to predict network dynamical behavior – for example, whether deleting a protein from a signaling network would maintain the network's dynamical behavior, or induce oscillations or chaos. Results Here we report that the balance between activating and inhibiting connections is important in determining whether network dynamics reach steady state or oscillate. We use a simple dynamical model of a network of interacting genes or proteins. Using the model, we study random networks, networks selected for robust dynamics, and examples of biological network topologies. The fraction of activating connections influences whether the network dynamics reach steady state or oscillate. Conclusion The activating fraction may predispose a network to oscillate or reach steady state, and neutral evolution or selection of this parameter may affect the behavior of biological networks. This principle may unify the dynamics of a wide range of cellular networks. Reviewers Reviewed by Sergei Maslov, Eugene Koonin, and Yu (Brandon Xia (nominated by Mark Gerstein. For the full reviews, please go to the Reviewers' comments section.

Immunosuppression by hypoxic cell radiosensitizers: a phenomenon of potential clinical importance

International Nuclear Information System (INIS)

Rockwell, S.; Kapp, D.S.

1982-01-01

The nitroimidazoles metronidazole, misonidazol, and desmethyl misonidazole are currently undergoing clinical trials as possible adjuncts to radiotherapy. Ongoing clinical trials are evaluating the effectiveness of these agents and also documenting the pharmacokinetics and toxicities of radiosensitizing doses of these drugs in man. A variety of toxic effects have been noted in man, including anorexia, nausea and vomiting, peripheral neuropathy, central nervous system symptoms, ototoxicity, allergy, and fear. Laboratory studies have also suggested that these agents have potential to be mutagenic, carcinogenic, and teratogenic. In the editorial presented, the author attempts to draw attention to an additional toxic effect of nitroimidazoles - the inhibition of cell-mediated immune responses

Re-evaluation of in vitro radiosensitivity of human fibroblasts of different genetic origins

Energy Technology Data Exchange (ETDEWEB)

Deschavanne, P.J.; Debieu, D.; Malaise, E.P.; Fertil, B.

1986-08-01

Statistical analysis of the radiosensitivity of 204 survival curves of non-transformed human fibroblast cell strains of different genetic origins was made using the multi-target one-hit model (characterized by parameters eta and D/sub 0/), the surviving fraction for a 2 Gy dose (S/sub 2/) and the mean inactivation dose (D-bar). D-bar is found to be the parameter for characterization of anomalous radiosensitivity linked to a genetic disorder and discrimination between groups of cell strains of differing radiosensitivity. It allows the description of a range of 'normal' radiosensitivity for control fibroblasts and classification of genetic disorders as a function of their mean radiosensitivity expressed in terms of D-bar. Nine groups of cell strains appear to exhibit radiosensitivity differing significantly from the controls: seven groups are hypersensitive (ataxia-telengiectasia homozygotes and heterozygotes, Cockayne's syndrome, Gardner's syndrome, 5-oxoprolinuria homozygotes and heterozygotes, Fanconi's anaemia) and two groups are more radioresistant (fibroblasts from retinoblastoma patients and individuals with chromosome 13 anomalies). Since the coupled parameter eta and D/sub 0/ failed to discriminate between the radiosensitivity of the different genetic groups, the use of D-bar to make an intercomparison of intrinsic radiosensitivity of non-transformed human fibroblasts is recommended. (U.K.).

Re-evaluation of in vitro radiosensitivity of human fibroblasts of different genetic origins

International Nuclear Information System (INIS)

Deschavanne, P.J.; Debieu, D.; Malaise, E.P.; Fertil, B.

1986-01-01

Statistical analysis of the radiosensitivity of 204 survival curves of non-transformed human fibroblast cell strains of different genetic origins was made using the multi-target one-hit model (characterized by parameters eta and D 0 ), the surviving fraction for a 2 Gy dose (S 2 ) and the mean inactivation dose (D-bar). D-bar is found to be the parameter for characterization of anomalous radiosensitivity linked to a genetic disorder and discrimination between groups of cell strains of differing radiosensitivity. It allows the description of a range of 'normal' radiosensitivity for control fibroblasts and classification of genetic disorders as a function of their mean radiosensitivity expressed in terms of D-bar. Nine groups of cell strains appear to exhibit radiosensitivity differing significantly from the controls: seven groups are hypersensitive (ataxia-telengiectasia homozygotes and heterozygotes, Cockayne's syndrome, Gardner's syndrome, 5-oxoprolinuria homozygotes and heterozygotes, Fanconi's anaemia) and two groups are more radioresistant (fibroblasts from retinoblastoma patients and individuals with chromosome 13 anomalies). Since the coupled parameter eta and D 0 failed to discriminate between the radiosensitivity of the different genetic groups, the use of D-bar to make an intercomparison of intrinsic radiosensitivity of non-transformed human fibroblasts is recommended. (U.K.)

Enhanced intrinsic radiosensitivity after treatment with stereotactic radiosurgery for an acoustic neuroma

International Nuclear Information System (INIS)

Adams, Gerard; Martin, Olga A.; Roos, Daniel E.; Lobachevsky, Pavel N.; Potter, Andrew E.; Zacest, Andrew C.; Bezak, Eva; Bonner, William M.; Martin, Roger F.; Leong, Trevor

2012-01-01

Enhanced radiosensitivity is an uncommon phenomenon attributable to deficient DNA repair after radiotherapy which can be assessed with the γ-H2AX assay. Reports of radiosensitivity after stereotactic radiosurgery (SRS) are uncommon. We describe a case where the clinical, radiological and laboratory findings suggest enhanced radiosensitivity after SRS for an acoustic neuroma.

Effect of postirradiation anoxia on radiosensitivity of lymphocytes

International Nuclear Information System (INIS)

Schrek, R.

1976-01-01

Radiosensitivity was measured by viable-lymphocyte counts and by uridine uptake. The viability of the lymphocytes was based on morphologic characteristics visualized by phase contrast microscopy of the cells in a special slide chamber. Low doses of x rays (10 to 1000 R) and incubation at 37 0 C killed lymphocytes in interphase with the production of pyknotic nuclei (nuclear death), and large doses (6000 R) produced nuclei with clear nucleoplasm (cytoplasmic death). Nuclear, but not cytoplasmic, death was inhibited by incubation of the irradiated cells at 27 0 C. Postirradiation anoxia had no effect on development of the nuclear and cytoplasmic death of lymphocytes irradiated with 100 to 6000 R. Anoxia had no effect on the early response of lymphocytes to phytohemagglutinin (PHA) [increase in ribonucleic acid (RNA) and protein synthesis] but inhibited completely the late effects [increase in deoxyribonucleic acid (DNA) synthesis and transformation into lymphoblastoid cells]. The PHA caused relative radioresistance of lymphocytes under aerobic conditions and, to a lesser extent, under anaerobic conditions. The slight radioresistance induced by PHA in anoxic lymphocytes apparently did not depend on an increase in DNA synthesis or on the transformation to lymphoblastoid cells

Radiosensitizing efficiency of sodium glycididazole on V79 cells in vitro

International Nuclear Information System (INIS)

Zheng Xiulong; Gao Jianguo; Zhang Hong; Zhu Qin; Meng Xiangshun; Zhao Fang

1995-01-01

Radiosensitizing effect of sodium glycididazole (SGDD) on the hypoxic V 79 cells by standard in vitro colon formation method has been further studied. The results showed its toxicity was low. Its ID 50 in cells under hypoxic and aerobic condition were 23.5 and 35.7 mmol/L respectively. These indicated that SGDD showed more toxicity under hypoxic than under aerobic condition (p 1.6 was 0.48 mmol/L. Its maximum SER was 2.3 at 1.38 mmol/L. Comparisons of radiosensitizing effect of SGDD versus MISO and its mother compound (metronidazole) under the same experimental condition, SER for SGDD, MISO and metronidazole were 1.75, 1.53 and 1.07 at 0.3 mmol/L respectively. SGDD showed more radiosensitizing efficiency than MISO and much greater than metronidazole. This study further confirms our previous results i.e. SGDD is a hypoxic radiosensitizer with low toxic, high efficiency and selectively enhances the radiosensitivity of hypoxic cells for tumor radiotherapy

Evaluation of 2-amino-5-nitrothiazole as a hypoxic cell radiosensitizer

International Nuclear Information System (INIS)

Rockwell, S.; Mroczkowski, Z.; Rupp, W.D.

1982-01-01

The nitroheterocyclic compound 2-amino-5-nitrothiazole (ANT) was evaluated as a hypoxic radiosensitizer. Experiments with bacteria showed that this agent was similar to misonidozole in radiosensitizing activity, but was less cytotoxic and less mutagenic than misonidazole. Experiments with EMT6 tumor cells in culture showed ANT to be an effective hypoxic radiosensitizer, although slightly less active than misonidazole, and to be less cytotoxic than misonidazole. ANT was more toxic to mice than misonidazole and produced a spectrum of symptoms, including hyperactivity and agitation, different from those of misonidazole. The toxicities of ANT and misonidazole were additive. The maximum levels of ANT achieveable in the tumors after ip injection of nontoxic doses of drug were low ( -4 M) and the radiosensitization obtainable with the drug in vivo was inferior to that obtainable with misonidazole. These findings suggest that nitrothiazoles might be an interesting class of nitroheterocyclic radiosensitizers, but that molecules with increased solubility and improved pharmacokinetics would be necessary for efficacy in vivo

Determining and predictive factors for the tumor radiosensitivity

International Nuclear Information System (INIS)

Hennequin, Ch.; Quero, L.; Hennequin, Ch.; Quero, L.; Favaudon, V.

2008-01-01

Many predictive factors of tumor radiosensitivity have been described. Number of clonogenic cells, proliferation rate, hypoxia and intrinsic radiosensitivity are usually considered as the main parameters of tumor control. Intrinsic radiosensitivity is correlated in a first approach to the ability of the cell to detect and repair DNA damages, and so integrity of the different pathways involved in this function: P.A.R.P.-1, X.R.C.C.1, A.T.M., p 53, M.R.N. complex or B.R.C.A.1. Genetic polymorphisms of some of these genes, found in normal lymphocytes, have been correlated to late toxicity of normal tissues. But, in tumors, because of the difficulty to obtain samplings and heterogeneity, accurate molecular analysis is not possible in many cases, and no valuable test of radiosensitivity exist at this moment. For example, T.P. 53 gene has been evaluated in many studies and results regarding its potential as a predictive factor of tumor sensitivity are conflicting. Surviving fraction at 2 Gy (S.F.2) allowed a global evaluation of sensitivity, but the obtention of this parameter often takes a long time and failed in 20 to 40%. Evaluation of double-strand break repair capacity by immuno chemistry quantification of phosphorylated forms of A.T.M., H.2 A.X. or M.R.E.11 is an interesting topic. However, discovery of tumor stem cells in a number of epithelial tumors could revolutionize the understanding of radiosensitivity. Combination of genomic and functional techniques are probably essential to better predict this parameter. (authors)

Effects of binding metronidazole to a copper-acetate compound on radiosensitizer properties

International Nuclear Information System (INIS)

Negron, Ana C. Valderrama; Silva, Denise de Oliveira; Cruz, Aurea S.

2009-01-01

Copper compounds exhibit interesting biological properties. Nitroimidazoles show radiosensitizer properties for radiotherapy tumor treatment. In the present work, the effect of binding metronidazole (1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole = MTZ) to copper-acetate on the radiosensitizer properties has been investigated. A compound of copper-acetate-MTZ was prepared and characterized. The experiments were carried out by gamma-irradiation of Hep2 (human larynx cancer) cells under hypoxic conditions. The radiation doses for 50% cell survival in the presence of radiosensitizer were about 8.2 Gy for CuAcMTZ or free MTZ. The effect of binding metronidazole to copper acetate on radiosensitizer properties is mainly related to the radiosensitizer process which involves two events for CuAcMTZ in contrast to one event observed for the MTZ free drug. (author)

On the Path to Seeking Novel Radiosensitizers

International Nuclear Information System (INIS)

Katz, David; Ito, Emma; Liu Feifei

2009-01-01

Radiation therapy is a highly effective cancer treatment modality, and extensive investigations have been undertaken over the years to augment its efficacy in the clinic. This review summarizes the current understanding of the biologic bases underpinning many of the clinically used radiosensitizers. In addition, this review illustrates how the advent of innovative, high-throughput technologies with integration of different disciplines could be harnessed for an expeditious discovery process for novel radiosensitizers, providing an exciting future for such pursuits in radiation biology and oncology

Radiosensitivity of Bombyx mori embryos and its modification by thermal shock

International Nuclear Information System (INIS)

Agaev, F.A.; Zakrzhevskaya, D.T.; Yusifov, N.I.; Gaziev, A.I.; AN Azerbajdzhanskoj SSR, Baku

1991-01-01

Radiosensitivity of Bombyx mori embryos on days 3-4 of their development is more than 10 times higher than that of 7-9 day embryos. The rate of DNA synthesis in the embryos correlates with their radiosensitivity. Heat treatment (40 deg C, 60 min) of embryos just before γ-irradiation increases their radioresistance (DMF=+1.6), whereas such a treatment immediately after irradiation reduces the survival rate of embryos as compared to the controls irradiated without heat treatment (DMA=-1.5). The radiomodifying effect of the thermal shock on the Bombyx mori embryos is the same with exposure at both the radioresistant and the radiosensitive stage of their development. However, it is more pronounced at the radiosensitive stage

Preliminary screening of the radiosensitivity-associated genes on colorectal cancer

International Nuclear Information System (INIS)

Xing Chungen; Yang Xiaodong; Zhou Liying; Wu Yongyou; Jiang Yinfen; Dai Hong; Lv Xiaodong; Gong Wei

2007-01-01

The screening of radiosensitive genes of human colorectal cancer was made by gene chip. Two human colorectal cancer cell lines LOVO and SW480 were cultivated and the total RNA was extracted from at least lxl0 7 cells. Then the gene expression profiling was performed by HG-U133 Plus 2.0 Array and the difference of gene expression has been analyzed. The results shows that there are 16882 genes expressed in LOVO cell and 17114 genes expressed in SW480 cell through gene expression profiling. It has been found that the genes with 2-fold expressed differentially include 908 genes up-regulated and 1312 genes down-regulated. The same genes, such as Fas and NFkB which is up-regulated, Caspas6, and RAD21 which is down-regulated, have been proved to be related to radiosensitivity. The genes with high expression level including CEACAM5, THBS1, SERPINE2, ARL7, HPGD in LOVO cell may also be related to the radiosensitivity. And the genes with high expression level including SCD, NQ01, LYZ, KRT20, ATP1B1 in SW480 cell may be related to the radioresistance of human colorectal cancer. It could be concluded that the radiosensitivity of colorectal cancer can be reflected from gene and protein expression level. And gene expression profiling is a fast and sensitive tool to predict the radiosensitivity and screen radiosensitive genes of colorectal cancer. (authors)

Genetic factors affecting radiosensitivity and cancer predisposition: application of a continuous low dose-rate irradiation colony formation assay to select radiosensitive retinoblastoma family members for correction with a cDNA library

International Nuclear Information System (INIS)

Wilson, P.F.; Nagasawa, H.; Bedford, J.S.; Little, J.B.

2003-01-01

Full text: The aim of this study is to identify new or undescribed functions of radiosensitivity and genomic instability genes using a continuous low dose-rate colony formation assay. This assay expands on the standard colony formation assay, whereby colony formation ability (retention of proliferative capacity) is measured during continuous low dose-rate irradiation rather than 10-14 days following the completion of such exposures. This approach has previously employed by the Bedford laboratory to identify a Prkdc (DNA-PKcs) mutant of CHO cells, irs-20. In this study we examine the growth response of fibroblasts derived from recently identified radiosensitive retinoblastoma family members, both affected probands and their unaffected parents, and various apparently normal fibroblast lines obtained from the NIGMS Human Genetic Cell Repository (Coriell Medical Institute, Camden, NJ). Colony formation was assayed by plating single cells, exposing them at 37 deg C to continuous Cs-137 gamma irradiation at dose rates of 0.5-8.5 cGy/h, and scoring survivors as colonies with >100 viable cells. The retinoblastoma family members display severely limited growth (survival less than 10E-3) at dose rates greater than 2-2.5 cGy/h, while the apparently normal cell lines do not display such inhibited growth until 6-7 cGy/h. Two of the retinoblastoma family cell lines, MF-6F and MF-15F (both unaffected but radiosensitive parents), were selected as targets of transfection with a viral cDNA library (ViraPort human cDNA library, Stratagene Cloning Systems, La Jolla, CA) and subjected to a ∼3 cGy/h selection dose rate, where uncorrected survival relative to normal cells is lower by a factor of 50-150. Colonies recovered will provide valuable information regarding the genetic nature of their radiosensitivity (possibly involving chromosome stability, DNA repair, and/or cell cycle regulatory pathways), that may influence risks for cancer and heritable effects for a previously

Radiosensitizers in cervical cancer. Cisplatin and beyond

International Nuclear Information System (INIS)

Candelaria, Myrna; Garcia-Arias, Alicia; Cetina, Lucely; Dueñas-Gonzalez, Alfonso

2006-01-01

Cervical cancer continues to be a significant health burden worldwide. Globally, the majority of cancers are locally advanced at diagnosis; hence, radiation remains the most frequently used therapeutical modality. Currently, the value of adding cisplatin or cisplatin-based chemotherapy to radiation for treatment of locally advanced cervical cancer is strongly supported by randomized studies and meta-analyses. Nevertheless, despite these significant achievements, therapeutic results are far from optimal; thus, novel therapies need to be assayed. A strategy currently being investigated is the use of newer radiosensitizers alone or in combination with platinum compounds. In the present work, we present preclinical information on known and newer cytotoxic agents as radiosensitizers on cervical cancer models, as well as the clinical information emanating from early phase trials that incorporate them to the cervical cancer management. In addition, we present the perspectives on the combined approach of radiation therapy and molecular target-based drugs with proven radiosensitizing capacity

Clinical and Functional Assays of Radiosensitivity and Radiation-Induced Second Cancer

Directory of Open Access Journals (Sweden)

Mohammad Habash

2017-10-01

Full Text Available Whilst the near instantaneous physical interaction of radiation energy with living cells leaves little opportunity for inter-individual variation in the initial yield of DNA damage, all the downstream processes in how damage is recognized, repaired or resolved and therefore the ultimate fate of cells can vary across the population. In the clinic, this variability is observed most readily as rare extreme sensitivity to radiotherapy with acute and late tissue toxic reactions. Though some radiosensitivity can be anticipated in individuals with known genetic predispositions manifest through recognizable phenotypes and clinical presentations, others exhibit unexpected radiosensitivity which nevertheless has an underlying genetic cause. Currently, functional assays for cellular radiosensitivity represent a strategy to identify patients with potential radiosensitivity before radiotherapy begins, without needing to discover or evaluate the impact of the precise genetic determinants. Yet, some of the genes responsible for extreme radiosensitivity would also be expected to confer susceptibility to radiation-induced cancer, which can be considered another late adverse event associated with radiotherapy. Here, the utility of functional assays of radiosensitivity for identifying individuals susceptible to radiotherapy-induced second cancer is discussed, considering both the common mechanisms and important differences between stochastic radiation carcinogenesis and the range of deterministic acute and late toxic effects of radiotherapy.

Novel radiosensitizers for locally advanced epithelial tumors: inhibition of the PI3K/Akt survival pathway in tumor cells and in tumor-associated endothelial cells as a novel treatment strategy?

International Nuclear Information System (INIS)

Riesterer, Oliver; Tenzer, Angela; Zingg, Daniel; Hofstetter, Barbara; Vuong, Van; Pruschy, Martin; Bodis, Stephan

2004-01-01

In locally advanced epithelial malignancies, local control can be achieved with high doses of radiotherapy (RT). Concurrent chemoradiotherapy can improve tumor control in selected solid epithelial adult tumors; however, treatment-related toxicity is of major concern and the therapeutic window often small. Therefore, novel pharmacologic radiosensitizers with a tumor-specific molecular target and a broad therapeutic window are attractive. Because of clonal heterogeneity and the high mutation rate of these tumors, combined treatment with single molecular target radiosensitizers and RT are unlikely to improve sustained local tumor control substantially. Therefore, radiosensitizers modulating entire tumor cell survival pathways in epithelial tumors are of potential clinical use. We discuss the preclinical efficacy and the mechanism of three different, potential radiosensitizers targeting the PTEN/PI3K/Akt survival pathway. These compounds were initially thought to act as single-target agents against growth factor receptors (PKI 166 and PTK 787) or protein kinase C isoforms (PKC 412). We describe an additional target for these compounds. PKI 166 (an epidermal growth factor [EGF] receptor inhibitor) and PKC 412, target the PTEN/PI3K/Akt pathway mainly in tumor cells, and PTK 787 (a vascular endothelial growth factor [VEGF] receptor inhibitor) in endothelial cells. Even for these broader range molecular radiosensitizers, the benefit could be restricted to human epithelial tumor cell clones with a distinct molecular profile. Therefore, these potential radiosensitizers have to be carefully tested in specific model systems before introduction in early clinical trials

Resveratrol-Induced Apoptosis and Increased Radiosensitivity in CD133-Positive Cells Derived From Atypical Teratoid/Rhabdoid Tumor

International Nuclear Information System (INIS)

Kao, C.-L.; Huang, P.-I; Tsai, P.-H.; Tsai, M.-L.; Lo, J.-F.; Lee, Y.-Y.; Chen, Y.-J.; Chen, Y.-W.; Chiou, S.-H.

2009-01-01

Purpose: CD133 has recently been proposed as a marker for cancer stem-like cells (CSC) in brain tumors. The aim of the present study was to investigate the possible role of resveratrol (RV) in radiosensitivity of CD133-positive/-negative cells derived from atypical teratoid/rhabdoid tumors (AT/RT-CD133 +/- ). Materials and Methods: AT/RT-CD133 +/- were isolated and characterized by flow cytometry and quantitative real-time reverse transcription-polymerase chain reaction, and then treated with RV at different doses. Migratory ability, colony formation, apoptotic activity, and xenotransplantation were assessed for RV alone, ionizing radiation (IR) alone, and IR with RV conditions. Results: AT/RT-CD133 + displayed enhanced self-renewal and highly coexpressed 'stem cell' genes and drug-resistant genes, in addition to showing significant resistance to chemotherapeutic agents and radiotherapy as compared with CD133 - cells. After treatment with 200 μM RV, the in vitro proliferation rates and in vivo tumor restoration abilities of ATRT-CD133 + were dramatically inhibited. Importantly, treatment with 150 μM RV can effectively inhibit the expression of drug-resistant genes in AT/RT-CD133 + , and further facilitate to the differentiation of CD133 + into CD133 - . In addition, treatment with 150 μM RV could significantly enhance the radiosensitivity and IR-mediated apoptosis in RV-treated ATRT-CD133 +/- . Kaplan-Meier survival analysis indicated that the mean survival rate of mice with ATRT-CD133 + that were treated with IR could be significantly improved when IR was combined with 150 μM RV treatment. Conclusions: AT/RT-CD133 + exhibit CSC properties and are refractory to IR treatment. Our results suggest that RV treatment plays crucial roles in antiproliferative, proapoptotic, and radiosensitizing effects on treated-CD133 +/- ; RV may therefore improve the clinical treatment of AT/RT.

Radiosensitivities of cultured barley of different type (Hordeum vulgare)

International Nuclear Information System (INIS)

Wang Cailian; Shen Mei; Xu Gang; Zhao Kongnan

1990-01-01

The dormant seeds (with 13% moisture) of 47 barley varieties were irradiated with various doses (0-40 krad) of 137 Cs γ-rays. The radiosensitivities of naked barley was significantly higher than that of hulled barley. The sensitive coefficients of seedling height were 0.04945 and 0.03667 for naked barley and hulled barley, respectively. The radiosensitivity of four-row naked barley was significantly higher than that of two-row hulled barley and six-row hulled barley. 47 varieties studied could be divided into five types with different radiosensitivities, i.e. extreme resistant, resistant, intermediate, sensitive and extreme sensitive. It was also found that the dose-effect curves of cell nucleus volume had a peal at 30 krad

The molecular basis of radiosensitivity

International Nuclear Information System (INIS)

McMillan, T.J.

1989-01-01

This paper considers how DNA damage induced by ionising radiation is processed within the cell. The current view of radiobiology is discussed. The author explains the molecular processes that underlie the differences in radiosensitivity

Formation of radical anions of radiosensitizers and related model compounds via electrospray ionization

DEFF Research Database (Denmark)

Feketeová, Linda; Albright, Abigail L; Sørensen, Brita Singers

2014-01-01

Radiosensitizers are used in radiotherapy to enhance tumour control of radioresistant hypoxic tumours. While the detailed mechanism of radiosensitization is still unknown, the formation of radical anions is believed to be a key step. Thus understanding the ionization reactions of radiosensitizers......, misonidazole and related compounds using a hybrid linear ion trap – Fourier Transform Ion Cyclotron Resonance mass spectrometer (Finnigan-LTQ-FT). A key finding is that negative electrospray ionization of these radiosensitizers leads to the formation of radical anions, allowing their fragmentation reactions...

Enterolactone: A novel radiosensitizer for human breast cancer cell lines through impaired DNA repair and increased apoptosis

International Nuclear Information System (INIS)

Bigdeli, Bahareh; Goliaei, Bahram; Masoudi-Khoram, Nastaran; Jooyan, Najmeh; Nikoofar, Alireza; Rouhani, Maryam; Haghparast, Abbas; Mamashli, Fatemeh

2016-01-01

Introduction: Radiotherapy is a potent treatment against breast cancer, which is the most commonly diagnosed cancer among women. However, the emergence of radioresistance due to increased DNA repair leads to radiotherapeutic failure. Applying polyphenols combined with radiation is a more promising method leading to better survival. Enterolactone, a phytoestrogenic polyphenol, has been reported to inhibit an important radioresistance signaling pathway, therefore we conjectured that enterolactone could enhance radiosensitivity in breast cancer. To assess this hypothesis, radiation response of enterolactone treated MDA-MB-231 and T47D cell lines and corresponding cellular mechanisms were investigated. Methods: Cytotoxicity of enterolactone was measured via MTT assay. Cells were treated with enterolactone before X-irradiation, and clonogenic assay was used to evaluate radiosensitivity. Cell cycle distribution and apoptosis were measured by flow cytometric analysis. In addition, DNA damages and corresponding repair, chromosomal damages, and aberrations were assessed by comet, micronucleus, and cytogenetic assays, respectively. Results: Enterolactone decreased the viability of cells in a concentration- and time dependent manner. Enterolactone significantly enhanced radiosensitivity of cells by abrogating G2/M arrest, impairing DNA repair, and increasing radiation-induced apoptosis. Furthermore, increased chromosomal damages and aberrations were detected in cells treated with enterolactone combined with X-rays than X-ray alone. These effects were more prominent in T47D than MDA-MB-231 cells. Discussion: To our knowledge, this is the first report that enterolactone is a novel radiosensitizer for breast cancer irrespective of estrogen receptor status. Authors propose enterolactone as a candidate for combined therapy to decrease the radiation dose delivered to patients and subsequent side effects. - Highlights: • Enterolactone is proposed to be a novel radiosensitizer for

Enterolactone: A novel radiosensitizer for human breast cancer cell lines through impaired DNA repair and increased apoptosis

Energy Technology Data Exchange (ETDEWEB)

Bigdeli, Bahareh, E-mail: bhr.bigdeli@ut.ac.ir [Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran (Iran, Islamic Republic of); Goliaei, Bahram, E-mail: goliaei@ut.ac.ir [Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran (Iran, Islamic Republic of); Masoudi-Khoram, Nastaran, E-mail: n.masoudi@alumni.ut.ac.ir [Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran (Iran, Islamic Republic of); Jooyan, Najmeh, E-mail: n.jooyan@ut.ac.ir [Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran (Iran, Islamic Republic of); Nikoofar, Alireza, E-mail: nikoofar@iums.ac.ir [Department of Radiotherapy, Iran University of Medical Sciences (IUMS), Shahid Hemmat Highway, Tehran (Iran, Islamic Republic of); Rouhani, Maryam, E-mail: rouhani@iasbs.ac.ir [Department of Biological Sciences, Institute for Advanced Studies in Basic Sciences (IASBS), Prof. Yousef Sobouti Blvd., Gava Zang, Zanjan (Iran, Islamic Republic of); Haghparast, Abbas, E-mail: Haghparast@sbmu.ac.ir [Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Daneshjo St., Evin, Tehran (Iran, Islamic Republic of); Mamashli, Fatemeh, E-mail: mamashli@ut.ac.ir [Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, 16th Azar St., Enghelab Sq., Tehran (Iran, Islamic Republic of)

2016-12-15

Introduction: Radiotherapy is a potent treatment against breast cancer, which is the most commonly diagnosed cancer among women. However, the emergence of radioresistance due to increased DNA repair leads to radiotherapeutic failure. Applying polyphenols combined with radiation is a more promising method leading to better survival. Enterolactone, a phytoestrogenic polyphenol, has been reported to inhibit an important radioresistance signaling pathway, therefore we conjectured that enterolactone could enhance radiosensitivity in breast cancer. To assess this hypothesis, radiation response of enterolactone treated MDA-MB-231 and T47D cell lines and corresponding cellular mechanisms were investigated. Methods: Cytotoxicity of enterolactone was measured via MTT assay. Cells were treated with enterolactone before X-irradiation, and clonogenic assay was used to evaluate radiosensitivity. Cell cycle distribution and apoptosis were measured by flow cytometric analysis. In addition, DNA damages and corresponding repair, chromosomal damages, and aberrations were assessed by comet, micronucleus, and cytogenetic assays, respectively. Results: Enterolactone decreased the viability of cells in a concentration- and time dependent manner. Enterolactone significantly enhanced radiosensitivity of cells by abrogating G2/M arrest, impairing DNA repair, and increasing radiation-induced apoptosis. Furthermore, increased chromosomal damages and aberrations were detected in cells treated with enterolactone combined with X-rays than X-ray alone. These effects were more prominent in T47D than MDA-MB-231 cells. Discussion: To our knowledge, this is the first report that enterolactone is a novel radiosensitizer for breast cancer irrespective of estrogen receptor status. Authors propose enterolactone as a candidate for combined therapy to decrease the radiation dose delivered to patients and subsequent side effects. - Highlights: • Enterolactone is proposed to be a novel radiosensitizer for

The development of genes associated with radiosensitivity of cervical cancer

International Nuclear Information System (INIS)

Li Hongyan; Chen Zhihua; He Guifang

2007-01-01

It has a good application prospect to predict effects of radiotherapy by examining radiosensitivity of patients with cervical cancers before their radiotherapy. Prediction of tumor cell radiosensitivity according to their level of gene expression and gene therapy to reverse radio-resistance prior to radiation on cervical cancers are heated researches on tumor therapy. The expression of some proliferation-related genes, apoptosis-related genes and hypoxia-related genes can inerease the radiosensitivity of cervical cancer. Microarray technology may have more direct applications to the study of biological pathway contributing to radiation resistance and may lead to development of alternative treatment modalities. (authors)

Control of a local neural network by feedforward and feedback inhibition

NARCIS (Netherlands)

Remme, M.W.H.; Wadman, W.J.

2004-01-01

The signal transfer of a neuronal network is shaped by the local interactions between the excitatory principal cells and the inhibitory interneurons. We investigated with a simple lumped model how feedforward and feedback inhibition in.uence the steady-state network signal transfer. We analyze how

Correlation between radiosensitivity of transplanted solid tumor and nutritive condition of host animal

Energy Technology Data Exchange (ETDEWEB)

Ando, K [Showa Univ., Tokyo (Japan). School of Medicine

1975-04-01

Studies on radiosensitivity of the transplanted tumor were carried out and the following results were obtained: 1. Radiosensitivity of the tumor ran parallel to the growth rate. 2. Malnutrition of the host after irradiation made the tumor radiosensitive, probably because the sublethally damaged tumor cell did not recover. 3. Mitotic index correlated well with radiosensitivity, and the low mitotic index caused by starvation made the tumor cell recover poorly. 4. The DNA synthetic rate measured by means of iodine labeled IUdR did not successfully correlate with the mitotic rate, presumably because of the role of thymidine pool size in this experiment. 5. The serum protein level possibly with the tumor growth, which modified the radiosensitivity. 6. Serum oxygen was difficult to interpret, however, it might be compensated by erythrocytosis in a starved condition.

Synergism between two helper cell subpopulations characterized by different radiosensitivity and nylon adherence

International Nuclear Information System (INIS)

Agarossi, G.; Mancini, C.; Doria, G.

1981-01-01

The present work extends our previous results on the radiosensitivity of the helper cell function. Two helper cell subpopulations, 1 radiosensitive and the other radioresistant, have been demonstrated in the spleen of mice at different times after priming with HRBC. The radiosensitive subpopulation increases with the increasing time interval between carrier-priming and irradiation. The 2 cell subpopulations have been further characterized by different nylon adherence properties: radioresistant helper cells adhere to nylon wool, whereas radiosensitive cells pass through. The 2 cell subpopulations were separated by x-irradiation and nylon wool filtration, and their helper activity was assessed separately or after recombination. The results favor the notion that 2 functionally independent helper T cells, as characterized by different radiosensitivity and nylon adherence, participate synergistically in the helper activity of primed spleen cells

Bacterial radiosensitivity to gamma and ultraviolet. Compositional dependence and repair mechanisms

International Nuclear Information System (INIS)

Saez Angulo, R. M.; Davila, C. A.

1974-01-01

The gamma and ultraviolet radiosensitivity of several species of bacteria has been determined its dependence on DNAs composition and repair processes has been studied. Base composition are evaluated by chromatography, DNA melting temperature and isopycnic sedimentation on CsCl gradient. Repair capacity of gamma -and UV- lesions has been studied in two bacterial strains with same DMA base composition. It is concluded that the postulated correlation between radiosensitivity and base composition can not be generalized, the enzymatic repair mechanisms being of determining on radiosensitivity. (Author) 248 refs

Inhibition of EGFR or IGF-1R signaling enhances radiation response in head and neck cancer models but concurrent inhibition has no added benefit

International Nuclear Information System (INIS)

Raju, Uma; Molkentine, David P; Valdecanas, David R; Deorukhkar, Amit; Mason, Kathryn A; Buchholz, Thomas A; Meyn, Raymond E; Ang, Kie-Kian; Skinner, Heath

2015-01-01

Interaction between the epidermal growth factor receptor (EGFR) and the insulin-like growth factor receptor (IGF-1R) has been well established in many cancer types. We investigated the effects of cetuximab (EGFR antibody) and IMC-A12 (IGF-1R antibody) on the response of head and neck squamous cell carcinoma (HNSCC) to radiation therapy (RT). The effects of cetuximab and IMC-A12 on cell viability and radiosensitivity were determined by clonogenic cell survival assay. Formation of nuclear γ-H2AX and 53BP1 foci was monitored by immunofluorescence. Alterations in target signaling were analyzed by Western blots. In vivo tumor growth delay assay was performed to determine the efficacy of triple therapy with IMC-A12, cetuximab, and RT. In vitro data showed that cetuximab differentially affected the survival and the radiosensitivity of HNSCC cells. Cetuximab suppressed DNA repair that was evident by the prolonged presence of nuclear γ-H2AX and 53BP1 foci. IMC-A12 did not have any effect on the cell survival. However, it increased the radiosensitivity of one of the cell lines. EGFR inhibition increased IGF-1R expression levels and also the association between EGFR and IGF-1R. Addition of IMC-A12 to cetuximab did not increase the radiosensitivity of these cells. Tumor xenografts exhibited enhanced response to RT in the presence of either cetuximab or IMC-A12. Concurrent treatment regimen failed to further enhance the tumor response to cetuximab and/or RT. Taken together our data suggest that concomitant inhibition of both EGFR and IGF-1R pathways did not yield additional therapeutic benefit in overcoming resistance to RT

Radiosensitization of mouse spermatogenic stem cells by Ro-07-0582

International Nuclear Information System (INIS)

Suzuki, N.; Withers, R.; Hunter, N.

1977-01-01

The hypoxic character of the spermatogenic stem cells of the mouse testis was investigated by measuring the effect on radiosensitivity of treatment with the hypoxic cell radiosensitizer, Ro-07-0582 or hyperbaric oxygen (30 psi). The D 0 values obtained were 181 (161-207) rad for irradiation alone, 140 (133-148) rad for irradiation after treatment with Ro-07-0582, and about 100 rad for irradiation in the presence of hyperbaric oxygen. Ro-07-0582 alone was slightly cytotoxic. The results demonstrate that mouse spermatogenic stem cells are radiosensitized by Ro-07-0582 or hyperbaric oxygen and are not as well oxygenated as other normal tissues

Study on ionizing radiosensitivity of respiratory deficiency yeast mutants

International Nuclear Information System (INIS)

Mao Shuhong; Chinese Academy of Sciences, Beijing; Jin Genming; Wei Zengquan; Xie Hongmei

2006-01-01

The radiosensitivity of respiratory deficiency yeast mutants has been studied in this work. The mutants which were screened from the yeasts after ionizing irradiation were irradiated with 12 C 6+ at different doses. Because of the great change in its mitochondria and mitochondrial DNA, the respiratory deficiency yeast mutants show radio-sensitivity at dose less than 1 Gy and radioresistance at doses higher than 1 Gy. (authors)

Analysis of the factors in determining radiosensitivity in mammalian cells by using radio-sensitive and -resistant clones isolated from HeLa S3 cells in vitro

International Nuclear Information System (INIS)

Nikaido, Osamu; Horikawa, Masakatsu

1976-01-01

The factors in determining radiosensitivity of cultured mammalian cells were analysed by using two clones each having different radiosensitivities. The radiosensitive clones were isolated from HeLa S3 cells by the N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-treatment, X-irradiation (200 R) and 5-bromodeoxyuridine (BUdR)-visible light method. On the other hand, the radioresistant clone was isolated by single X-irradiation (2000 R) from MNNG-treated HeLa S3 cell population. The radiosensitivities expressed in D sub(o) and D sub(q) values were 110 and 140 R in radiosensitive SM-1a clone and 180 and 230 R in radioresistant RM-1b clone respectively. The biological and biochemical characteristics of both clones such as the distribution of chromosome numbers, formation and rejoining of single strand breaks in DNA caused by X-irradiation, non-protein sulfhydryl (NPSH) and apparent total sulfhydryl (APSH) contents were measured. Among the characteristics analysed, different contents of NPSH in the cell were well correlated to their daiosensitivities among the original HeLa S3 cells, SM-1a and RM-1b clone. Additionally, it was found that the radioresistant L.P3 Co-3 cells isolated by Tsuboi et al. from the original mouse L.P3 cells by means of serial irradiation with 60 Co γ-rays have more abundant NPSH than the original L.P3 cells. From these results, it can be concluded that the amount of NPSH play the main role in determining radiosensitivity in cultured mammalian cells. (auth.)

The combination of olaparib and camptothecin for effective radiosensitization

International Nuclear Information System (INIS)

Miura, Katsutoshi; Sakata, Koh-ichi; Someya, Masanori; Matsumoto, Yoshihisa; Matsumoto, Hideki; Takahashi, Akihisa; Hareyama, Masato

2012-01-01

Poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme involved in the repair of radiation-induced single-strand DNA breaks. PARP inhibitors such as olaparib (KU-0059436, AZD-2281) enhance tumor sensitivity to radiation and to topoisomerase I inhibitors like camptothecin (CPT). Olaparib is an orally bioavailable inhibitor of PARP-1 and PARP-2 that has been tested in multiple clinical trials. The purpose of this study was to investigate the characteristics of the sensitizing effect of olaparib for radiation and CPT in order to support clinical application of this agent. DLD-1 cells (a human colorectal cancer cell line) and H1299 cells (a non-small cell lung cancer cell line) with differences of p53 gene status were used. The survival of these cells was determined by clonogenic assay after treatment with drugs and X-ray irradiation. The γH2AX focus formation assay was performed to examine the influence of olaparib on induction and repair of double-stranded DNA breaks after exposure to radiation or CPT. A radiosensitizing effect of olaparib was seen even at 0.01 μM. Its radiosensitizing effect after exposure for 2 h was similar to that after 24 h. H1299 cells with depletion or mutation of p53 were more radioresistant than H1299 cells with wild-type p53. However, similar enhancement of radiosensitization by olaparib was observed with all of the tested cell lines regardless of the p53 status. Olaparib also sensitized cells to CPT. This sensitizing effect was seen at low concentrations of olaparib such as 0.01 μM, and its sensitizing effect was the same at both 0.01 μM and 1 μM. The combination of olaparib and CPT had a stronger radiosensitizing effect. The results of the γH2AX focus assay corresponded with the clonogenic assay findings. Olaparib enhanced sensitivity to radiation and CPT at low concentrations and after relatively short exposure times such as 2 h. The radiosensitizing effect of olaprib was not dependent on the p53 status of tumor cells. These

Potential clinical impact of normal-tissue intrinsic radiosensitivity testing

International Nuclear Information System (INIS)

Bentzen, Soeren M.

1997-01-01

A critical appraisal is given of the possible benefit from a reliable pre-treatment knowledge of individual normal-tissue sensitivity to radiotherapy. The considerations are in part, but not exclusively, based on the recent experience with in vitro colony-forming assays of the surviving fraction at 2 Gy, the SF 2 . Three strategies are reviewed: (1) to screen for rare cases with extreme radiosensitivity, so-called over-reactors, and treat these with reduced total dose, (2) to identify the sensitive tail of the distribution of 'normal' radiosensitivities, refer these patients to other treatment, and to escalate the dose to the remaining patients, or (3) to individualize dose prescriptions based on individual radiosensitivity, i.e. treating to isoeffect rather than to a specific dose-fractionation schedule. It is shown that these strategies will have a small, if any, impact on routine radiotherapy. Screening for over-reactors is hampered by the low prevalence of these among otherwise un-selected patients that leads to a low positive predictive value of in vitro radiosensitivity assays. It is argued, that this problem may persist even if the noise on current assays could be reduced to (the unrealistic value of) zero, simply because of the large biological variation in SF 2 . Removing the sensitive tail of the patient population, will only have a minor effect on the dose that could be delivered to the remaining patients, because of the sigmoid shape of empirical dose-response relationships. Finally, individualizing dose prescriptions based exclusively on information from a normal-tissue radiosensitivity assay, leads to a nearly symmetrical distribution of dose-changes that would produce a very small gain, or even a loss, of tumor control probability if implemented in the clinic. From a theoretical point of view, other strategies could be devised and some of these are considered in this review. Right now the most promising clinical use of in vitro radiosensitivity

Radiosensitive effect of hypoxia-inducible factor 1α inhibitor YC-1 on hypoxic glioma SHG44 cell line

International Nuclear Information System (INIS)

Guo Xinwei; Lu Xueguan; Tong Liumei; Zong Tianzhou; Chen Liesong

2011-01-01

Objective: To investigate the radiosensitive effect of hypoxia-inducible factor 1α (HIF-1α) inhibitor YC-1 on hypoxic glioma SHG44 cell line and its related mechanism. Methods: Glioma SHG44 cell line was cultured in normoxic (20% O 2 ), continuous hypoxia (1% O 2 ) for 12 h and 24 h, continuous hypoxia plus YC-1 was performed for 12 h and 24 h, respectively. The expression of HIF-1α was assessed by Western blot. The radiosensitivity was evaluated by the survival curve, and the sublethal damage repair (SLDR) ability was measured by dose-fraction experiment. Results: HIF-1α protein levels of glioma SHG44 cells were significantly increased after hypoxic cultures for 12 h and 24 h than those of the corresponding cells cultured in normoxic, while the radiosensitivity was lower. The OER (oxygen-enhancement ratio) of SHG44 cells in hypoxia for 12 h and 24 h were 1.22 and 1.37, respectively. By the further statistical analysis it was found that SLDR ability of glioma SHG44 was increased at hypoxia, and when irradiation was carried one at the interval of 8, 10, 12 h it was statistically significant (P<0.05). HIF-1α protein levels of glioma SHG44 cells cultured in hypoxia plus YC-1 for 12 h and 24 h were decreased significantly compared to the corresponding cells cultured in hypoxia only, while the radiosensitivity was significantly increased. the EF (enhancement factor) of YC-1 for glioma SHG44 cells at hypoxia for 12 h and 24 h was 1.27. By the further statistical analysis it was also found that SLDR ability was decreased significantly for hypoxic SHG44 cells which was co-cultured with YC-1, and at the interval of 8, 10, 12 h irradiation was statistically significant (P<0.05). Conclusion: YC-1 can increase the radiosensitivity of hypoxic glioma SHG44 cell line, and its mechanism is related to SLDR inhibited by YC-1. (authors)

Influence of the 100% w/v perfluorooctyl bromide (PFOB) emulsion dose on tumour radiosensitivity

International Nuclear Information System (INIS)

Thomas, C.; Guichard, M.; Riess, J.

1991-01-01

The radiosensitizing effect of a 100% w/v emulsion of a fluuorocarbon PFOB, which carries 4 times more oxygen than Fluosol-DA 20% emulsion, was studied on two human tumour xenografts (HRT18 and HT29) and murine tumour EMT6. This effect was compared to that of carbogen alone. The fluorocrit (amount of fluorocarbon in the blood) and haematocrit remained unchanged from 7 to 65 min post-injection of the emulsion (8ml/kg). Significant tumour radiosensitization was obtained with relatively low amounts of 100% w/v concentrated emulsion of PFOB plus carbogen. Maximum radiosensitization occurs at low fluorocarbon dose of about 3g/kg. These results are comparable to those obtained with Fluosol-DA 20% or Therox emulsion. Since this radiosensitization occurs only at relatively low fluorocrit without haematocrit modification, the oxygen-carrying capacity of the fluorocarbon is not the only factor involved in radiosensitization of tumor cells, regardless of the effect of carbogen on radiosensitivity. (author)

Radiosensitization by hematocrit manipulation

International Nuclear Information System (INIS)

Hirst, D.G.; Hazlehurst, J.L.; Brown, J.M.

1985-01-01

The authors show that tumors in mice adapt to anemia in a rather complex manner. Radiosensitivity may be lower, higher or equal to normal depending on when the anemia is induced prior to irradiation. The authors study these changes in radiosensitivity which occur during a period of anemia followed by the restoration of the hematocrit. When mice were made anemic immediately before irradiation, their tumors were very resistant, but the resistance was lost over the following 24 hrs even though the anemia was maintained. If mice which had been anemic for 24 hrs were retransfused to normal levels with red blood cells immediately before irradiation, their tumors were considerably more sensitive than normal. As the interval between retransfusion and irradiation was increased, sensitization was rapidly lost so that by 24 hrs sensitivity was the same as that of control tumors. They attribute this loss of sensitization to rapid tumor growth in response to a restored oxygen supply so that new hypoxic cells are created. The implications of this for the treatment of the anemic patient are discussed

Release from the Crabtree effect by hypoxic cell radiosensitizers

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Mustea, I.; Bara, A.

1979-01-01

The Crabtree effect can be observed when the 0 2 consumption of tumour cells or of mammalian cells grown in culture is measured in physiological medium containing glucose. The effect of 2 hypoxic cell radiosensitizers, misonidazole and NDPP, on the 0 2 consumption of Ehrlich ascites tumour cells was compared in media with and without glucose. A stimulatory effect on 0 2 consumption was found for 5-20 mM misonidazole as well as for 0.5mM NDPP, both in media containing 10 -2 M glucose. Thus glucose induced a Crabtree effect in Ehrlich tumour cells, expressed as 38-45% inhibition of 0 2 consumption relative to that in the same medium without glucose. The stimulatory effect of misonidazole and NDPP on 0 2 utilization in medium with glucose undoubtedly appeared as a release from the Crabtree effect. (author)

Systems Biology Modeling of the Radiation Sensitivity Network: A Biomarker Discovery Platform

International Nuclear Information System (INIS)

Eschrich, Steven; Zhang Hongling; Zhao Haiyan; Boulware, David; Lee, Ji-Hyun; Bloom, Gregory; Torres-Roca, Javier F.

2009-01-01

Purpose: The discovery of effective biomarkers is a fundamental goal of molecular medicine. Developing a systems-biology understanding of radiosensitivity can enhance our ability of identifying radiation-specific biomarkers. Methods and Materials: Radiosensitivity, as represented by the survival fraction at 2 Gy was modeled in 48 human cancer cell lines. We applied a linear regression algorithm that integrates gene expression with biological variables, including ras status (mut/wt), tissue of origin and p53 status (mut/wt). Results: The biomarker discovery platform is a network representation of the top 500 genes identified by linear regression analysis. This network was reduced to a 10-hub network that includes c-Jun, HDAC1, RELA (p65 subunit of NFKB), PKC-beta, SUMO-1, c-Abl, STAT1, AR, CDK1, and IRF1. Nine targets associated with radiosensitization drugs are linked to the network, demonstrating clinical relevance. Furthermore, the model identified four significant radiosensitivity clusters of terms and genes. Ras was a dominant variable in the analysis, as was the tissue of origin, and their interaction with gene expression but not p53. Overrepresented biological pathways differed between clusters but included DNA repair, cell cycle, apoptosis, and metabolism. The c-Jun network hub was validated using a knockdown approach in 8 human cell lines representing lung, colon, and breast cancers. Conclusion: We have developed a novel radiation-biomarker discovery platform using a systems biology modeling approach. We believe this platform will play a central role in the integration of biology into clinical radiation oncology practice.

Radiosensitization of hypoxic tumor cells in vitro by nitric oxide

International Nuclear Information System (INIS)

Griffin, Robert J.; Makepeace, Carol M.; Hur, Won-Joo; Song, Chang W.

1996-01-01

Purpose: The effects of nitric oxide (NO) on the radiosensitivity of SCK tumor cells in oxic and hypoxic environments in vitro were studied. Methods and Materials: NO was delivered to cell suspensions using the NO donors 2,2-diethyl-1-nitroso-oxyhydrazine sodium salt (DEA/NO), and a spermine/nitric oxide complex (SPER/NO), which release NO at half-lives of 2.1 min and 39 min at pH 7.4, respectively. The cells were suspended in media containing DEA/NO or SPER/NO for varying lengths of time under oxic or hypoxic conditions, irradiated, and the clonogenicity determined. Results: Both compounds markedly radiosensitized the hypoxic cells. The drug enhancement ratios (DER) for 0.1, 1.0, and 2.0 mM DEA/NO were 2.0, 2.3 and 3.0, respectively, and those for 0.1, 1.0, and 2.0 mM SPER/NO were 1.6, 2.3, and 2.8, respectively. Aerobic cells were not radiosensitized by DEA/NO or SPER/NO. When DEA/NO and SPER/NO were incubated in solution overnight to allow release of NO, they were found to have no radiosensitizing effect under hypoxic or oxic conditions indicating the sensitization by the NO donors was due to the NO molecule released from these drugs. At the higher concentrations, SPER/NO was found to be cytotoxic in aerobic conditions but not in hypoxic conditions. DEA/NO was only slightly toxic to the cells in both aerobic and hypoxic conditions. Conclusions: NO released from NO donors DEA/NO and SPER/NO is as effective as oxygen to radiosensitize hypoxic cells in vitro. Its application to the radiosensitization of hypoxic cells in solid tumors remains to be investigated

Impacts of berberine on the growth, migration and radiosensitivity of breast cancer cells

International Nuclear Information System (INIS)

Zhao Chaoqian; Xu Jiaying; Jiao Yang; Hu Xudong; Che Jun; Fan Saijun

2012-01-01

Objective: To study the impacts of berberine on the growth, migration and radiosensitivity in human breast cancer cells. Methods: MTT assay was used to evaluate cell growth.In vitro scratch migration assay was used to determine cell migration. Annexin V assay was used to detect cell apoptosis. The distribution of cell cycle was evaluated by flow cytometry assay. Colony formation assay was used to detect the influence of berberine on cell radiosensitivity. Western blot assay was employed to measure protein expression. Results: Berberine inhibited cell growth and migration in two human breast cancer cell lines, MCF-7 and MDA-MB-231, in a dose-and time-dependent manner. Furthermore, berberine resulted in a cell cycle G 0 /G 1 arrest. Compared with control, the early apoptosis in MDA-MB-231 and MCF-7 cells treated with 40 pμmol/L of berberine was as high as 86.6% and 66.6% (t=8.79, 10.32, P<0.01), respectively. Berberine caused a dose-dependent increase in Bax and Caspase-3 protein expressions, but did not change Cyclin D1 protein expression, while suppressed the expressions of Cyclin B1 and Bcl-2 protein. As analyzed with multi-target click model fitting curves, the SER D0 of berberine-treated cells were 1.12 and 1.22 for MDA-MB-231 and MCF-7 cells respectively at the dose D 0 of X-rays. Conclusions: The berberine inhibited the growth and migration of breast cancer cells via apoptosis induction and cell cycle arrest. Moreover, berberine increases cell sensitivity to X-ray irradiation. (authors)

Reaction between nitracrine and glutathione: implications for hypoxic cell radiosensitization and cytotoxicity

International Nuclear Information System (INIS)

Wilson, W.R.; Anderson, R.F.

1989-01-01

Nitracrine (NC) is an electron affinic DNA intercalating agent and a potent hypoxia-selective cytotoxin and radiosensitizer in cell culture. Although NC is too cytotoxic and too rapidly metabolized to provide hypoxic cell radiosensitization in tumors, it is of mechanistic interest as an example of a DNA affinic radiosensitizer. We have observed a rapid chemical reaction between NC and reduced glutathione (GSH), which suggests that the observed potent in vitro cytotoxicity and radiosensitization might be dependent on thiol depletion by the large extracellular reservoir of drug. However, no GSH depletion was observed under conditions providing radiosensitization or rapid cell killing, and prior depletion of GSH by buthionine sulphoximine had no effect on cytotoxicity or formation of macromolecular adducts. Further, the intracellular reaction of NC with GSH is slower than predicted on the basis of the measured second order rate constant and the total intracellular concentrations of both species. The results are consistent with a role for DNA binding in protecting NC from reaction with GSH, and in improving the efficiency with which reduced electrophilic metabolites react with DNA in preference to GSH

In vivo radiosensitizing effect of nitroimidazole derivative KIN-804

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Tada, Takuhito; Nakajima, Toshifumi; Onoyama, Yasuto; Murayama, Chieko; Mori, Yomoyuki; Nagasawa, Hideko; Hori, Hitoshi; Inayama, Seiichi

1994-01-01

In vivo characteristics of 2-nitroimidazole-1-methylacetohydroxamate (KIN-804), which is a newly developed hypoxic cell radiosensitizer, are presented. The toxicity, pharmacokinetics, and radiosensitizing effect of KIN-804 were studied by in vivo experiments using C3H/He mice bearing the SCCVII tumor. Results were compared with misonidazole (MISO). LD 50 7 of KIN-804 and MISO were 3200 mg/kg and 2000 mg/kg, respectively. The peak concentration of KIN-804 in the tumor occurred 20 min after intraperitoneal injection and reached about 62% of the maximum concentration in the blood. The concentrations in brain and sciatic nerve were very low and clearance from sciatic nerve was rapid. Enhancement ratios of KIN-804 calculated using the growth delay method were 1.22, 1.50, and 1.71 at doses of 50, 100, and 200 mg/kg, respectively, compared with 1.36 for MISO at a dose of 100 mg/kg. In the TCD 50 assay, enhancement ratios at a dose of 200 mg/kg were 1.69 for KIN-804 and 1.52 for MISO, respectively. KIN-804 is a promising radiosensitizer since it shows less toxicity and higher radiosensitizing activity than MISO. 10 refs., 5 figs

Comparison of radiosensitivities of human autologous normal and neoplastic thyroid epithelial cells

International Nuclear Information System (INIS)

Miller, R.C.; Kopecky, K.J.; Hiraoka, T.; Ezaki, H.; Clifton, K.H.

1986-01-01

Studies were conducted to examine differences between the radiosensitivities of normal and neoplastic epithelial cells of the human thyroid. Freshly excised thyroid tissues from the tumours of eight patients with papillary carcinoma (PC) and five with follicular adenoma (FA) were cultured in vitro separately from normal thyroid tissue obtained from the surgical margins of the same patients. Plating efficiency of unirradiated control tissue was lower, on average for tumour tissue compared with normal tissue. Radiosensitivity, measured by the 37% inactivation dose D 0 , was greater for carcinoma tissue than for normal tissue in seven out of eight PC cases. Adenomatous tissue was less radiosensitive than normal tissue in four out of five FA cases. This is the first report comparing the radiosensitivity of autologous normal and abnormal epithelial tissue from the human thyroid. (author)

The measurement of intrinsic cellular radiosensitivity in human tumours and normal tissues

International Nuclear Information System (INIS)

Lawton, P.A.

1995-01-01

Human tumour and normal cell radiosensitivity are thought to be important factors determining the response of tumour and normal tissues to radiotherapy, respectively. Clonogenic assays are the standard method for measuring radiosensitivity but they are of limited applicability for clinical use with fresh human tumours. The main aim of this work was to evaluate the Adhesive Tumour Cell Culture System (ATCCS), as a method for measuring the radiosensitivity of human tumours. A soft agar clonogenic assay, the modified Courtenay-Mills assay, was used as a standard to compare with the ATCCS. The demonstration that fibroblast contamination could occur with both assay methods led to the investigation of a new technique for removing unwanted fibroblasts from tumour cell suspensions and to the use of a multiwell assay for measuring fibroblast radiosensitivity. (author)

The measurement of intrinsic cellular radiosensitivity in human tumours and normal tissues

Energy Technology Data Exchange (ETDEWEB)

Lawton, P.A.

1995-12-31

Human tumour and normal cell radiosensitivity are thought to be important factors determining the response of tumour and normal tissues to radiotherapy, respectively. Clonogenic assays are the standard method for measuring radiosensitivity but they are of limited applicability for clinical use with fresh human tumours. The main aim of this work was to evaluate the Adhesive Tumour Cell Culture System (ATCCS), as a method for measuring the radiosensitivity of human tumours. A soft agar clonogenic assay, the modified Courtenay-Mills assay, was used as a standard to compare with the ATCCS. The demonstration that fibroblast contamination could occur with both assay methods led to the investigation of a new technique for removing unwanted fibroblasts from tumour cell suspensions and to the use of a multiwell assay for measuring fibroblast radiosensitivity. (author).

Heterogeneity of the radiosensitivity and origins of tissue macrophage colony-forming cells

Energy Technology Data Exchange (ETDEWEB)

Oghiso, Yoichi; Yamada, Yutaka (National Inst. of Radiological Sciences, Chiba (Japan))

1992-12-01

Previous studies suggest that the radiosensitivity and origin of tissue macrophage precursors differ from those of hemopoietic macrophage colony-forming units (CFU-Ms) committed to macrophage-lineage cells. We assessed the origins of tissue macrophage colony-forming cells (M-CFCs) in mice by comparing their kinetics and radiosensitivities in the normal steady state and under the conditions of bone marrow depletion by [sup 89]Sr-administration and/or splenectomy. The results indicate that the radiosensitive peritoneal M-CFCs elicited by thioglycollate are derived from bone marrow macrophage precursors; where as alveolar M-CFCs, which are radioresistant, are self-sustained locally and independent of hemopoietic macrophage precursors. In contrast, highly radiosensitive liver M-CFCs are probably derived from CFU-Ms that appear to be propagated in the spleen in association with hemopoietic responses. (author).

Increasing the radiosensitivity of tumours in an hypoxic environment using inhibitors of the pentose phosphate pathway

International Nuclear Information System (INIS)

Sahasrabudhe, M.B.; Bhonsle, S.R.; Krishnamurti, K.; Tilak, B.D.

1977-01-01

Rapidly growing tumours contain few blood vessels in the tumour mass. Cells in such tumours obtain nutrients and oxygen from the periphery by diffusion, resulting in a diminishing oxygen and nutrient gradient from the periphery to centre of the tumour mass. In normal tissues, oxygen is utilized via a tricarboxylic acid (TCA) cycle; in tumour cells oxygen is utilized via a hexose monophosphate (HMP) pathway and through the TCA cycle at a 30% reduced level. Interference with the HMP pathway selectively inhibits the utilization of oxygen by tumour cells, thus increasing the availability of oxygen to hypoxic cells situated deeper in the tumour mass. This effect has been exploited for increasing the radiosensitivity of tumour cells situated in an hypoxic environment. The influence of sixteen potential antimetabolites on the HMP pathway has been studied. Of these, six compounds, namely, (1) 2-carboxy 5-hydroxymethyl thiophene, (2) the sodium salt of 2:5 dicarbethoxy 3:4 dihydroxy thiophene, (3) the dihydrazide of 2:5 dicarboxy thiophene, (4) the dihydrazide of 3:4 dimethoxy 2:5 dicarboxy thiophene, (5) trithiocyanuric acid, and (6) cyanuric trithioglycollic acid showed an inhibiting effect on the HMP pathway without any influence on the TCA cycle. Influence of administration of compounds (1), (2) and (4) prior to radiation on the growth of transplanted fibrosarcomas in mice has been studied and is reported here. These three compounds showed marked potentiation of radiosensitivity of tumours. (author)

Effect of DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine on radiosensitivity of the human lung cancer cells in three-dimensional culture

International Nuclear Information System (INIS)

Pan Dong; Xue Gang; Li Xiaoman; Chen Yaxiong; Ren Zhenxin; Du Yarong; Hu Burong

2014-01-01

5-Aza-CdR is a specific inhibitor of DNMTs which could suppress tumor growth by demethylation of genomic DNA. There have only few studies thus far concerning it as radiosensitizers in three-dimensional (3D) cells. The principal aim of this study is to evaluate the effects of 5-Aza-CdR on the radiosensitivity of A549 cells in monolayer (2D) and 3D cultures in an attempt to find out a new combination treatments with radiotherapy. The cell proliferation was detected by MTT assay after pretreated with different doses of 5-Aza-CdR for 72 h. A549 cells were treated with or without 5-Aza-CdR (2, 5 μmol/L) for 72 h before be exposed to X-rays of 1, 2, 4, 6 Gy, respectively. The DNA damage was evaluated by micronucleus assay and clonogenic assays. Pretreatment with 5-Aza-CdR inhibited the A549 cell proliferation significantly. More micronucleus were observed after irradiation in 3D cells pretreated with 2 and 5 μmol/L concentration of drug than those without treatment. The survival fractions of cells pretreated by both 2 and 5 μmol/L drug reduced significantly in 3D cultures after irradiation. These significances, however, were found in 2D cells pretreated by only 5 μmol/L drug. Our results suggest that 5-Aza-CdR can inhibit the A549 cells proliferation and apparently enhance the radiosensitivity of cells in 3D cultures. Using of the low dose 5-Aza-CdR in clinical radiotherapy may reduce side effects and enhance effectively the cancer target therapy. (authors)

Radiosensitivity of the swiss-rap mouse as a function of its growth rate

International Nuclear Information System (INIS)

Legeay, G.; Glas, J.F.

1969-01-01

The results of an exhaustive study of the age dependence of the radiosensitivity of female Swiss-Rap mice are given. A close relationship of radiosensitivity versus age could not be brought out, whereas the weekly growth rate could be accurately related to radiosensitivity. Thus, the latter should be studied when a strain is to be used for biological experiments, as the rates of growth are different with the strains. (author) [fr

Radiosensitivity of continuous cultures: experiments with diploid yeast

International Nuclear Information System (INIS)

Kiefer, J.; Wagner, E.

1975-01-01

To study the influence of systems parameters on the radiosensitivity of cell populations, stationary chemostat cultures of diploid yeast with different dilution rates were γ-irradiated. Proliferation and budding kinetics were investigated and the doses necessary to eliminate the entire population determined as a function of dilution rate. It was found that this killing dose decreases with dilution rate in a linear manner. The radiosensitivity of the cells was shown to depend on the dilution rate which is presumably due to differing compositions of the population. (U.S.)

Balance of excitation and inhibition determines 1/f power spectrum in neuronal networks.

Science.gov (United States)

Lombardi, F; Herrmann, H J; de Arcangelis, L

2017-04-01

The 1/f-like decay observed in the power spectrum of electro-physiological signals, along with scale-free statistics of the so-called neuronal avalanches, constitutes evidence of criticality in neuronal systems. Recent in vitro studies have shown that avalanche dynamics at criticality corresponds to some specific balance of excitation and inhibition, thus suggesting that this is a basic feature of the critical state of neuronal networks. In particular, a lack of inhibition significantly alters the temporal structure of the spontaneous avalanche activity and leads to an anomalous abundance of large avalanches. Here, we study the relationship between network inhibition and the scaling exponent β of the power spectral density (PSD) of avalanche activity in a neuronal network model inspired in Self-Organized Criticality. We find that this scaling exponent depends on the percentage of inhibitory synapses and tends to the value β = 1 for a percentage of about 30%. More specifically, β is close to 2, namely, Brownian noise, for purely excitatory networks and decreases towards values in the interval [1, 1.4] as the percentage of inhibitory synapses ranges between 20% and 30%, in agreement with experimental findings. These results indicate that the level of inhibition affects the frequency spectrum of resting brain activity and suggest the analysis of the PSD scaling behavior as a possible tool to study pathological conditions.

Radiosensitivity of soft tissue sarcomas

International Nuclear Information System (INIS)

Hirano, Toru; Iwasaki, Katsuro; Suzuki, Ryohei; Monzen, Yoshio; Hombo, Zenichiro

1989-01-01

The correlation between the effectiveness of radiation therapy and the histology of soft tissue sarcomas was investigated. Of 31 cases with a soft tissue sarcoma of an extremity treated by conservative surgery and postoperative radiation of 3,000-6,000 cGy, local recurrence occurred in 12; 5 out of 7 synovial sarcomas, 4 of 9 MFH, one of 8 liposarcomas, none of 4 rhabdomyosarcomas and 2 of 3 others. As for the histological subtyping, the 31 soft tissue sarcomas were divided into spindle cell, pleomorphic cell, myxoid and round cell type, and recurrence rates were 75%, 33.3%, 16.7% and 0%, respectively. From the remarkable difference in recurrent rate, it was suggested that round cell and myxoid type of soft tissue sarcomas showed a high radiosensitivity compared to the spindle cell type with low sensitivity. Clarifying the degree of radiosensitivity is helpful in deciding on the management of limb salvage in soft tissue sarcomas of an extremity. (author)

The combination of olaparib and camptothecin for effective radiosensitization

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Miura Katsutoshi

2012-04-01

Full Text Available Abstract Background Poly (ADP-ribose polymerase-1 (PARP-1 is a key enzyme involved in the repair of radiation-induced single-strand DNA breaks. PARP inhibitors such as olaparib (KU-0059436, AZD-2281 enhance tumor sensitivity to radiation and to topoisomerase I inhibitors like camptothecin (CPT. Olaparib is an orally bioavailable inhibitor of PARP-1 and PARP-2 that has been tested in multiple clinical trials. The purpose of this study was to investigate the characteristics of the sensitizing effect of olaparib for radiation and CPT in order to support clinical application of this agent. Methods DLD-1 cells (a human colorectal cancer cell line and H1299 cells (a non-small cell lung cancer cell line with differences of p53 gene status were used. The survival of these cells was determined by clonogenic assay after treatment with drugs and X-ray irradiation. The γH2AX focus formation assay was performed to examine the influence of olaparib on induction and repair of double-stranded DNA breaks after exposure to radiation or CPT. Results A radiosensitizing effect of olaparib was seen even at 0.01 μM. Its radiosensitizing effect after exposure for 2 h was similar to that after 24 h. H1299 cells with depletion or mutation of p53 were more radioresistant than H1299 cells with wild-type p53. However, similar enhancement of radiosensitization by olaparib was observed with all of the tested cell lines regardless of the p53 status. Olaparib also sensitized cells to CPT. This sensitizing effect was seen at low concentrations of olaparib such as 0.01 μM, and its sensitizing effect was the same at both 0.01 μM and 1 μM. The combination of olaparib and CPT had a stronger radiosensitizing effect. The results of the γH2AX focus assay corresponded with the clonogenic assay findings. Conclusion Olaparib enhanced sensitivity to radiation and CPT at low concentrations and after relatively short exposure times such as 2 h. The radiosensitizing effect of olaprib

DNA-radiosensitivity and repair in mammolian cells

International Nuclear Information System (INIS)

Proskuryakov, S.Ya.; Ivannik, B.P.; Ryabchenko, N.I.

1979-01-01

Determination was made of the formation and repair of single-stranded DNA breaks (SB) in cells of rat thymus and liver and Ehrlich's ascites tumor (EAT) with the use of the method of low-gradient viscosimetry of alkaline cell lysates. The radiochemical yield of single-stranded breaks (Gsub(SB)) induced by irradiation of animals is 41.2 eV/break for hepatocytes, 96.8 eV/break, for thymocytes, and 129.7 eV/break, for EAT cells. The half-recovery time of single-stranded DNA breaks for cells of thymus and EAT exposed in vivo is 16.0 and 5.1 s -1 , correspondingly. In hepatocytes exposed in vivo and in vitro no repairs occurs for 3 h. Under conditions of inhibition of SB repair, when suspensions of thymocytes and hepatocytes were exposed in vitro at 4 deg C, Gsub(SB) is 35.5 and 38.7 eV/break, respectively. The analysis of the data obtained prompts the conclusion that under in vivo conditions, there is a correlation between DNA radiosensitivity and the rate of repair processes

HIF-1α inhibition by siRNA or chetomin in human malignant glioma cells: effects on hypoxic radioresistance and monitoring via CA9 expression

Directory of Open Access Journals (Sweden)

Bache Matthias

2010-11-01

Full Text Available Abstract Background Hypoxia induces activation of the HIF-1 pathway and is an essential characteristic of malignant gliomas. Hypoxia has been linked to tumor progression, therapy resistance and poor prognosis. However, little is known about the impact of HIF-1α inhibition on radioresistance of malignant glioma. Methods In this study, we investigated the effects of the inhibition of HIF-1α on cell survival and radiosensitivity in U251MG and U343MG glioma cells, using two different strategies. HIF-1α inhibition was achieved by siRNA targeting of HIF-1α or via chetomin, a disruptor of interactions between HIF-1α and p300. The inhibition of the HIF-1 pathway was monitored by quantitative real-time PCR and Western blot analyses of the expression levels of HIF-1α and CA9. CA9 expression was investigated as a potential indicator of the efficacy of HIF-1 inhibition and the resulting radiosensitivity of malignant glioma cell lines was determined by clonogenic assay after irradiation under normoxic (2-10 Gy or hypoxic (2-15 Gy conditions. Results Although siRNA and chetomin show distinct modes of action, both attenuated the hypoxia-induced radioresistance of malignant glioma cell lines U251MG (DMF10: 1.35 and 1.18 and U343MG (DMF10: 1.78 and 1.48. However, siRNA and chetomin showed diverse effects on radiosensitivity under normoxic conditions in U251MG (DMF10: 0.86 and 1.35 and U343MG (DMF10: 1.33 and 1.02 cells. Conclusions Results from this in vitro study suggest that inhibition of HIF-1α is a promising strategy to sensitize human malignant gliomas to radiotherapy and that CA9 could serve as an indicator of effective HIF-1-related radiosensitization.

The modulation of radiosensitivity by combined treatment of selective COX-2 inhibitor, NS 398 and EGF receptor blocker AG 1478 in HeLa cell line

International Nuclear Information System (INIS)

Youn, Seon Min; Oh, Young Kee; Kim, Joo Heon; Park, Mi Ja; Seong, In Ock; Kang, Ki Mun; Chai, Gyu Yong

2005-01-01

Selective inhibition of multiple molecular targets may improve the antitumor activity of radiation. Two specific inhibitors of selective cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) were combined with radiation on the HeLa cell line. To investigate cooperative mechanism with selective COX-2 inhibitor and EGFR blocker, in vitro experiments were done. Antitumor effect was obtained by growth inhibition and apoptosis analysis by annexin V-Flous method. Radiation modulation effects were determined by the clonogenic cell survival assay. Surviving fractions at 2 Gy (SF 2 ) and dose enhancement radio at a surviving fraction of 0.25 were evaluated. To investigate the mechanism of the modulation of radiosensitivity, the cell cycle analyses were done by flow cytometry. The bcl-2 and bax expressions were analyzed by western blot. A cooperative effect were observed on the apoptosis of the HeLa cell line when combination of the two drugs, AG 1478 and NS 398 with radiation at the lowest doses, apoptosis of 22.70% compare with combination of the one drug with radiation, apoptosis of 8.49%. In cell cycle analysis, accumulation of cell on G 0 /G 1 phase and decrement of S phase fraction was observed from 24 hours to 72 hours after treatment with radiation, AG 1478 and NS 398. The combination of NS 398 and AG 1478 enhanced radiosensitivity in a concentration-dependent manner in HeLa cells with dose enhancement ratios of 3.00 and SF 2 of 0.12 but the combination of one drug with radiation was not enhanced radiosensitivity with dose enhancement ratios of 1.12 and SF2 of 0.68 (ρ = 0.005). The expression levels of bcl-2 and bax were reduced when combined with AG 1478 and NS 398. Our results indicate that the selective COX-2 inhibitor and EGFR blocker combined with radiation have potential additive or cooperative effects on radiation treatment and may act through various mechanisms including direct inhibition of tumor cell proliferation, suppression of tumor cell

Chromosomal radiosensitivity in breast cancer patients with a known or putative genetic predisposition.

LENUS (Irish Health Repository)

Baeyens, A

2002-12-02

The chromosomal radiosensitivity of breast cancer patients with a known or putative genetic predisposition was investigated and compared to a group of healthy women. The chromosomal radiosensitivity was assessed with the G2 and the G0-micronucleus assay. For the G2 assay lymphocytes were irradiated in vitro with a dose of 0.4 Gy (60)Co gamma-rays after 71 h incubation, and chromatid breaks were scored in 50 metaphases. For the micronucleus assay lymphocytes were exposed in vitro to 3.5 Gy (60)Co gamma-rays at a high dose rate or low dose rate. 70 h post-irradiation cultures were arrested and micronuclei were scored in 1000 binucleate cells. The results demonstrated that the group of breast cancer patients with a known or putative genetic predisposition was on the average more radiosensitive than a population of healthy women, and this with the G2 as well as with the high dose rate and low dose rate micronucleus assay. With the G2 assay 43% of the patients were found to be radiosensitive. A higher proportion of the patients were radiosensitive with the micronucleus assay (45% with high dose rate and 61% with low dose rate). No correlation was found between the G2 and the G0-micronucleus chromosomal radiosensitivity. Out of the different subgroups considered, the group of the young breast cancer patients without family history showed the highest percentage of radiosensitive cases in the G2 (50%) as well as in the micronucleus assay (75-78%).

Wnt activation affects proliferation, invasiveness and radiosensitivity in medulloblastoma.

Science.gov (United States)

Salaroli, Roberta; Ronchi, Alice; Buttarelli, Francesca Romana; Cortesi, Filippo; Marchese, Valeria; Della Bella, Elena; Renna, Cristiano; Baldi, Caterina; Giangaspero, Felice; Cenacchi, Giovanna

2015-01-01

Medulloblastomas (MBs) associated with the Wnt activation represent a subgroup with a favorable prognosis, but it remains unclear whether Wnt activation confers a less aggressive phenotype and/or enhances radiosensitivity. To investigate this issue, we evaluated the biological behavior of an MB cell line, UW228-1, stably transfected with human β-catenin cDNA encoding a nondegradable form of β-catenin (UW-B) in standard culture conditions and after radiation treatment. We evaluated the expression, transcriptional activity, and localization of β-catenin in the stably transfected cells using immunofluorescence and WB. We performed morphological analysis using light and electron microscopy. We then analyzed changes in the invasiveness, growth, and mortality in standard culture conditions and after radiation. We demonstrated that (A) Wnt activation inhibited 97 % of the invasion capability of the cells, (B) the growth of the UW-B cells was statistically significantly lower than that of all the other control cells (p < 0.01), (C) the mortality of irradiated UW-B cells was statistically significantly higher than that of the controls and their nonirradiated counterparts (p < 0.05), and (D) morphological features of neuronal differentiation were observed in the Wnt-activated cells. In tissue samples, the Ki-67 labeling index (LI) was lower in β-catenin-positive samples compared to non-β-catenin positive ones. The Ki-67 LI median (LI = 40) of the nuclear β-catenin-positive tumor samples was lower than that of non-nuclear β-catenin-positive samples (LI = 50), but the difference was not statistically significant. Overall, our data suggest that activation of the Wnt pathway reduces the proliferation and invasion of MBs and increases the tumor's radiosensitivity.

Radiosensitivity of two populations of Clethrionomys glareolus Schreber from East Lithuania

International Nuclear Information System (INIS)

Mazheikyte, R.

1997-01-01

The basic radiosensitivity of bank vole population inhabiting the region of the Ignalina NPP (INPP) and the control zones, 50 km to the south-west from the INPP, i.e., radiosensitivity of bank voles overwintered and bank vole underyearlings as well as that of males and females in spring and autumn was investigated. In the investigated points the bank voles were caught in May and September 1984. In all, in the experiment there were used 18 bank voles overwintered at the age of 10-13 months and 42 bank vole underyearlings of 2 months. The investigations were carried out using cytologic method because it was shown that there is a direct relationship between the radiosensitivity of animal and that of its organs and tissues to ionizing radiation. The investigations of radiosensitivity of bank voles overwintered and bank vole underyearlings in spring and autumn have shown that the number of cells with spontaneous chromosome structure aberrations in tissues of bank voles of all the investigated age groups was almost the same, i.e., ecological living conditions of bank voles in population A and population B were the same. It should be noted that some differences in radiosensitivity of the investigated populations revealed the different genetic structure of these populations during the abundance dynamics of bank voles. (author).3 tabs

Interaction of nitroaromatic radiosensitizers with irradiated polyadenylic acid as measured by an indirect immunochemical assay with specificity for the 8,5'-cycloadenosine moiety

Energy Technology Data Exchange (ETDEWEB)

Fuciarelli, A F; Mele, F G; Raleigh, J A

1987-04-01

The relative reactivity of a series of nitroaromatic radiosensitizers toward the C(5') radical intermediate leading to 8,5'-cycloadenosine formation in deoxygenated solutions of irradiated polyadenylic acid (poly A) was assessed using standard competition kinetic analysis. Formation of 8,5'-cycloadenosine was assayed by an indirect, competitive, enzyme-linked immunosorbent assay (ELISA) described in an earlier report. In the absence of oxygen, the nitroaromatics inhibit 8,5'-cyclonucleoside formation in a way which generally increases with radiosensitizer electron affinity. Although hydroxyl radical scavenging by the nitroaromatics may account for a relatively small decrease in 8,5'cyclonucleoside formation, the data suggest that oxidation of the C(5') radical intermediate is the more plausible explanation for the decreased yield of the 8,5'-cyclonucleoside with increasing nitroaromatic electron affinity.

Radiosensitizers action on Iodine 131 therapeutical effect

International Nuclear Information System (INIS)

Agote, Marcos; Kreimann, Erica L.; Bocanera, Laura V.; Dagrosa, Maria A.; Juvenal, Guillermo J.; Pisarev, Mario A.

1999-01-01

Present studies were aimed to research the possible application of a radiosensitizer, nicotinamide, to increase the therapeutical effect of radioiodine. There were used goitrous and normal rats with growing dose of Iodine 131, with and without simultaneous treatment with nicotinamide. The obtained results show that the nicotinamide treatment importantly increases the thyroid radio destructive effect induced by radioiodine. Under these experimental conditions, nicotinamide induces to a significant increase of thyroid vascularisation, without changes in the proteins ADP-ribosylation activity. These results show, for the first time, the radiosensitizer effect of nicotinamide in front of Iodine 131 and give the possibility of using it in the treatment of hyperthyroid or thyroid difference cancer patients. (author)

Thermo-radiosensitivity of the granulocyte and macrophage precursor cells of mice. II. - X irradiation effects and influence of hyperthermia on the radiosensitivity

International Nuclear Information System (INIS)

Bueren, J.A.; Nieto, M.

1983-01-01

The effects of the X-irradiation on the viability of the granulocyte-macrophage precursors, has been determined by means of the agar diffusion chamber culture technique. The results show the high radiosensitivity of these cells, with survival parameter similar to those previously reported in the literature about different granulocyte-macrophage precursors. When a hyperthermic treatment is performed prior to the X-irradiation, a radiosensitization phenomenon is observed due to the synergism existent between hyperthermia and X rays on the lethality of the precursors. (Authors) 37 refs

Base excision repair of both uracil and oxidatively damaged bases contribute to thymidine deprivation-induced radiosensitization

International Nuclear Information System (INIS)

Allen, Bryan G.; Johnson, Monika; Marsh, Anne E.; Dornfeld, Kenneth J.

2006-01-01

Purpose: Increased cellular sensitivity to ionizing radiation due to thymidine depletion is the basis of radiosensitization with fluoropyrimidine and methotrexate. The mechanism responsible for cytotoxicity has not been fully elucidated but appears to involve both the introduction of uracil into, and its removal from, DNA. The role of base excision repair of uracil and oxidatively damaged bases in creating the increased radiosensitization during thymidine depletion is examined. Methods and Materials: Isogenic strains of S. cerevisiae differing only at loci involved in DNA repair functions were exposed to aminopterin and sulfanilamide to induce thymidine deprivation. Cultures were irradiated and survival determined by clonogenic survival assay. Results: Strains lacking uracil base excision repair (BER) activities demonstrated less radiosensitization than the parental strain. Mutant strains continued to show partial radiosensitization with aminopterin treatment. Mutants deficient in BER of both uracil and oxidatively damaged bases did not demonstrate radiosensitization. A recombination deficient rad52 mutant strain was markedly sensitive to radiation; addition of aminopterin increased radiosensitivity only slightly. Radiosensitization observed in rad52 mutants was also abolished by deletion of the APN1, NTG1, and NTG2 genes. Conclusion: These data suggest radiosensitization during thymidine depletion is the result of BER activities directed at both uracil and oxidatively damaged bases

MiR-124 Inhibits Growth and Enhances Radiation-Induced Apoptosis in Non-Small Cell Lung Cancer by Inhibiting STAT3

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Mengjie Wang

2017-12-01

Full Text Available Background/Aims: A growing body of evidence indicates that the abnormal expression of microRNAs (miRNAs play an important role in sensitizing the cellular response to ionizing radiation (IR. The aim of this study was to investigate whether the expression of miR-124 correlated with radiosensitivity in the context of non-small-cell lung carcinoma (NSCLC. Methods: Quantitative reverse transcription polymerase chain reaction (RT-PCR was used to quantify miR-124 expression in NSCLC tissues and cell lines. The role of miR-124 in NSCLC proliferation and radiosensitivity was analyzed using CCK-8 and flow cytometry apoptosis assays. Luciferase activity assays, RT-PCR, and Western blot assays were performed to confirm the target gene of miR-124. Results: In this study, we found that miR-124 was downregulated both in clinical NSCLC samples and in cell lines. miR-124 inhibited the proliferation of NSCLC cells and enhanced the apoptosis of NSCLC cells exposed to ionizing radiation. We identified signal transducer and activator of transcription 3 (STAT3 as a direct target of miR-124 by using target prediction algorithms and luciferase assays. Overexpression of STAT3 in A549 cell lines restored the enhanced radiosensitivity induced by miR-124. Conclusion: Taking these observations into consideration, we illustrated that miR-124 is a potential target for enhancing the radiosensitivity of NSCLC cells by targeting STAT3.

Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin

International Nuclear Information System (INIS)

Noguchi, Miho; Yu, Dong; Hirayama, Ryoichi; Ninomiya, Yasuharu; Sekine, Emiko; Kubota, Nobuo; Ando, Koichi; Okayasu, Ryuichi

2006-01-01

In order to investigate the mechanism of radio-sensitization by an Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), we studied repair of DNA double strand breaks (DSBs) in irradiated human cells pre-treated with 17-AAG. DSBs are thought to be the critical target for radiation-induced cell death. Two human tumor cell lines DU145 and SQ-5 which showed clear radio-sensitization by 17-AAG revealed a significant inhibition of DSB repair, while normal human cells which did not show radio-sensitization by the drug indicated no change in the DSB repair kinetics with 17-AAG. We further demonstrated that BRCA2 was a novel client protein for Hsp90, and 17-AAG caused the degradation of BRCA2 and in turn altered the behavior of Rad51, a critical protein for homologous recombination (HR) pathway of DSB repair. Our data demonstrate for the first time that 17-AAG inhibits the HR repair process and could provide a new therapeutic strategy to selectively result in higher tumor cell killing

Radiosensitization of hypoxic tumor cells by simultaneous administration of hyperthermia and nitroimidazoles

International Nuclear Information System (INIS)

Hofer, K.G.; Hofer, M.G.; Ieracitano, J.; McLaughlin, W.H.

1977-01-01

The radiation response of oxygenated and hypoxic L1210 leukemia cells subjected to in vivo treatments with hyperthermia and/or chemical radiosensitizers was evaluated with the [ 125 I]iododeoxyuridine prelabeling assay. X irradiation of L1210 cells at body temperatures of 41 0 C or higher resulted in strongly enhanced tumor cell death. The magnitude of this thermal effect increased with increasing temperatures. Hypoxic L1210 cells were particularly sensitive to heat induced enhancement of radiation damage, i.e., the sensitizing effects were more pronounced and occurred at lower temperatures. Chemical radiosensitizers (metronidazole, Ro 7-0582) selectively sensitized hypoxic L1210 populations; fully oxygenated cells were not affected. Considerable radiosensitization was achieved at nontoxic dose levels of the two sensitizers. Experiments designed to determine the degree of radiosensititization as a function of drug dose showed that Ro 7-0582 was consistently more effective than metronidazole in sensitizing hypoxic tumor populations. At the highest drug dose used (3 mg/g body wt) the DMF was 2.2 for metronidazole and 2.8 for Ro 7-0582. Combined administration of hyperthermia and Ro 7-0582 (or metronidazole) produced synergistic potentiation of radiation damage in hypoxic L1210 populations (DMF of 4.2). Under optimal conditions, hypoxic L1210 cells subjected simultaneously to both modes of radiosensitization became more radiosensitive than untreated, fully oxygenated L1210 cells. Experiments on two other tumor lines (BP-8 murine sarcoma and Ehrlich ascites cells) indicate that such synergistic radiosensitization effects are not unique to L1210 cells

Mutations in the FHA-domain of ectopically expressed NBS1 lead to radiosensitization and to no increase in somatic mutation rates via a partial suppression of homologous recombination

International Nuclear Information System (INIS)

Ohara, Maki; Funyu, Yumi; Ebara, Shunsuke

2014-01-01

Ionizing radiation induces DNA double-strand breaks (DSBs). Mammalian cells repair DSBs through multiple pathways, and the repair pathway that is utilized may affect cellular radiation sensitivity. In this study, we examined effects on cellular radiosensitivity resulting from functional alterations in homologous recombination (HR). HR was inhibited by overexpression of the forkhead-associated (FHA) domain-mutated NBS1 (G27D/R28D: FHA-2D) protein in HeLa cells or in hamster cells carrying a human X-chromosome. Cells expressing FHA-2D presented partially (but significantly) HR-deficient phenotypes, which were assayed by the reduction of gene conversion frequencies measured with a reporter assay, a decrease in radiation-induced Mre11 foci formation, and hypersensitivity to camptothecin treatments. Interestingly, ectopic expression of FHA-2D did not increase the frequency of radiation-induced somatic mutations at the HPRT locus, suggesting that a partial reduction of HR efficiency has only a slight effect on genomic stability. The expression of FHA-2D rendered the exponentially growing cell population slightly (but significantly) more sensitive to ionizing radiation. This radiosensitization effect due to the expression of FHA-2D was enhanced when the cells were irradiated with split doses delivered at 24-h intervals. Furthermore, enhancement of radiation sensitivity by split dose irradiation was not seen in contact-inhibited G0/G1 populations, even though the cells expressed FHA-2D. These results suggest that the FHA domain of NBS1 might be an effective molecular target that can be used to induce radiosensitization using low molecular weight chemicals, and that partial inhibition of HR might improve the effectiveness of cancer radiotherapy. (author)

Hematoporphyrin derivatives potentiate the radiosensitizing effects of 2-deoxy-D-glucose in cancer cells

International Nuclear Information System (INIS)

Dwarakanath, B.S.; Adhikari, J.S.; Jain, Viney

1999-01-01

Purpose: Two deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolysis, has been shown to differentially inhibit the repair of radiation damage in cancer cells by reducing the flow of metabolic energy. Since hematoporphyrin derivatives (Hpd) inhibit certain enzymes of the respiratory metabolism, resulting in an increase in the glucose usage and glycolysis, Hpd could possibly enhance the energy-linked radiosensitizing effects of 2-DG in cancer cells. The purpose of the present work was to verify this suggestion. Methods and Materials: Two human tumor cell lines (cerebral glioma, BMG-1 and squamous cell carcinoma, 4197) and a murine tumor cell line (Ehrlich ascites tumor [EAT], F-15) in vitro were investigated. A commercially available preparation of Hpd, Photosan-3 (PS-3) was used in the present studies. Cells incubated with 0-10 μg/ml PS-3 for 0-24 h before irradiation were exposed to 2.5 Gy of Co-60 gamma rays and maintained under liquid holding conditions for 1-4 h to facilitate repair. 2-DG (0-5 mM) added at the time of irradiation was present during the liquid holding. Radiation-induced cytogenetic damage (micronuclei formation) and cell death (macrocolony assay) were analyzed as parameters of radiation response. Effects of these radiosensitizers on glucose usage and glycolysis were also studied by measuring the glucose consumption and lactate production using enzymatic assays. Results: The glucose consumption and lactate production of BMG-1 cells (0.83 and 1.43 pmole/cell/h) were twofold higher than in the 4197 cells (0.38 and 0.63 pmole/cell/h). Presence of PS-3 (10 μg/ml) enhanced the rate of glycolysis (glucose consumption and lactate production) in these cells by 35% to 65%, which was reduced by 20% to 40% in the presence of 5 mM 2-DG. In exponentially growing BMG-1 and EAT cells, presence of 2-DG (5 mM; equimolar with glucose) for 4 hours after irradiation increased the radiation-induced micronuclei formation and cell death by nearly 40

Radiosensitivity is increased by knockdown of FTS in uterine cervical cancer cells

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Park, Wo Yoon; Anandharaj, Arunkumar; Cinghu, Senthikumar; Kim, Won Dong [Dept. of Radiation Oncology, Chungbuk National University College of Medicine, Cheongju (Korea, Republic of); Yu, Jae Ran [Dept. of Environmental and Tropical Medicine, Konkuk University College of Medicine, Seoul (Korea, Republic of)

2012-04-15

Uterine cervical cancer is still the second largest cancer in women worldwide, despite of effective screening methods. Radiotherapy is used to treat all the stages of cervical cancer and more than 60% of cervical cancer patients receive radiotherapy. New therapeutic targets or approaches are needed to further increase the results of radiotherapy. In the present study, we demonstrated the radiation induced overexpression and nuclear export of FTS in cervical cancer cells. Furthermore, we showed that silencing of FTS expression with FTS shRNA enhanced radiosensitivity of cervical cancer cells, induced cell cycle arrest and apoptosis FTS is involved in radioresistance of cervical cancer. Targeted inhibition of FTS can shutdown the key elemental characteristics of cervical cancer and could lead to an effective therapeutic strategy.

Radiosensitivity is increased by knockdown of FTS in uterine cervical cancer cells

International Nuclear Information System (INIS)

Park, Wo Yoon; Anandharaj, Arunkumar; Cinghu, Senthikumar; Kim, Won Dong; Yu, Jae Ran

2012-01-01

Uterine cervical cancer is still the second largest cancer in women worldwide, despite of effective screening methods. Radiotherapy is used to treat all the stages of cervical cancer and more than 60% of cervical cancer patients receive radiotherapy. New therapeutic targets or approaches are needed to further increase the results of radiotherapy. In the present study, we demonstrated the radiation induced overexpression and nuclear export of FTS in cervical cancer cells. Furthermore, we showed that silencing of FTS expression with FTS shRNA enhanced radiosensitivity of cervical cancer cells, induced cell cycle arrest and apoptosis FTS is involved in radioresistance of cervical cancer. Targeted inhibition of FTS can shutdown the key elemental characteristics of cervical cancer and could lead to an effective therapeutic strategy

Study on relationship between apoptosis-related genes and radiosensitivity of esophageal squamous cell carcinoma

International Nuclear Information System (INIS)

Li Huixiang; Wang Yaohe; Shi Yonggang; Gao Dongling; Zhang Yunhan

2000-01-01

Objective: To observing the relationship between apoptosis-related genes bcl-2,c-myc, p53 and the radiosensitivity of esophageal squamous cell carcinoma. Methods: The expression levels of bcl-2, c-myc and p53 genes in 57 biopsy samples from patients of esophageal squamous cell carcinoma were detected with the LSAB immunohistochemistry method. All the patients were treated with radiotherapy. The radiotherapeutic effect in these patients was observed and the relation between gene expression and radiosensitivity was analyzed. Results: Compared with the bcl-2-negative group, the radiosensitivity of bcl-2-positive one was lower(P<0.01). The radiosensitivity of p53-positive group was slightly lower than that of the p53-negative one (P<0.05). The c-myc protein expression was not related to radiosensitivity. Conclusion: Detection and comprehensive analysis of bcl-2, c-myc and p53 protein expressions are useful in forecasting the radiotherapeutic effect on squamous cell carcinoma of esophagus

THERMAL RADIOSENSITIZATION IN HEAT-SENSITIVE AND RADIATION-SENSITIVE MUTANTS OF CHO CELLS

NARCIS (Netherlands)

KAMPINGA, HH; KANON, B; KONINGS, AWT; STACKHOUSE, MA; BEDFORD, JS

Recently, it has been hypothesized (Iliakis and Seaner 1990) that DNA double-strand break (dsb) repair proficiency is a prerequisite for heat radiosensitization on the basis of the finding that the radiosensitive and dsb-repair-deficient mutant xrs-5 cell line shows no significant heat-induced

Radiosensitivity evaluation of Human tumor cell lines by single cell gel electrophoresis

International Nuclear Information System (INIS)

Zhang Yipei; Cao Jia; Wang Yan; Du Liqing; Li Jin; Wang Qin; Fan Feiyue; Liu Qiang

2011-01-01

Objective: To explore the feasibility of determining radiosensitivity of human tumor cell lines in vitro using single cell gel electrophoresis (SCGE). Methods: Three human tumor cell lines were selected in this study, HepG 2 , EC-9706 and MCF-7. The surviving fraction (SF) and DNA damage were detected by MTT assay, nested PCR technique and comet assay respectively. Results: MTT assay: The SF of HepG 2 and EC-9706 after irradiated by 2, 4 and 8 Gy was lower significantly than that of MCF-7, which showed that the radiosensitivity of HepG 2 and EC-9706 was higher than that of MCF-7. But there was no statistical difference of SF between HepG 2 and EC-9706. SCGE: The difference of radiosensitivity among these three tumor cell lines was significant after 8 Gy γ-ray irradiation. Conclusion: The multi-utilization of many biological parameter is hopeful to evaluate the radiosensitivity of tumor cells more objectively and exactly. (authors)

Leukocyte apoptosis as a predictor of radiosensitivity in Fanconi anemia

International Nuclear Information System (INIS)

Petrovic, Sandra; Leskovac, Andreja; Joksic, Ivana; Filipovic, Jelena; Joksic, Gordana; Vujic, Dragana; Guc-Scekic, Marija

2013-01-01

Fanconi anemia (FA) is a rare cancer-prone genetic disease characterized by impaired oxygen metabolism and defects in DNA damage repair. Response of FA cells to ionizing radiation has been an issue intensively debated in the literature. To study in vitro radiosensitivity in patients suffering from FA and their parents (heterozygous carriers), we determined radiation-induced leukocyte apoptosis using flow cytometry. As TP53 gene is involved in the control of apoptosis, we studied its status in FA lymphocytes using dual colour fluorescence in situ hybridization (FISH). FA patients and female heterozygous carriers display radiosensitive response to ionizing radiation seen as abnormal elimination of cells via apoptosis. By employment of FISH, the TP53 allele loss in FA lymphocytes was not observed. In diseases related to oxidative stress, determination of radiation-induced apoptosis is the method of choice for testing the radiosensitivity. (author)

Radiation mutagenesis in lavender. I.Dose and emissive power as affecting the radiosensitivity of lavender seeds in gamma-ray treatment

International Nuclear Information System (INIS)

Tsvetkov, R.

1977-01-01

The radiosensitivity has been investigated of dormant seeds of the widely distributed aboriginal Hemus and Karlovo varieties and of the Soviet Stepnaya lavender variety in treatment with gamma rays using 60 Co. Doses within 1 to 100 kRad are applied at different emissive power of the emitter. Both irradiated and nonirradiated control seeds are gibberellic acid treated. The dynamics of seed sprouting is followed up. The number of survived plants and peculiarities of their growth are registered. The radiosensitivity of Lavandula vera D.C. seeds is modified by the emissive power in equal doses applied. Stepnaya variety showed highest resistance, followed by Karlovo and Hemus varieties. Doses are ascertained with a stimulating, inhibiting, semilethal and lethal effect in regard to the separate varietoes. Both stimulation and injuring prove to be of saltatory character. The radiation injuring of doses with an inhibitory, semilethal and lethal effect positively correlate with the dose of all tested emissive powers of the gamma-emitter. (author)

Interspecies variations inchromosomal radiosensitivity and repair among mammals

International Nuclear Information System (INIS)

Leonard, A.

1988-01-01

A review is presented of studies comparing relative chromosomal radiosensitivity of different mammalian species with the objective of assessing the induction of chromosomal aberrations in somatic cells following acute irradiation, the in vivo survival of peripheral blood lymphocytes carrying chromosomal abberations, and the correlation between chromosomal radiosensitivity of peripheral blood lymphocytes and of male germ cells. The ultimate aim was to find whether animal cell experiments can be used to replace experiments in man. The studies showed that the differences in radiosensitivity of the peripheral blood lymphocytes in the most commonly used animals and in man are insignificant and the results in animals are qualitatively and quantitatively representative of what can be expected for man. The life of peripheral blood lymphocytes carrying chromosomal abberations, however, is very short in most experimental animals. The animals thus cannot be used in studies of chromosome damage resulting from chronic irradiation. The studies also show that the yields of dicentric chromosomes in peripheral blood lymphocytes and of reciprocal translocations induced in germ cells are characteristic of each species and animal experiments cannot replace direct studies in man in this respect. (L.O.). 3 tabs., 40 refs

Nicotinamide and carbogen: relationship between pO2 and radiosensitivity in three tumour lines

International Nuclear Information System (INIS)

Martin, L.M.; Thomas, C.D.; Guichard, M.

1994-01-01

The effects of carbogen breathing, nicotinamide injection and their combination on tumour radiosensitivity were correlated with changes in tumour O 2 tension to determine the relationship between radiosensitivity and measured pO 2 . The radiosensitivity (in vivo-in vitro colony assay) and O 2 tension (computerized pO 2 histograph KIMOC 6650) of two human xenografted tumours (HRT18 and NA11 +) and one murine tumour (EMT6) were measured under similar experimental conditions. (author)

Chromosomal radiosensitivity in breast cancer patients and BRCA1 and 2 mutation carriers

International Nuclear Information System (INIS)

Vral, Anne

2004-01-01

Enhanced chromosomal radiosensitivity is observed in significant proportions of cancer patients. In breast cancer patients, this elevated sensitivity is confirmed in several independent studies with the G2 assay as well as with the GO micronucleus (MN) assay for peripheral blood lymphocytes (PBL). Enhanced chromosomal radiosensitivity is a common feature of sporadic breast cancer patients as well as breast cancer patients with a family history of the disease. Segregation analysis showed Mendelian heritability of chromosomal radiosensitivity. As mutations in the highly penetrant breast cancer predisposing genes, BRCA1 and 2, are only present in about 3-5 % of familial breast cancer patients, they cannot solely account for the high proportion of radiosensitive cases found among all breast cancer patients. A review on chromosomal radiosensitivity in BRCA1 and 2 mutation carriers shows that breast cancer patients with a BRCAl or 2 mutation are on the average more radiosensitive than healthy individuals, but not different from breast cancer patients without a BRCA mutation. The radiation response of healthy BRCA1/2 mutation carriers, on the contrary, is not significantly different from controls. Most studies performed on wild type and BRCA +/- EBV lymphoblastoid cell lines also could not demonstrate any differences in MN response between both groups. These findings suggest that mutations in BRCA 1 and 2 are not playing a major role in chromosomal radiosensitivity as measured by G2 and MN assay. The enhanced sensitivity observed in a substantial proportion of breast cancer patients, irrespective of a BRCA1/2 mutation or not, suggests that this feature may be related to the presence of other mutations in low penetrance breast cancer predisposing genes, which may be involved in the process of DNA damage. (author)

Doranidazole (PR-350), a hypoxic cell radiosensitizer, radiosensitizes human lung tumors (RERF-LC- AI) and causes changes in tumor oxygenation

International Nuclear Information System (INIS)

Kubota, N.; Griffin, R.J.; Williams, B.W.; Song, C.W.; Yahiro, T.

2003-01-01

Full text: We previously have reported the radiosensitizing capability of Doranidazole (PR-350) on SCCVII cells and tumors (Puerto Rico, 2001). In the present study, we have investigated the efficacy of PR-350 as a hypoxic cell radiosensitizer using human lung cancer cells (RERF-LC-AI) in vitro and also RERF-LC-AI tumors grown s.c. in Balb/c nude mice. Using the micronucleus assay method, we determined the effect of PR-350 on the response of RERF-LC-AI cells to radiation under hypoxic conditions and enhancement ratios (ER) of 1.45∼2.26 were obtained. The in vivo radiosensitizing effect was studied by irradiating RERF-LC-AI tumors with 15 Gy at 20 min. after i.v. injection of PR-350 (200mg/kg) and measuring the tumor growth delay. Significant growth delay occurred after i.v. injection of PR-350 before irradiation compared to radiation alone. We measured tumor pO 2 at 3, 7 and 14 days after treatment using an Eppendorf pO 2 histograph. The frequency of pO 2 values 2 in tumors treated with radiation plus PR-350 were higher than that in tumors treated with radiation plus saline. These data suggest that the O 2 consumption in tumors treated with radiation plus PR-350 was less than that in tumors treated with radiation plus saline due to greater drug and radiation-induced cell death. This hypothesis is supported by the fact that the tumor size in the combined treatment group was smaller than in radiation alone. These results suggest that PR-350 may improve the response of tumors to radiotherapy not only by increasing the radiosensitivity of hypoxic cells but also by improving tumor oxygenation over many days during fractionated radiotherapy

Effect of cisplatin on the clinically relevant radiosensitivity of human cervical carcinoma cell lines

International Nuclear Information System (INIS)

Britten, Richard A.; Evans, Andrew J.; Allalunis-Turner, M. Joan; Pearcey, Robert G.

1996-01-01

Purpose: To evaluate the effect of clinically relevant levels of cisplatin on the radiosensitivity of human cervical tumor cells, and to estimate what changes in local control rates might be expected to accrue from the concomitant use of cisplatin during fractionated radiotherapy. Methods and Materials: The effects of concomitant cisplatin (1 μg/ml, a typical intratumor concentration) on the clinically relevant radiosensitivity, i.e., surviving fraction after 2 G (SF 2 ) values, was determined in 19 cloned human cervical tumor cell lines. These early passage cell lines had SF 2 values ranging from 0.26 to 0.87. Results: The concomitant administration of cisplatin reduced the clinically relevant radiosensitivity in the majority (11 out of 19) of the human tumor cell lines investigated. In only 4 out of 19 was any radiosensitization observed, and in 4 out of 19 cell lines there was no significant change in radiosensitivity. However, the sum of the independent cell killing by radiation and cisplatin, was approximately twofold higher than after radiation alone. There was no apparent dependence of the cisplatin-induced changes in SF 2 values upon the level of cell killing by cisplatin. However, there is a suggestion that concomitant cisplatin administration may have a differential effect in inherently radiosensitive and resistant human tumor cell lines. Conclusions: Our data suggest that concomitant cisplatin/radiotherapy regimens may result in a higher level of local tumor control, but primarily through additive toxicity and not through radiosensitization. Future improvements in local tumor control may, thus, be derived by increasing the total dose of cisplatin

Roscovitine strongly enhances the effect of olaparib on radiosensitivity for HPV neg. but not for HPV pos. HNSCC cell lines.

Science.gov (United States)

Ziemann, Frank; Seltzsam, Steve; Dreffke, Kristin; Preising, Stefanie; Arenz, Andrea; Subtil, Florentine S B; Rieckmann, Thorsten; Engenhart-Cabillic, Rita; Dikomey, Ekkehard; Wittig, Andrea

2017-12-01

At present, advanced stage human Papillomavirus (HPV) negative and positive head and neck squamous cell carcinoma (HNSCC) are treated by intense multimodal therapy that includes radiochemotherapy, which are associated with relevant side effects. Patients with HPV positive tumors possess a far better prognosis than those with HPV negative cancers. Therefore, new therapeutic strategies are needed to improve the outcome especially of the latter one as well as quality of life for all HNSCC patients. Here we tested whether roscovitine, an inhibitor of cyclin-dependent kinases (CDKs), which hereby also blocks homologous recombination (HR), can be used to enhance the radiation sensitivity of HNSCC cell lines. In all five HPV negative and HPV positive cell lines tested, roscovitine caused inhibition of CDK1 and 2. Surprisingly, all HPV positive cell lines were found to be defective in HR. In contrast, HPV negative strains demonstrated efficient HR, which was completely suppressed by roscovitine. In line with this, for HPV negative but not for HPV positive cell lines, treatment with roscovitine resulted in a pronounced enhancement of the radiation-induced G2 arrest as well as a significant increase in radiosensitivity. Due to a defect in HR, all HPV positive cell lines were efficiently radiosensitized by the PARP-1 inhibitor olaparib. In contrast, in HPV negative cell lines a significant radiosensitization by olaparib was only achieved when combined with roscovitine.

Skin test of radiosensitivity. Application to Fanconi anemia

International Nuclear Information System (INIS)

Dutreix, J.; Gluckman, E.

1983-01-01

A test of skin radiosensitivity is described. It is achieved by irradiating small skin fields (15 mm in diameter) with 50 kV X-rays. The radiosensitivity is evaluated from the skin reaction observed for a single acute dose of 8 and 10 Gy; it is considered increased if the reaction for 10 Gy exceeds the desquamation threshold, and scored according to the observed reaction. The test includes an evaluation of the cellular repair, assessed on the comparison of the reactions for single dose and split irradiation. The time of the reaction peak is also reported. Abnormal reactions have been observed on 4 out of 8 patients with Fanconi Anemia

Skin test of radiosensitivity. Application to Fanconi anemia

Energy Technology Data Exchange (ETDEWEB)

Dutreix, J. (Institut Gustave-Roussy, 94 - Villejuif (France)); Gluckman, E. (Centre Hayem, Hopital St.-Louis, 75 Paris (France))

1983-01-01

A test of skin radiosensitivity is described. It is achieved by irradiating small skin fields (15 mm in diameter) with 50 kV X-rays. The radiosensitivity is evaluated from the skin reaction observed for a single acute dose of 8 and 10 Gy; it is considered increased if the reaction for 10 Gy exceeds the desquamation threshold, and scored according to the observed reaction. The test includes an evaluation of the cellular repair, assessed on the comparison of the reactions for single dose and split irradiation. The time of the reaction peak is also reported. Abnormal reactions have been observed on 4 out of 8 patients with Fanconi Anemia.

Gemcitabine radiosensitizes multiple myeloma cells to low let, but not high let, irradiation

International Nuclear Information System (INIS)

Supiot, Stephane; Thillays, Francois; Rio, Emmanuel; Gouard, Sebastien; Morgenstern, Alfred; Bruchertseifer, Frank; Mahe, Marc-Andre; Chatal, Jean-Francois; Davodeau, Francois; Cherel, Michel

2007-01-01

The radiosensitizing properties of gemcitabine in relation to low Linear Energy Transfer (LET) particles (Cobalt 60) and high-LET particles (alpha-RIT 213 Bi-radiolabeled CHX-DTPA-B-B4) were analyzed. Three multiple myeloma cell lines (LP1, RPMI 8226, U266) were irradiated with or without 10 nM gemcitabine 24 h prior to radiation. Gemcitabine led to radiosensitization of LP1 and U266 cells with low-LET (Radiation Enhancement Ratio: 1.55 and 1.49, respectively) but did not radiosensitize any cell line when combined with high-LET

Cloning of smac gene and its overexpression effects on radiosensitivity of HeLa cells to γ-rays

International Nuclear Information System (INIS)

Zhao Baofeng; Tian Mei; Lei Hongwei; Su Xu

2006-01-01

Objective: To clone smac gene and construct eukaryocytic expression vector pcDNA3.1/ smac. The smac gene was transfected into HeLa cells to explore the effects of over-expression of extrinsic smac gene on radiosensitivity to γ-rays of HeLa cells. Methods: The full-length smac gene was amplified from total RNA of HeLa cells by RTPCR. The RTPCR product was ligated with the vector pcDNA3.1 and sequenced. The correct pcDNA3.1/smac was transfected into HeLa cells. The expression of smac gene was tested by RTPCR and Western blot. The cellular growth inhibition rates were evaluated by MTT 48 horns after irradiation with different doses of γ-rays. Results: Recombinant eukaryocytic expression vector pcDNA3.1/smac was successfully constructed. RTPCR and Western blot results indicated that the expression of smac gene of HeLa/smac cells was significantly enhanced compared with the expression of smac gene of HeLa/pcDNA3.1 and HeLa cells. 48 hours after different doses of γ-ray irradiation was significantly higher in pcDNA3.1/smac transfected HeLa/smac cells than those of non-transfected HeLa cells or pcDNA3.1 transfected HeLa/pcDNA3.1 cells, inhabitation rates were 38.85%, 17.64% and 20.32%, respectively. Conclusions: smac gene was successfully cloned. Extrinsic smac gene over-expression could significantly enhance radiosensitivity to γ-ray of HeLa cells, which would herald a new approach to improve radiosensitivity of cervical cancer. (authors)

Radiosensitizing effect of artesunate on nude mice transplanted with HeLa cells of cervical cancer

International Nuclear Information System (INIS)

Zhou Yuanyuan; Feng Yang; Zhang Xuguang; Zhu Wei; Ni Qianying; Geng Chong; Chen Guanglie; Luo Judong; Fan Saijun; Cao Jianping

2011-01-01

Objective: To investigate the radiosensitization of artesunate on nude mouse transplanted with HeLa cells,and to explore its possible mechanisms. Methods: HeLa cells were inoculated into the nude mice to establish tumor model. Mice were randomly divided into 4 groups as blank control,artesunate group, radiation group and artesunate + radiation group when average volume of tumor were about 5 mm × 5 mm× 5 mm. During the term of treatment, the volume of tumors were measured every 2 days. After 14 days treatment, the mice were killed and tumor tissues were harvested for flow cytometry to detect the alteration of cell cycle. Meanwhile, the pathological change of the tumor tissue was observed with HE staining method, and the change of expression of cycle regulatory protein Cyclin B1, Cdc2 and Wee1 were detected by Western blot. Results: The growth of tumor was significantly inhibited by artesunate combined with radiation and its inhibition rate was 72.34%. Flow cytometry results showed that the percent of cells in G 1 phase increased and G 2 phase decreased in the artesunate + radiation group compared with those in irradiation group (t=4.41, 4.12, P<0.05). The expression level of Cyclin B1 was obviously increased while that of Wee1 decreased in the artesunate + radiation compared with irradiation group. There was no difference in the expression of Cdc2 among the four groups. Conclusions: Artesunate can dramatically increase the radiosensitivity of transplanted tumor of HeLa cells. The possible mechanism might be related to the decreasing G 2 phase by regulating the expression of Cyclin B1 and Wee1. (authors)

Activity-dependent switch of GABAergic inhibition into glutamatergic excitation in astrocyte-neuron networks.

Science.gov (United States)

Perea, Gertrudis; Gómez, Ricardo; Mederos, Sara; Covelo, Ana; Ballesteros, Jesús J; Schlosser, Laura; Hernández-Vivanco, Alicia; Martín-Fernández, Mario; Quintana, Ruth; Rayan, Abdelrahman; Díez, Adolfo; Fuenzalida, Marco; Agarwal, Amit; Bergles, Dwight E; Bettler, Bernhard; Manahan-Vaughan, Denise; Martín, Eduardo D; Kirchhoff, Frank; Araque, Alfonso

2016-12-24

Interneurons are critical for proper neural network function and can activate Ca 2+ signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition vs potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABA A receptors, potentiation involved astrocyte GABA B receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABA B receptor ( Gabbr1 ) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay.

Enhancement of misonidazole radiosensitization by an inhibitor of glutathione biosynthesis

International Nuclear Information System (INIS)

Hodgkiss, R.J.; Middleton, R.W.

1983-01-01

A well known inhibitor of glutathione biosynthesis, buthione sulphoximine (S-n-butyl homocysteine sulphoximine, BSO) depletes non-protein sulphydryls (NPSH) in Chinese hamster cells in vitro, resulting in a marked increase in the radiosensitization efficiency of misonidazole. V79 379A Chinese hamster cells were maintained in suspension cultures and irradiated in monolayers using 250 kVp X-rays at a dose rate of 3.93 Gy/min. Radiosensitization by misonidazole alone gave results within 0.1 sensitizer enhancement ratio (s.e.r.) of the curve reported by Watts et al. (1980). GSH (2 mmol dm - 3 ) added to the extracellular medium resulted in a marked decrease in the radiosensitization efficiency of misonidazole, eliminating the effect at 0.1 mmol dm - 3 misonidazole (s.e.r. = 1.0 relative to nitrogen control). A marked enhancement of the radiosensitization by misonidazole was observed when the cells had been incubated with BSO (0.1 mmol dm - 3 ). BSO alone at this concentration gave s.e.r. = 1.17; misonidazole alone (0.1 mmol dm - 3 ) gave s.e.r. = 1.18 and misonidazole with BSO (both 0.1. mmol dm - 3 ) gave s.e.r. = 1.9. The BSO treatment gave little effect in aerated cells. The concentration of BSO needed to produce these effects in vitro is ca. 40-fold lower than doses tolerated by mice in repeated administrations. (U.K.)

Chromatin structure and cellular radiosensitivity : A comparison of two human tumour cell lines

NARCIS (Netherlands)

Woudstra, EC; Roesink, JM; Rosemann, M; Brunsting, JF; Driessen, C; Orta, T; Konings, AWT; Peacock, JH; Kampinga, HH

1996-01-01

The role of variation in susceptibility to DNA damage induction was studied as a determinant for cellular radiosensitivity. Comparison of the radiosensitive HX142 and radioresistant RT112 cell lines previously revealed higher susceptibility to X-ray-induced DNA damage in the sensitive cell line

The potential role of G2- but not of G0-radiosensitivity for predisposition of prostate cancer

International Nuclear Information System (INIS)

Borgmann, Kerstin; Raabe, Annette; Reuther, Sebastian; Szymczak, Silke; Schlomm, Thorsten; Isbarn, Hendrik; Gomolka, Maria; Busjahn, Andreas; Bonin, Michael; Ziegler, Andreas; Dikomey, Ekkehard

2010-01-01

Purpose: Comparing the chromosomal radiosensitivity of prostate cancer patients with that of healthy donors. Materials and methods: The study was performed on 81 prostate cancer patients characterised by a clinical stage of predominantly pT2c or pT3a and a median age of 67 years. As healthy donors 60 male monozygotic twin pairs were recruited with a median age of 28 years. Chromosomal radiosensitivity was measured using both G0- and G2-assay. Results: No difference between healthy donors and prostate cancer patients was detected concerning G0-radiosensitivity, since medians were similar (Hodges-Lehmann estimate: -0.05, 95% CI: -0.18-0.08, p = 0.4167). However, a pronounced difference was determined for G2-radiosensitivity with prostate cancer patients showing a significantly higher sensitivity compared to healthy donors (Hodges-Lehmann estimate: -0.41, 95% CI: -0.53 to -0.30, p = 1.75 -9 ). Using the 90% quantile of G2-radiosensitivity in healthy donors as a threshold for discrimination the fraction of prostate cancer patients with elevated radiosensitivity increased to 49%. Conclusion: G2-, but not G0-radiosensitivity is a promising marker for predisposition of prostate cancer.

Chromosomal fragility syndrome and family history of radiosensitivity as indicators for radiotherapy dose modification

International Nuclear Information System (INIS)

Alsbeih, Ghazi; Story, Michael D.; Maor, Moshe H.; Geara, Fady B.; Brock, William A.

2003-01-01

Beside a few known radiosensitive syndromes, a patient's reaction to radiotherapy is difficult to predict. In this report we describe the management of a pediatric cancer patient presented with a family history of radiosensitivity and cancer proneness. Laboratory investigations revealed a chromosomal fragility syndrome and an increased cellular radiosensitivity in vitro. AT gene sequencing revealed no mutations. The patient was treated with reduced radiation doses to avoid the presumed increased risks of toxicity to normal tissues. The patient tolerated well the treatment with no significant acute or late radiation sequelae. Five years later, the patient remains both disease and complications free. While an accurate laboratory test for radiosensitivity is still lacking, assessments of chromosomal fragility, cell survival and clinical medicine will continue to be useful for a small number of patients

Effect of thorium, cerium and lanthanium metals on the radiosensitivity of human osteoblasts

International Nuclear Information System (INIS)

Iwahara, Lucas Kiyoshi da Fonseca

2016-01-01

This work analyzed the effects of Th, Ce and La combinations on the human osteoblast proliferation. Due to the osteotropic potential of actinides and lanthanides, a human osteoblast cell line was used to evaluate the effects of metals on cell radiosensitivity using cell proliferation and total proteins as indicators. Assays were performed using cultures exposed to metal alone and in combination and to ionising radiation. It was not observed effects on proliferation for cultures exposed to the metals alone. Concerning the influence of the three elements on the radiosensitivity, it was seen that all three metals were able to interfere on this indicator, in a concentration dependent manner. Evaluating cultures exposed to binary mixtures (Th-Ce and Th-La) and a ternary mixture (Th-Ce-La), it was verified that there were chemical interactions between the metals, for the combinations tested. The results showed very strong antagonism on the inhibition of cell proliferation in cultures exposed to Th-La and Th- Ce-La combinations. Regarding the osteoblasts exposed to mixtures and to radiation it was seen an antagonistic effect on the cell proliferation in all tested combinations, and the Th-Ce combination with a higher degree. These results show that metal mixtures containing thorium, in association with ionising radiation, induced different effects on cell proliferation, regarding the exposure to the metals alone, suggesting the possibility that the combinations interfere on osteoblast radiosensitivity expressing the increase of the occupational hazard among workers involved with monazite sands. The results also indicate that the analysis of the effects of metal mixtures on human cells is a more realistic risk assessment in comparison with the analysis of risk for single elements. The work displays the need to development of risk assessment models that include the study of mixtures obtained in the work environment for the evaluation of cytotoxic and radiotoxic effects in

Radiosensitization: enhancing the radiation inactivation of foodborne bacteria

Science.gov (United States)

Borsa, J.; Lacroix, M.; Ouattara, B.; Chiasson, F.

2004-09-01

Irradiation of meat products to kill pathogens can be limited by radiation-induced detriment of sensory quality. Since such detriment is directly related to dose, one approach to reduce it is by devising means to lower the dose of radiation required for processing. Increasing the radiation sensitivity of the target microorganisms would lower the dose required for a given level of microbial kill. In this work, the radiation sensitivities of inoculated Escherichia coli and Salmonella typhi in ground beef were examined under a variety of conditions. Results showed that specific manipulations of treatment conditions significantly increased the radiation sensitivity of the test organisms, ranging from a few percent to several-fold reduction in D10. In particular, radiation sensitization could be effected by certain additives, including carvacrol, thymol and trans-cinnamaldehyde, and also by certain compositions of modified atmosphere in the package headspace. A combination of additives and modified atmosphere effected a greater radiosensitization effect than could be achieved by either factor applied alone. Radiosensitization could be demonstrated with irradiation of either fresh or frozen ground meat. The radiosensitization phenomenon may be of practical utility in enhancing the technical effectiveness and feasibility of irradiation of a variety of meat and other food products.

Radiosensitization: enhancing the radiation inactivation of foodborne bacteria

Energy Technology Data Exchange (ETDEWEB)

Borsa, J. E-mail: jborsa@mds.nordion.com; Lacroix, M.; Ouattara, B.; Chiasson, F

2004-10-01

Irradiation of meat products to kill pathogens can be limited by radiation-induced detriment of sensory quality. Since such detriment is directly related to dose, one approach to reduce it is by devising means to lower the dose of radiation required for processing. Increasing the radiation sensitivity of the target microorganisms would lower the dose required for a given level of microbial kill. In this work, the radiation sensitivities of inoculated Escherichia coli and Salmonella typhi in ground beef were examined under a variety of conditions. Results showed that specific manipulations of treatment conditions significantly increased the radiation sensitivity of the test organisms, ranging from a few percent to several-fold reduction in D{sub 10}. In particular, radiation sensitization could be effected by certain additives, including carvacrol, thymol and trans-cinnamaldehyde, and also by certain compositions of modified atmosphere in the package headspace. A combination of additives and modified atmosphere effected a greater radiosensitization effect than could be achieved by either factor applied alone. Radiosensitization could be demonstrated with irradiation of either fresh or frozen ground meat. The radiosensitization phenomenon may be of practical utility in enhancing the technical effectiveness and feasibility of irradiation of a variety of meat and other food products.

The modulation of radiosensitivity by combined treatment of selective COX-2 inhibitor, NS 398 and EGF receptor blocker AG 1478 in HeLa cell line

Energy Technology Data Exchange (ETDEWEB)

Youn, Seon Min; Oh, Young Kee; Kim, Joo Heon; Park, Mi Ja; Seong, In Ock [Eulji University School of Medicine, Daejeon (Korea, Republic of); Kang, Ki Mun; Chai, Gyu Yong [Gyeongsang National University College of Medicine, Jinju (Korea, Republic of)

2005-03-15

Selective inhibition of multiple molecular targets may improve the antitumor activity of radiation. Two specific inhibitors of selective cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) were combined with radiation on the HeLa cell line. To investigate cooperative mechanism with selective COX-2 inhibitor and EGFR blocker, in vitro experiments were done. Antitumor effect was obtained by growth inhibition and apoptosis analysis by annexin V-Flous method. Radiation modulation effects were determined by the clonogenic cell survival assay. Surviving fractions at 2 Gy (SF{sub 2}) and dose enhancement radio at a surviving fraction of 0.25 were evaluated. To investigate the mechanism of the modulation of radiosensitivity, the cell cycle analyses were done by flow cytometry. The bcl-2 and bax expressions were analyzed by western blot. A cooperative effect were observed on the apoptosis of the HeLa cell line when combination of the two drugs, AG 1478 and NS 398 with radiation at the lowest doses, apoptosis of 22.70% compare with combination of the one drug with radiation, apoptosis of 8.49%. In cell cycle analysis, accumulation of cell on G{sub 0}/G{sub 1} phase and decrement of S phase fraction was observed from 24 hours to 72 hours after treatment with radiation, AG 1478 and NS 398. The combination of NS 398 and AG 1478 enhanced radiosensitivity in a concentration-dependent manner in HeLa cells with dose enhancement ratios of 3.00 and SF{sub 2} of 0.12 but the combination of one drug with radiation was not enhanced radiosensitivity with dose enhancement ratios of 1.12 and SF2 of 0.68 ({rho} = 0.005). The expression levels of bcl-2 and bax were reduced when combined with AG 1478 and NS 398. Our results indicate that the selective COX-2 inhibitor and EGFR blocker combined with radiation have potential additive or cooperative effects on radiation treatment and may act through various mechanisms including direct inhibition of tumor cell proliferation

Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines.

LENUS (Irish Health Repository)

Anoopkumar-Dukie, S

2009-10-01

Oxygen-dependent radiosensitivity of tumour cells reflects direct oxidative damage to DNA, but non-nuclear mechanisms including signalling pathways may also contribute. Mitochondria are likely candidates because not only do they integrate signals from each of the main kinase pathways but mitochondrial kinases responsive to oxidative stress communicate to the rest of the cell. Using pharmacological and immunochemical methods, we tested the role of mitochondrial permeability transition (MPT) and the Bcl-2 proteins in oxygen-dependent radiosensitivity. Drug-treated or untreated cervical cancer HeLa, breast cancer MCF-7 and melanoma MeWo cell lines were irradiated at 6.2 Gy under normoxic and hypoxic conditions then allowed to proliferate for 7 days. The MPT blocker cyclosporin A (2 microM) strongly protected HeLa but not the other two lines against oxygen-dependent radiosensitivity. By contrast, bongkrekic acid (50 microM), which blocks MPT by targeting the adenine nucleotide transporter, had only marginal effect and calcineurin inhibitor FK-506 (0.1 microM) had none. Nor was evidence found for the modulation of oxygen-dependent radiosensitivity by Bax\\/Bcl-2 signalling, mitochondrial ATP-dependent potassium (mitoK(ATP)) channels or mitochondrial Ca(2+) uptake. In conclusion, calcineurin-independent protection by cyclosporin A suggests that MPT but not mitoK(ATP) or the mitochondrial apoptosis pathway plays a causal role in oxygen-dependent radiosensitivity of HeLa cells. Targeting MPT may therefore improve the effectiveness of radiotherapy in some solid tumours.

Chromosomes, cancer and radiosensitivity

International Nuclear Information System (INIS)

Samouhos, E.

1983-01-01

Some specific chromosomal abnormalities are associated with certain cancers. The earliest description of such a specific association is the one of the Philadelphia chromosome and myelogenous leukemia (1960). Other congenital karyotype abnormalities are associated with specific cancers. Examples of these are Down's syndrome with leukemia and Klinefelter's syndrome with male breast cancer. Genetic diseases of increased chromosome breakage, or of defective chromosome repair, are associated with greatly increased cancer incidence. Three such diseases have been recognized: 1) Fanconi's anemia, associated with leukemias and lymphomas, 2) Bloom's syndrome, associated with acute leukemias and lymphosarcoma, and 3) ataxia telangiectasia, associated with Hodgkin's disease, leukemia, and lymphosarcomas. Ten percent of individuals with ataxia telangiectasia will develop one of these neoplasms. Individuals with certain of these syndromes display an unusually high radiosensitivity. Radiation therapy for cancers has been fatal in patients who received as low as 3000 rad. This remarkable radiosensitivity has been quantitated in cell cultures from such cases. Evidence suggests that the apparent sensitivity may reflect subnormal ability to repair radiation damage. The rapid proliferation of information in this field stems from the interdigitation of many disciplines and specialties, including cytogenetics, cell biology, molecular biology, epidemiology, radiobiology, and several others. This paper is intended for clinicians; it presents a structured analytic scheme for correlating and classifying this multidisciplinary information as it becomes available

Studies on varietal radiosensitivity and genetical effect in triticum aestivum L

International Nuclear Information System (INIS)

Feng Zhijie; Wang Linqing

1987-09-01

The Dormand seeds (with 13% water content) of 49 wheat varieties (T riticum aestivum L.) were irradiated with 60 Co-γ ray of various doses, and the varietal radiosensitivities and the genetical effects were studied in experimental plots and laboratories. Significant differences in radiosensitivity were found among the varieties used in present experiment. The varietal radiosensitivity of T riticum aestivum L. manifested a continuous variation, which accords approximately with the normal distribution, from the sensitive to the resistant to 60 Co-γ rays. 49 varieties utilized could be divided into five groups with different radiosensitivity to 60 Co-γ rays: higher resistent, resistant, intermediat respose, sensitive and higher sensitive. It was found that most of the mutant varieties improved by irradiation were more resistant to γ rays than the local varieties which were more resistant than recombination varieties bred by crossbreeding, that is radiation-induced mutant varieties 2 generation. The results showed that mutation frequencies, mutation spectra and variebilities of the quantative traits varied with varieties. Higher mutation frequencies, wider mutation spectra and greater variabilities were observed in the sensitive varieties than in the resistant ones, and it suggested that there is a greater potential for selecting mutants in M 2 generation of more sensitive varieties

Enhancement of radiosensitivity of recombinant Ad-p53 gene on human lung adenocarcinoma cell with different p53 status

International Nuclear Information System (INIS)

Pang Dequan; Wang Peiguo; Wang Ping; Zhang Weiming

2008-01-01

Objective: To investigate the enhancement of radiosensitivity of recombinant Ad-p53 gene on human lung adenocarcinoma cell lines(A549 and GLC-82) with different p53 status in vitro. Methods: Two human lung adenocarcinoma cell lines of A549 and GLC-82 were examined on their difference in p53 status with immunohistochemistry stain and PCR-SSCP technique. Expand Ad-wtp53 was transfected into tumor cells. Clonogenic assays were performed to evaluate the inhibition effect on cell growth and the degree of sensitization to irradiation. Apoptosis and cell cycle changes were determined using the flow cytometry assay. Results: The A549 cell line presented positive P53 expression while GLC-82 negative. GLC-82 bore mutant p53 on the exon 7. The wtp53 gene could be efficiently expressed in the two cell lines and greatly inhibit the cell growth. Its efficiency didn't depend on the intrinsic p53 genetic status. After irradiation, its function of inducing G 1 arrest and apoptosis on GLC-82 cell line was much stronger than the A549 cell line. In both the A549 and GLC-82 cell lines, the combination of Ad-p53 plus radiation resulted in more apoptosis than the others. There was no significant difference between two groups. Conclusions: Ad-p53 can depress the tumor growth and enhance the radiosensitivity of human lung adenocarcinoma cells. And this effect is independent of endogenous p53 status. (authors)

Effect of constitutive androstane receptor on radiosensitization of mictomycin C and its homologoue-629

International Nuclear Information System (INIS)

Zhang Jianghong; Jin Yizun

2008-01-01

The object of this work is to evaluate radiosensitization of MMC and its analogue 5-(aziridin-l-yl)-3- hydroxymethyl-1-methylindole-4,7-dione(629) and how transfection of constitutive androstane receptor (CAR) affect their biological effects. The expressions of CAR mRNA and CYP2B6 mRNA in HepG2 cells and g2car cells were detected by RT-PCR. The radiosensitization of MMC and 629 in vitro were evaluated in HepG2 cells and g2car cells by colony formation under anaerobic and aerobic condition. The effect of 629 on cell cycle and apoptosis of HepG2 cells and g2car cells were assayed by flow cytometry. It was found that plasmid mCAR1/pCR3 was transfected into g2car cells successfully and target CYP2B6 was transactivated by CAR. To compare with aerobic and anaerobic, the radiosensitization of MMC and 629 to HepG2 cells and g2car cells had significantly enhanced, the radiosensitization of 629 was stronger than its parent compound-MMC under aerobic and anaerobic condition, and transfect CAR gene could improve the radiosensitization of MMC and 629. Furthermore, CYP2B6 is one master enzyme for the metabolism of MMC and 629. Transfection of CAR can increase expression of CYP2B6 mRNA in HepG2 cells, and can affect radiosensitization of MMC and 629. (authors)

Effect of laser radiation on rat radiosensitivity

Energy Technology Data Exchange (ETDEWEB)

Laprun, I.B.

1979-03-01

Quite a few experimental data have been obtained to date indicating that radioresistance of the organism is enhanced under the influence of electromagnetic emissions in the radiofrequency and optical ranges. But no studies were made of the possible radioprotective properties of coherent laser radiation. At the same time, it was demonstrated that the low-energy emission of optical quantum generators (lasers) in the red band stimulates the protective forces of the organism and accelerates regenerative processes; i.e., it induces effects that are the opposite of that of ionizing radiation. Moreover, it was recently demonstrated that there is activation of catalase, a radiosensitive enzyme that plays an important role in the metabolism of peroxide compounds, under the influence of lasers. For this reason, the effect of pre-exposure to laser beams on radiosensitivity of rats was tested.

Radiosensitivity of mesothelioma cell lines

International Nuclear Information System (INIS)

Haekkinen, A.M.; Laasonen, A.; Linnainmaa, K.; Mattson, K.; Pyrhoenen, S.

1996-01-01

The present study was carried out in order to examine the radiosensitivity of malignant pleural mesothelioma cell lines. Cell kinetics, radiation-induced delay of the cell cycle and DNA ploidy of the cell lines were also determined. For comparison an HeLa and a human foetal fibroblast cell line were simultaneously explored. Six previously cytogenetically and histologically characterized mesothelioma tumor cell lines were applied. A rapid tiazolyl blue microtiter (MTT) assay was used to analyze radiosensitivity and cell kinetics and DNA ploidy of the cultured cells were determined by flow cytometry. The survival fraction after a dose of 2 Gy (SF2), parameters α and β of the linear quadratic model (LQ-model) and mean inactivation dose (D MID ) were also estimated. The DNA index of four cell lines equaled 1.0 and two cell lines equaled 1.5 and 1.6. Different mesothelioma cell lines showed a great variation in radiosensitivity. Mean survival fraction after a radiation dose of 2 Gy (SF2) was 0.60 and ranged from 0.36 to 0.81 and mean α value was 0.26 (range 0.48-0.083). The SF2 of the most sensitive diploid mesothelioma cell line was 0.36: Less than that of the foetal fibroblast cell line (0.49). The survival fractions (0.81 and 0.74) of the two most resistant cell lines, which also were aneuploid, were equal to that of the HeLa cell line (0.78). The α/β ratios of the most sensitive cell lines were almost an order of magnitude greater than those of the two most resistant cell lines. Radiation-induced delay of the most resistant aneuploid cell line was similar to that of HeLa cells but in the most sensitive (diploid cells) there was practically no entry into the G1 phase following the 2 Gy radiation dose during 36 h. (orig.)

Radiosensitivity of mesothelioma cell lines

Energy Technology Data Exchange (ETDEWEB)

Haekkinen, A.M. [Dept. of Oncology, Univ. Central Hospital, Helsinki (Finland); Laasonen, A. [Dept. of Pathology, Central Hospital of Etelae-Pohjanmaa, Seinaejoki (Finland); Linnainmaa, K. [Dept. of Industrial Hygiene and Toxicology, Inst. of Occupational Health, Helsinki (Finland); Mattson, K. [Dept. Pulmonary Medicine, Univ. Central Hospital, Helsinki (Finland); Pyrhoenen, S. [Dept. of Oncology, Univ. Central Hospital, Helsinki (Finland)

1996-10-01

The present study was carried out in order to examine the radiosensitivity of malignant pleural mesothelioma cell lines. Cell kinetics, radiation-induced delay of the cell cycle and DNA ploidy of the cell lines were also determined. For comparison an HeLa and a human foetal fibroblast cell line were simultaneously explored. Six previously cytogenetically and histologically characterized mesothelioma tumor cell lines were applied. A rapid tiazolyl blue microtiter (MTT) assay was used to analyze radiosensitivity and cell kinetics and DNA ploidy of the cultured cells were determined by flow cytometry. The survival fraction after a dose of 2 Gy (SF2), parameters {alpha} and {beta} of the linear quadratic model (LQ-model) and mean inactivation dose (D{sub MID}) were also estimated. The DNA index of four cell lines equaled 1.0 and two cell lines equaled 1.5 and 1.6. Different mesothelioma cell lines showed a great variation in radiosensitivity. Mean survival fraction after a radiation dose of 2 Gy (SF2) was 0.60 and ranged from 0.36 to 0.81 and mean {alpha} value was 0.26 (range 0.48-0.083). The SF2 of the most sensitive diploid mesothelioma cell line was 0.36: Less than that of the foetal fibroblast cell line (0.49). The survival fractions (0.81 and 0.74) of the two most resistant cell lines, which also were aneuploid, were equal to that of the HeLa cell line (0.78). The {alpha}/{beta} ratios of the most sensitive cell lines were almost an order of magnitude greater than those of the two most resistant cell lines. Radiation-induced delay of the most resistant aneuploid cell line was similar to that of HeLa cells but in the most sensitive (diploid cells) there was practically no entry into the G1 phase following the 2 Gy radiation dose during 36 h. (orig.).

Radiosensitization of tumors and normal tissues by combined treatment with misonidazole and heat

International Nuclear Information System (INIS)

Hofer, K.G.; MacKinnon, A.R.; Schubert, A.L.; Lehr, J.E.; Grimmett, E.V.

1981-01-01

Combination treatment of mice with misonidazole (0.5 mg/g body wt.) and hyperthermia (41.5/sup o/C for 45 mins.) produced dramatic radiosensitization in hypoxic BP-8 murine sarcoma cells. The dose modifying factor (DMF: 4.3) was such that hypoxic BP-8 cells subjected to combination therapy became more radiosensitive than untreated, fully oxygenated cell populations. In contrast, radiosensitization by combination treatment was comparatively minor or completely absent in normal body tissues such as skin (DMF: 1.57), intestine (DMF: 1.0), and bone marrow (DMF: 1.0). These results suggest that simultaneous administration of misonidazole and hyperthermia may prove an effective adjuvant to conventional clinical radiation therapy

Lack of dependence of 5-fluorodeoxyuridine-mediated radiosensitization on cytotoxicity

International Nuclear Information System (INIS)

Lawrence, T.S.; Davis, M.A.; Chang, E.Y.

1995-01-01

It has been proposed that fluoropyrimidine-mediated cytotoxicity and radiosensitization are closely correlated. We have shown that HT29 human colon cancer cells transfected with the E. coli dUTPase gene are resistant to 5-fluorodeoxyuridine (FdUrd)-mediated cytotoxicity, presumably through more effective elimination of dUTP. We used these cells to assess the association between radiosensitization and cytotoxicity produced by FdUrd. The radiation sensitivities of the clones expressing elevated dUTPase activity (dutE clones) were similar to those of untransfected HT29 cells or HT29 cells which has been transfected with only the expression vector for the E. coli gene (con clones). We found that FdUrd produced similar increases in radiation sensitivity regardless of dUTPase activity. Levels of dUTPase in the dutE clones remained elevated during the entire period of FdUrd exposure, demonstrating that the lack of difference between dutE and Con clones was not a reflection of down-regulation of dUTPase activity by FdUrd, Flow cytometry showed that all clones progressed past the G 1 /S-phase boundary and into early S phase during FdUrd treatment. These data suggest that the mechanisms of FdUrd-mediated cytotoxicity and radiosensitization are not closely linked. These findings, combined with our previous investigations, are consistent with the hypothesis that radiosensitization occurs in cells which progress past the G 1 /S-phase boundary in the presence of FdUrd. 24 refs., 2 figs., 2 tabs

Preferential radiosensitization of G1 checkpoint--deficient cells by methylxanthines

International Nuclear Information System (INIS)

Russell, Kenneth J.; Wiens, Linda W.; Demers, G. William; Galloway, Denise A.; Le, Tiep; Rice, Glenn C.; Bianco, James A.; Singer, Jack W.; Groudine, Mark

1996-01-01

Purpose: To develop a checkpoint-based strategy for preferential radiosensitization of human tumors with deficient and/or mutant p53. Methods and Materials: A549 human lung adenocarcinoma cell lines differing in their expression of the p53 tumor suppressor gene were produced by transduction with the E6 oncogene from human papilloma virus type 16. The cells expressing E6 (E6+) lack a G1 arrest in response to ionizing radiation, are deficient in p53 and p21 expression, and exhibit a fivefold greater clonogenic survival following 10 Gy radiation. Results: Postirradiation incubation with millimolar concentrations of the methylxanthine pentoxifylline (PTX) results in preferential radiosensitization of the E6+ cells compared to the LXSN+ vector transduced controls. There is a threefold sensitization of the LXSN+ cells and a 15-fold sensitization of the E6+ cells, which results in equal clonogenic survival of the two lines. Flow cytometry reveals PTX abrogation of the radiation induced G2 arrest for both cell lines. PTX also prolongs G1 transit for both cell lines. Preliminary results are presented using a novel methylxanthine, lisofylline (LSF), which has similar cell cycle effects on G1 and G2 and achieves differential radiosensitization at micromolar concentrations that are sustainable in humans. Conclusions: This checkpoint-based strategy is a promising approach for achieving preferential radiosensitization of p53- tumors relative to p53+ normal tissues

Heat shock protein 90 chaperone complex inhibitor enhanced radiosensitivity through modification of response to hormone and degradation of androgen receptor in hormone sensitive prostate cancer cell line

International Nuclear Information System (INIS)

Mitsuhashi, N.; Harashima, K.; Akimoto, T.

2003-01-01

It is easily speculated that androgen or androgen deprivation affects proliferative activity or radiosensitivity, but there has been enough information how androgen or androgen deprivation influences the response to radiation. In this setting, the effect of dihydrotestosterone (DHT) on cellular growth and radiosensitivity was examined in hormone-responsive human prostate cancer cell line (LnCap). The binding of androgen receptor (AR) with heat shock protein 90 (Hsp90) plays an important role in stability of the function of receptor. It was, therefore, examined how Hsp90 chaperone complex inhibitor modified the effect of DHT on radiosensitivity in addition to the effect of DHT, especially focusing on AR and its downstream signal transduction pathways. Hydroxy-flutamide (OH-flutamide) was also used to confirm the effect of activation of AR on radiosensitivity because AR of LnCap has a point mutation, leading to activation of AR caused by the binding of OH-flutamide. Radicicol was used as a Hsp90 chaperone complex inhibitor, and incubated with cells at a concentration of 500 nM. Radicicol was incubated with cells for 9 h, and cells were irradiated 1 h after the start of incubation. DHT and OH-flutamide were incubated with cells until staining. DHT or OH-flutamide resulted in stimulation of cellular growth in contrast to inhibition of cellular growth caused by higher concentrations, so that we adopted 1 nM as a concentration of DHT and 1μM as a concentration of OH-flutamide. DHT or OH-flutamide in combination with radiation resulted in slight decrease in radiosensitivity compared with radiation alone. Radicicol at a concentration of 500 nM in combination with DHT or OH-flutamide abolished decrease in radiosensitivity caused by DHT or OH-flutamide. In terms of the expression of AR, radicicol in combination with radiation and/or DHT, OH-flutamide induced degradation of AR. In consistent with degradation of AR, the expression of prostate specific antigen (PSA) decreased

Evaluation of Radiosensitivity of HeLa Cells Infected with Polio Virus Irradiated by Co 60

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F Seif

2008-04-01

Full Text Available ABSTRACT: Introduction & Objective: The main purpose of radiotherapy is exposing enough doses of radiation to tumor tissue and protecting the normal tissues around it. Tumor dose for each session in radiotherapy will be considered based on radiosensitivity of the tissues. The presence of viral diseases in tumoral area can affect the radiosensitivity of cells. This study aimed to evaluate the radiosensitivity of Hela cells infected with poliomyelitis virus irradiated by Co 60. Materials & Methods: In this study, the radiosensitivity of HeLa cells, with or without the viral infection, after gamma radiation of cobalt 60, was assessed. Results: Results of comparison of the radisensitivity of infected and uninfected cells indicates that after 2 Gy irradiation by Co 60, polio infection in low, moderate and high virus load, increases the cell death by 20-30%, 30-40% and 70-90% respectively. Conclusion : Radiosensitivity of tumoral cells increase when they are infected with viral agents. Results of this study showed that non cancer diseases should be considered when prescribing dose fraction in radiotherapy of cancers.

Pronounced radiosensitization of cultured human cancer cells by COX inhibitor under acidic microenvironment

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Shah, Tushar; Ryu, Samuel; Lee, Ho Jun; Brown, Stephen; Kim, Jae Ho

2002-01-01

Purpose: To demonstrate the influence of pH on the cytotoxicity and radiosensitization by COX (cyclooxygenase) -1 and -2 inhibitors using established human cancer cells in culture. Methods and Materials: Nonselective COX inhibitor, ibuprofen (IB), and selective COX-2 inhibitor, SC-236, were used to determine the cytotoxicity and radiosensitization at varying pH of culture media. Human colon carcinoma cell line (HT-29) was exposed to the drug alone and in combination with radiation at different pH of the cell culture media. The end point was clonogenic ability of the single-plated cells after the treatment. Results: Cytotoxicity and radiosensitization of IB increased with higher drug concentration and longer exposure time. The most significant radiosensitization was seen with IB (1.5 mM) for 2-h treatment at pH 6.7 before irradiation. The dose-modifying factor as defined by the ratio of radiation doses required to achieve the same effect on cell survival was 1.8 at 10% survival level. In contrast, SC-236 (50 μM for 2-8 h) showed no pH-dependent cytotoxicity. There was modest increase in the cell killing at lower doses of radiation. Conclusion: An acidic pH was an important factor affecting the increased cytotoxicity and radiosensitization by ibuprofen. Radiation response was enhanced at shoulder portion of the cell survival curve by selective COX-2 inhibitor

Ginsenoside Rg3 enhances radiosensitization of hypoxic oesophageal cancer cell lines through vascular endothelial growth factor and hypoxia inducible factor 1α.

Science.gov (United States)

Ge, Xiaolin; Zhen, Fuxi; Yang, Baixia; Yang, Xi; Cai, Jing; Zhang, Chi; Zhang, Sheng; Cao, Yuandong; Ma, Jianxin; Cheng, Hongyan; Sun, Xinchen

2014-06-01

To determine if the pretreatment of hypoxic human oesophageal carcinoma cell lines (EC109, TE1 and KYSE170) with ginsenoside Rg3 (Rg3) increases their radiosensitivity to X-rays. The growth inhibitory effect of different Rg3 concentrations was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. Radiation sensitivity was measured using a clone formation assay and flow cytometry was used to measure the effects of Rg3 on radiation-induced apoptosis. Western blot analysis was used to measure the effects of Rg3 on the levels of hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF). Rg3 inhibited EC109, TE1 and KYSE170 cell growth in a dose- and time-dependent manner. Pretreatment with 10 µmol/ml Rg3 increased EC109, TE1 and KYSE170 radiosensitivity. Rg3 plus radiation significantly increased the apoptosis rate compared with radiation alone. Rg3 also decreased VEGF and HIF-1α protein levels in EC109 cells in a dose-dependent manner. The combination of Rg3 and radiation increased the fragmentation of double-stranded DNA. Rg3 enhanced the radiosensitivity of human oesophageal carcinoma cell lines cultured under hypoxic conditions possibly by downregulating VEGF and HIF-1α protein levels. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Axin gene methylation status correlates with radiosensitivity of lung cancer cells

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Yang, Lian-He; Stoecker, Maggie; Wang, Endi; Xu, Ke; Wang, En-Hua; Han, Yang; Li, Guang; Xu, Hong-Tao; Jiang, Gui-Yang; Miao, Yuan; Zhang, Xiu-Peng; Zhao, Huan-Yu; Xu, Zheng-Fan

2013-01-01

We previously reported that Axin1 (Axin) is down-regulated in many cases of lung cancer, and X-ray irradiation increased Axin expression and inhibited lung cancer cells. The mechanisms, however, were not clear. Four lung cancer cell lines were used to detect the methylation status of Axin with or without X-ray treatment. Real-time PCR was used to quantify the expression of Axin, and western blot analysis was applied to measure protein levels of Axin, β-catenin, Cyclin D1, MMP-7, DNMTS, MeCP2 and acetylated histones. Flow cytometric analysis, colony formation assay, transwell assay and xenograft growth experiment were used to study the biological behavior of the cells with hypermethylated or unmethylated Axin gene after X-ray treatment. Hypermethylated Axin gene was detected in 2 of 4 cell lines, and it correlated inversely with Axin expression. X-ray treatment significantly up-regulated Axin expression in H446 and H157 cells, which possess intrinsic hypermethylation of the Axin gene (P<0.01), but did not show up-regulation in LTE and H460 cells, which have unmethylated Axin gene. 2Gy X-ray significantly reduced colony formation (from 71% to 10.5%) in H157 cells, while the reduction was lower in LTE cells (from 71% to 20%). After X-ray irradiation, xenograft growth was significantly decreased in H157 cells (from 1.15 g to 0.28 g) in comparison with LTE cells (from 1.06 g to 0.65 g). Significantly decreased cell invasiveness and increased apoptosis were also observed in H157 cells treated with X-ray irradiation (P<0.01). Down-regulation of DNMTs and MeCP2 and up-regulation of acetylated histones could be detected in lung cancer cells. X-ray-induced inhibition of lung cancer cells may be mediated by enhanced expression of Axin via genomic DNA demethylation and histone acetylation. Lung cancer cells with a different methylation status of the Axin gene showed different radiosensitivity, suggesting that the methylation status of the Axin gene may be one important factor

Effects of glutathione depletion by buthionine sulfoximine on radiosensitization by oxygen and misonidazole in vitro

International Nuclear Information System (INIS)

Shrieve, D.C.; Denekamp, J.; Minchinton, A.I.

1985-01-01

Buthionine sulfoximine (BSO) has been used to deplete glutathione (GSH) in V79-379A cells in vitro, and the effect on the efficiency of oxygen and misonidazole (MISO) as radiosensitizers has been determined. Treatment with 50 or 500 μM BSO caused a rapid decline in GSH content to less than 5% of control values after 10 hr of exposure. Removal of BSO resulted in a rapid regeneration of GSH after 50 μM BSO, but little regeneration was observed over the subsequent 10-hr period after 500 μM. Cells irradiated in monolayer on glass had an oxygen enhancement ratio (OER) of 3.1. After 10-14 hr pretreatment with 50 μM BSO, washed cells were radiosensitized by GSH depletion at all oxygen tensions tested. The OER was reduced to 2.6, due to greater radiosensitization of hypoxic cells than aerated ones by GSH depletion. In similar experiments performed with MISO, an enhancement ratio of 2.0 could be achieved with 0.2 mM MISO in anoxic BSO-pretreated cells, compared to 2.7 mM MISO in non-BSO-treated cells. These apparent increases in radiosensitizer efficiency in GSH-depleted cells could be explained on the basis of radiosensitization of hypoxic cells by GSH depletion alone. These results are consistent with hypoxic cell radiosensitization by GSH depletion and by MISO or oxygen acting by separate mechanisms

Atomoxetine restores the response inhibition network in Parkinson's disease.

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Rae, Charlotte L; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E; Jones, P Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

2016-08-01

Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction

Radiosensitivity of quince seeds (Cydonia oblonga Mill.)

International Nuclear Information System (INIS)

Dall'Orto, F.A.C.; Ojima, M.; Hiroce, R.; Igue, T.; Ferraz, E.S.B.; Nascimento Filho, V.F. do; Menten, J.O.M.; Tulmann Neto, A.; Ando, A.

1984-01-01

The investigation with quince seeds (Cydonia oblonga Mill.) radiosensitivity and the mineral composition of the plants obtained for mutation breeding are related. The concentration of some macro and micronutrients in quince seedlings obtained from irradiated seeds are studied. (M.A.C.) [pt

Characterization of tumorigenicity and radio-sensitivity markers by an ex vivo approach. In vivo identification of p53 dependent radio-sensitivity markers

International Nuclear Information System (INIS)

Alvarez, S.

2003-12-01

After a detailed discussion of the relationship between cancer and genetic instability, of the structure, activation mechanisms, activity and biological functions of the p53 protein, a presentation of p53 mutants, and a recall of the effects of ionizing radiations, the author reports a biology research during which he investigated a cell model established from rat embryo lungs treated with Benzo[a]pyrene and made of tumoral lines muted by the p53 gene. He tried to identify markers which could report differences of tumorigenicity and radio-sensitivity observed in these different lines. He also tried to characterize radio-sensitivity molecular markers dependent on the p53 gene in a context of normal cells

Taxonomic and developmental aspects of radiosensitivity

International Nuclear Information System (INIS)

Harrison, F.L.; Anderson, S.L.

1996-11-01

Considerable information is available on the effects of radioactivity on adult and early life stages of organisms. The preponderance of data is on mortality after a single irradiation with relatively high doses. Unfortunately, because experiments were carried out under different conditions and for different time periods, the validity of comparing the results from different laxonomic groups is questionable. In general, the conclusions are that there is a relationship (1) between radioresistance to high doses of acute radiation and taxonomy of the organism, primitive forms being more radioresistant than complex vertebrates and (2) between radiosensitivity and developmental stage, early life stages being more sensitive than later stages. The first conclusion may be related to the capability of the organism to repopulate cells and to differentiate and redifferentiate them; the second to the rate of cellular division and to the degree of differentiation. In question, however, is the relevance of the responses from high levels of acute radiation to that of the responses to long-term exposure to low levels of radiation, which are ecologically of more interest. Data from studies of the effects of acute and chronic exposure on development of gametes and zygotes indicate that, for some fishes and invertebrates, responses at the cellular and molecular levels show effect levels comparable to those observed in some mammals. Acute doses between 0,05 and 0.5Cy and dose rates between 0.02 to 0.2mCy/h appear to define critical ranges in which detrimental effects on fertility are first observed in a variety of radiosensitive organisms. To better understand inherent radiosensitivity, we need more information on the ability of cells to repopulate and differentiate and to prevent or repair damage to biological critical molecules, such as DNA, because these factors may alter significantly organisms'' responses to radiation

Taxonomic and developmental aspects of radiosensitivity

Energy Technology Data Exchange (ETDEWEB)

Harrison, F.L. [Lawrence Livermore National Lab., CA (United States); Anderson, S.L. [Lawrence Berkeley National Lab., CA (United States)

1996-11-01

Considerable information is available on the effects of radioactivity on adult and early life stages of organisms. The preponderance of data is on mortality after a single irradiation with relatively high doses. Unfortunately, because experiments were carried out under different conditions and for different time periods, the validity of comparing the results from different laxonomic groups is questionable. In general, the conclusions are that there is a relationship (1) between radioresistance to high doses of acute radiation and taxonomy of the organism, primitive forms being more radioresistant than complex vertebrates and (2) between radiosensitivity and developmental stage, early life stages being more sensitive than later stages. The first conclusion may be related to the capability of the organism to repopulate cells and to differentiate and redifferentiate them; the second to the rate of cellular division and to the degree of differentiation. In question, however, is the relevance of the responses from high levels of acute radiation to that of the responses to long-term exposure to low levels of radiation, which are ecologically of more interest. Data from studies of the effects of acute and chronic exposure on development of gametes and zygotes indicate that, for some fishes and invertebrates, responses at the cellular and molecular levels show effect levels comparable to those observed in some mammals. Acute doses between 0,05 and 0.5Cy and dose rates between 0.02 to 0.2mCy/h appear to define critical ranges in which detrimental effects on fertility are first observed in a variety of radiosensitive organisms. To better understand inherent radiosensitivity, we need more information on the ability of cells to repopulate and differentiate and to prevent or repair damage to biological critical molecules, such as DNA, because these factors may alter significantly organisms` responses to radiation.

Gamma radiosensitivity of a common bean cultivar

International Nuclear Information System (INIS)

Colaco, W.; Martinez, C.R.

1995-01-01

A preliminary experiment was conducted to evaluate the radiosensitivity of common bean (Phaseolous vulgaris L.), cultivar to gamma rays from a 60 Co source. Sets of seeds (60 seed/sample) irradiated with 50, 100, 150, 200, and 250 Gy, were compared to a control without irradiation (0 Gy), under greenhouse conditions. The radiosensitivity was evaluated through seedling height reduction, determined at 15 days after emergence (DAE), and also through seedling survival, root length, and dry matter production of leaves, shoots and roots. Seedling height was significantly reduced for the treatments with 150 and 250 Gy, in relation to the control. The dose causing reduction of 50% seedling height was between 150 and 200 Gy. Survival rates corresponding to these doses, were, respectively, 85% and 60%. Root length and dry matter of leaves, shoots and roots, were inversely related to the doses. (author). 15 refs, 3 figs, 1 tab

Radiosensitivity of garlic air bulbs

International Nuclear Information System (INIS)

Zhila, Eh.D.

1975-01-01

The paper presents data on the radiosensitivity of various sorts of garlic. It is shown that the frequency of chromosomal aberrations in the irradiated aerial bulbs of stemmed varieties of garlic is directly dependent upon the gmma-ray dose. With increasing dose the germination capacity and the viability of the plants diminishes. A dose of 750 r was found to be critical for the bulbs of the garlic varieties studied

PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility

International Nuclear Information System (INIS)

Godon, C.; Cordelieres, F.P.; Giocanti, N.; Megnin-Chanet, F.; Hall, J.; Favaudon, V.; Godon, C.; Giocanti, N.; Megnin-Chanet, F.; Hall, J.; Favaudon, V.; Cordelieres, F.P.; Cordelieres, F.P.; Biard, D.

2008-01-01

The consequences of PARP-1 disruption or inhibition on DNA single-strand break repair (SSBR) and radio-induced lethality were determined in synchronized, iso-genic HeLa cells stably silenced or not for poly(ADP-ribose) polymerase-1 (PARP-1) (PARP-1(KD)) or XRCC1 (XRCC1(KD)). PARP-1 inhibition prevented XRCC1-YFP recruitment at sites of 405 nm laser micro irradiation, slowed SSBR 10-fold and triggered the accumulation of large persistent foci of GFP-PARP-1 and GFP-PCNA at photo damaged sites. These aggregates are presumed to hinder the recruitment of other effectors of the base excision repair (BER) pathway.PARP-1 silencing also prevented XRCC1-YFP recruitment but did not lengthen the lifetime of GFP-PCNA foci. Moreover, PARP-1(KD) and XRCC1(KD) cells in S phase completed SSBR as rapidly as controls, while SSBR was delayed in G1. Taken together, the data demonstrate that a PARP-1- and XRCC1-independent SSBR pathway operates when the short patch repair branch of the BER is deficient. Long patch repair is the likely mechanism, as GFP-PCNA recruitment at photo-damaged sites was normal in PARP-1(KD) cells. PARP-1 silencing elicited hyper-radiosensitivity, while radiosensitization by a PARP inhibitor reportedly occurs only in those cells treated in S phase. PARP-1 inhibition and deletion thus have different outcomes in terms of SSBR and radiosensitivity. (authors)

Study on the relationship between DNA-PKcs and genomic instability and hyper-radiosensitivity

International Nuclear Information System (INIS)

Yang Kang; Zhu Jiayun; Ding Nan; Li Junhong; Hu Wentao; Su Fengtao; He Jinpeng; Li Sha

2010-01-01

To investigate the relationship between DNA-PKcs and genome instability and hyper-radiosensitivity, human glioma cell lines M059K and M059J, as a model expressing wild-type DNA-PKcs and a model defective in DNA-PKcs activity, were exposed to low doses of X-rays. Cells survival fractions were assessed by colony-forming assay and Cytochalasin-B micronucleus assay was employed to detect the genomic instability happening in each single irradiated colony. It has been found that as the post-incubation time increased, M059K cells expressing wild-type DNA-PKcs exhibited low-dose hyper-radiosensitivity and showed a similar genomic instability after 0.2 Gy and 0.6 Gy irradiations, but the M059J cells lacking in DNA-PKcs didn't present low-dose hyper-radiosensitivity and showed a higher genomic instability of 0.6 Gy than that of 0.2 Gy. The results indicate that DNA-PKcs may act as one of the key factors that lead to low-dose hyper-radiosensitivity. (authors)

Local excitation-inhibition ratio for synfire chain propagation in feed-forward neuronal networks

Science.gov (United States)

Guo, Xinmeng; Yu, Haitao; Wang, Jiang; Liu, Jing; Cao, Yibin; Deng, Bin

2017-09-01

A leading hypothesis holds that spiking activity propagates along neuronal sub-populations which are connected in a feed-forward manner, and the propagation efficiency would be affected by the dynamics of sub-populations. In this paper, how the interaction between local excitation and inhibition effects on synfire chain propagation in feed-forward network (FFN) is investigated. The simulation results show that there is an appropriate excitation-inhibition (EI) ratio maximizing the performance of synfire chain propagation. The optimal EI ratio can significantly enhance the selectivity of FFN to synchronous signals, which thereby increases the stability to background noise. Moreover, the effect of network topology on synfire chain propagation is also investigated. It is found that synfire chain propagation can be maximized by an optimal interlayer linking probability. We also find that external noise is detrimental to synchrony propagation by inducing spiking jitter. The results presented in this paper may provide insights into the effects of network dynamics on neuronal computations.

Variation of radiosensitivity of bean seeds depending where they come from

International Nuclear Information System (INIS)

Perez Talavera, S.

1988-01-01

Seeds from three cuban beans varieties were irradiated at different doses in a gamma source. They were cultivated in Krimsk, USSR by 5-8 generations and in Havana, Cuba. The height, root longitude and the fresh mass of the plantules 10-11 days after being sown in laboratory conditions were used as radiosensitivity indicators. Values significantly higher were obtained from 50-200 Gy for the relative values of the three indexes taken as radiosensitivity criteria in plantules from the tree

Radiosensitizing and cytotoxic properties of DNA targeted phenanthridine-linked nitroheterocycles of varying electron affinities

International Nuclear Information System (INIS)

Cowan, D.S.M.; Rauth, A.M.; Toronto Univ., ON; Matejovic, J.F.; McClelland, R.A.; Wardman, P.

1994-01-01

2-Nitroimidazoles targeted to DNA via intercalation have previously been shown to be as much as 10-100 times more efficient on a molar basis than the untargeted nitroimidazole, misonidazole, in vitro as hypoxic cell selective radiosensitizers and cytotoxins based on extracellular concentrations. In this work the effect of varying the nitroaromatic group has been examined through the preparation of a DNA-targeted 4-nitroimidazole (4-MeNLP-3), a 5-nitroimidazole (5-NLP-3) and a 5-nitrofuran (FEP-2) linked to phenanthridinium ions. With the previously synthesized 2-nitroimidazoles, this provides a series of DNA targeted compounds of varying electron affinity as well as structure at the nitroaromatic position. The present series of compounds was tested for partition coefficient, DNA binding ability, reduction potentials and in vitro radiosensitizing and cytotoxic abilities. The results obtained indicate that targeting such compounds to DNA diminishes the dependency of radiosensitizing and cytotoxic properties on reduction potential and may allow significant uncoupling of toxicity from radiosensitizing ability. (author)

Glutathione in the modulation of radiosensitivity: a review

International Nuclear Information System (INIS)

Umadevi, P.; Prasanna, P.G.S.

1993-01-01

Glutathione (γ - glutamyl cysteinyl glycine, GSH) constitutes the major low molecular weight thiol compound in the mammalian cells. GSH has been assigned an important role in determining the inherent radiosensitivity of cells. Endogenous GSH involved in a number of radiation induced chemical processes, which help in the repair of radiation injury to the target molecules. Experimental evidence suggests that GSH competes with molecular oxygen in the cells to prevent fixation of DNA damage. Certain chemicals like buthionine sulfoximine are found to deplete the cellular GSH content by interactions at specific sites in the GSH cycle. It may be possible to take advantage of this phenomenon by increasing the radiosensitivity of hypoxic tumor cells, without seriously affecting the normal cells, so as to increase the therapeutic efficiency of radiation treatment. (author). 52 refs., 1 fig

Potential predictive assay using RAR-β for radiosensitization by 13-cis-retinoic acid and interferonα2a in human carcinoma cells

International Nuclear Information System (INIS)

Ryu, Samuel; Nevaldine, Barbara H.; Unguraneau, Carmen; Chung, Chung T.; King, Gerald A.; Stein, Joseph P.

1997-01-01

Purpose: Cell culture studies have shown increased cytotoxicity and inhibition of cell proliferation by combined use of 13-cis-retinoic acid (CRA) and interferon-α2a (IFN). Clinically, a direct antitumor activity has been observed by combined use of CRA and IFN in patients with cancer of the cervix and skin. Since IFN is known to enhance radiation response in selected human carcinoma cell lines, we carried out a series of experiments in an effort to improve the efficacy of radiation therapy by CRA and IFN in combination. Materials and Methods: Human cervical carcinoma ME-180 and HeLa cell lines were exposed to 10 μM CRA and 1000 unit/ml IFN in combination for 48 hours prior to radiation. Endpoint of radiosensitization study was colony-forming ability of single cells. Retinoic acid receptors (RAR and RXR) were detected by RNAse protection assay. Apoptosis was quantitated by using immunohistochemical staining method (Apop Tag). The cells were also transfected with bcl-2 or RAR-β gene to explore the mechanism of radiation-induced cell killing. Results: A substantial radiosensitization was observed by the combined use of CRA and IFN in human cervical carcinoma ME-180 cells in culture. The radiation enhancement ratio was 2.0 at 1% cell survival level. The principal mode of radiation-induced cell killing was apoptosis since more than 90% of the ME-180 cells showed evidence of apoptosis by combined treatment of CRA, IFN, and radiation. Both apoptosis and radiosensitization were blocked by transfecting bcl-2 gene into ME-180 cells. In contrast to these results with ME-180 cells, no radiosensitization was observed in HeLa cells by CRA and IFN under the same experimental conditions. Both cell lines express various RXR and RAR mRNAs. However, the RAR-β was undetectable in HeLa cells but present at high levels in ME-180 cells, as determined by RNAse protection assay. Because of this differential expression of RAR-β mRNA, we hypothesized that RAR-β may mediate the

Cytogenetic radiosensitivity of G0-lymphocytes of breast and esophageal cancer patients as determined by micronucleus assay

International Nuclear Information System (INIS)

Mozdarani, H.; Mansouri, Z.; Haeri, S.A.

2005-01-01

Enhanced chromosomal radiosensitivity is a feature of many cancer predisposition conditions, indicative of the important role of chromosomal alterations in carcinogenesis. In this study the cytokinesis-blocked micronucleous assay was used to compare the radiosensitivity of blood lymphocytes obtained from Iranian breast or esophageal cancer patients (n=50, n=16; respectively) with that of control individuals (n=40). For each sample, one thousand binucleate lymphocytes were analyzed before and after in vitro exposure to 3 Gy of γ rays. The radiation-induced frequency of micronucleus was significantly higher in the breast cancer group (261/1,000 binucleated cells) than in esophageal cancer group (241/1,000 binucleated cells, P<0.01) or in the control group (240/1,000 binucleated cells, P<0.01). The results indicate that breast cancer patients are more radiosensitive compared to normal healthy individuals or esophageal cancer patients. Increased radiosensitivity could be due to defects in DNA repair genes involved in breast cancer formation. Since patients with esophageal cancer did not show elevated radiosensitivity, it is assumed that the contribution of radiosensitivity-related genes to the development of esophageal cancer may be smaller than the contribution of those genes to breast cancer. (author)

Relationship between α/β and radiosensitivity and biologic effect of fractional irradiation of tumor cells

International Nuclear Information System (INIS)

Guo Chuanling; Chinese Academy of Sciences, Beijing; Wang Jufang; Jin Xiaodong; Li Wenjian

2006-01-01

Five kinds of malignant human tumor cells, i.e. SMMC-7721, HeLa, A549, HT29 and PC3 cell lines, were irradiated by 60 Co γ-rays to 1-6 Gy in a single irradiation or two irradiations of half dose. The radiosensitivity was compared with the dose-survival curves and D 50 and D 10 values. Differences in the D 50 and D 10 between the single and fractional irradiation groups showed the effect of fractional irradiation. Except for PC3 cells, all the cell lines showed obvious relationship between radiosensitivity and biologic effect of fractional irradiation and the α/β value. A cell line with bigger α/β was more radiation sensitive, with less obvious effect of fractional irradiation. The results indicate that there were obvious differences in radiosensitivity, repair ability and biologic effect of fractional irradiation between tumor cells from different tissues. To some tumor cell lines, the relationship between radiosensitivity, biologic effect of fractional irradiation and repair ability was attested. The α/β value of single irradiation can be regarded as a parameter to investigate the radiosensitivity and biologic effect of fractional irradiation of tumor cells. (authors)

Studies on radiosensitization of Escherichia coli cells by cis-platinum complexes

International Nuclear Information System (INIS)

Zimbrick, J.D.; Sukrochana, A.; Richmond, R.C.

1979-01-01

We recently reported that the antitumor drug cis-Pt(NH 3 ) 2 Cl 2 (cis-DDP) produces significant radiosensitization of anoxic E coli C cells. We have extended these studies to three other platinum drugs, all of which have been shown to be more effective antitumor drugs than cis-DDP. The drugs are: cis-dichloro bis(ethylene imine) Pt(II) (cis-DEP); cis-dichlorobicyclopentylamine Pt(II) (cis-PAD); and Pt-thymine blue (cis-PTB). Survival curve studies indicate that these drugs all produce greater anoxic radiosensitization of E coli C than cis-DDP at concentrations which are less toxic to the cells than similar concentrations of cis-DDP. If the cells are treated with any one of these drugs for two hours and then washed to remove the drug before irradiation, no detectable radiosensitization is found. We conclude that these drugs have the potential for being useful agents in combined modality therapy and that they warrant further study in mammalian systems

Radiosensitization effect of CMNa on hypoxic pancreatic cancer cell in vitro

International Nuclear Information System (INIS)

Yin Lijie; Zhang Li; Ding Tiangui; Peng Zhaoxiang; Yu Huan; Gao Yuwei

2006-01-01

Objective: To investigate the effects of glycodidazolum natrium (CMNa) on pancreatic cancer cells under hypoxic condition. Methods: The human pancreatic cancer Panc-1 cells were exposed to a single fraction of high-dose γ-ray radiation either with CMNa or under hypoxic condition. The percentage of dead cells was detected with a multiwell plated reader, and fluorescence intensities of propidium iodide were measured before and after digitonin treatment. The sensitizing effect of CMNa on cell killing induced by high-dose irradiation was evaluated by time and concentration dependence. The selective radiosensitive effect of CMNa on hypoxia was evaluated by flow cytometry. Results: The death rate of pancreatic cancer Panc-1 cells paralleled with the increasing concentration of CMNa under hypoxic condition after 30 gray irradiation. The selective radiosensitive effect of CMNa on hypoxia was time-dependent. Conclusions: CMNa can enhance the radiosensitivity of pancreatic cancer Pane-1 cells under hypoxic condition with high-dose irradiation. (authors)

Parotid radiosensitivity changes: a temporal relation to glandular circadian rhythms

International Nuclear Information System (INIS)

El-Mofty, S.K.; Hovenga, T.L.; Russell, J.E.; Simmons, D.J.

1982-01-01

The radiosensitivity of the rat parotid gland to X-radiation increased considerably towards the end of the daily light span (0800-2000 hours) and to a lesser extent before the onset of that period. The major sensitivity peak occurred at 1600 hours and coincides with a diurnal nadir in the rates of protein and RNA synthesis. The minor peak occurred at 0400 hours and was temporally related to a daily period of maximal secretory activity. It is suggested that suboptimal repair and secretion-linked cellular perturbations might contribute to the pathogenesis of the circadian increases in radiosensitivity of parotid cells. (author)

The dependence of fibroblast radiosensitivity on cell pH

International Nuclear Information System (INIS)

Veksler, A.M.; Kublik, L.N.; Degtyareva, O.V.; Ehjdus, L.Kh.

1983-01-01

The problem of the change of radiosensitivity of Chinese hamster fibroblasts, irradiated under aerobic and hypoxic conditions in the course of intracellular pH (pHsub(intr.)) change by means of a phosphate buffer has been studied. It has been found that pHsub(intr.) reduction considerably increases the radiosensitivity, the effect being more pronounced on hypoxic cells which is essential for radiotherapy of tumors. The survival rate of cell irradiated under hypoxia conditions does not depend on season while cell resistance in case of irradiation in open air in spring and autumn is different. The effect discovery in case of pHsub(intr.) reduction upon irradiation shows up the influence of the studied factor on repair processes

Overview of Radiosensitivity of Human Tumor Cells to Low-Dose-Rate Irradiation

International Nuclear Information System (INIS)

Williams, Jerry R.; Zhang Yonggang; Zhou Haoming; Gridley, Daila S.; Koch, Cameron J.; Slater, James M.; Little, John B.

2008-01-01

Purpose: We compared clonogenic survival in 27 human tumor cell lines that vary in genotype after low-dose-rate (LDR) or high-dose rate (HDR) irradiation. We measured susceptibility to LDR-induced redistribution in the cell cycle in eight of these cell lines. Methods and Materials: We measured clonogenic survival after up to 96 hours of LDR (0.25 Gy/h) irradiation. We compared these with clonogenic survival after HDR irradiation (50 Gy/h). Using flow cytometry, we measured LDR-induced redistribution as a function of time during LDR irradiation in eight of these cell lines. Results: Coefficients that describe clonogenic survival after both LDR and HDR irradiation segregate into four radiosensitivity groups that associate with cell genotype: mutant (mut)ATM, wild-type TP53, mutTP53, and an unidentified gene in radioresistant glioma cells. The LDR and HDR radiosensitivity correlates at lower doses (∼2 Gy HDR, ∼6 Gy LDR), but not at higher doses (HDR > 4 Gy; LDR > 6 Gy). The rate of LDR-induced loss of clonogenic survival changes at approximately 24 hours; wild-type TP53 cells become more resistant and mutTP53 cells become more sensitive. Redistribution induced by LDR irradiation also changes at approximately 24 hours. Conclusions: Radiosensitivity of human tumor cells to both LDR and HDR irradiation is genotype dependent. Analysis of coefficients that describe cellular radiosensitivity segregates 27 cell lines into four statistically distinct groups, each associating with specific genotypes. Changes in cellular radiosensitivity and redistribution in the cell cycle are strongly time dependent. Our data establish a genotype-dependent time-dependent model that predicts clonogenic survival, explains the inverse dose-rate effect, and suggests possible clinical applications

Atomoxetine restores the response inhibition network in Parkinson’s disease

Science.gov (United States)

Rae, Charlotte L.; Nombela, Cristina; Rodríguez, Patricia Vázquez; Ye, Zheng; Hughes, Laura E.; Jones, P. Simon; Ham, Timothy; Rittman, Timothy; Coyle-Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

2016-01-01

Abstract Parkinson’s disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson’s disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson’s disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson’s disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson’s disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced

Influence of some methodological factors on the radiosensitivity of the mouse zygote

International Nuclear Information System (INIS)

Jacquet, P.; Grinfeld, S.

1990-01-01

The experiments reported here were undertaken to investigate the influence of some methodological factors on the radiosensitivity of the mouse zygote. The following factors were studied: (1) the use of natural or hormone-stimulated ovulation; (2) the procedure followed for fertilization:mating overnight, or only during a short period in the morning after all oocytes have been ovulated, in vitro fertilization; (3) the type of irradiation, i.e., in vivo or in vitro irradiation. The radiosensitivity of the zygotes was estimated under the different experimental conditions by measuring the ability of the irradiated embryos to cleave and to develop further to the blastocyst stage. Our results suggest that the protocols used for mating and fertilization probably have a greater influence on embryonic survival following irradiation than the use of gonadotropins to stimulate ovulation. The highest degree of synchrony in the development of the embryos is achieved by restricting mating to a short period or by using in vitro fertilization. The very low LD50s obtained under such synchronous conditions confirm the high radiosensitivity of the mouse zygote at the early pronuclear stage. Comparison between the effects of in vivo and in vitro irradiation does not indicate a greater radiosensitivity of the embryo irradiated in vitro in comparison to the embryo irradiated in vivo

Radiosensitivity study of salmonella enteritidis in chickens

International Nuclear Information System (INIS)

Fernandez Gianotti, Tomas

1997-01-01

One of the applications of ionizing radiations in food is the inactivation of vegetative phatogenic bacteria (radicidation) such as Salmonella, Shigella, Campylobacter, Vibro and Listeria. These bacteria are associated with the diseases transmitted by food (ETA). Fresh and frozen farmyard fowls can be contaminated with pathogenic microorganisms, between them Salmonella. In Argentine, between years 1987-1990, Salmonella enteritidis was the main cause of salmonellosis. In food irradiation, with the aim of improving and assuring its hygienic quality, it is important to know the radiosensitivity of microorganisms to be inactivated. Inactivation of a determined microorganism shall depend, between others factors, of the species, strain, number and of the irradiation conditions (temperature, media, etc.). D 10 value is a very useful data in order to compare radiosensitivities between the microorganisms and the influence of different factors in their sensitivities. In this paper, it was determined the sensitivity to the gamma radiation of Salmonella enteritidis in fresh and frozen chickens

Wee1 Kinase Inhibitor AZD1775 Radiosensitizes Hepatocellular Carcinoma Regardless of TP53 Mutational Status Through Induction of Replication Stress

Energy Technology Data Exchange (ETDEWEB)

Cuneo, Kyle C., E-mail: kcuneo@umich.edu; Morgan, Meredith A.; Davis, Mary A.; Parcels, Leslie A.; Parcels, Joshua; Karnak, David; Ryan, Caila; Liu, Na; Maybaum, Jonathan; Lawrence, Theodore S.

2016-06-01

Purpose: Wee1 kinase inhibitors are effective radiosensitizers in cells lacking a G{sub 1} checkpoint. In this study we examined the potential effect of Wee1 kinase inhibition on inducing replication stress in hepatocellular carcinoma (HCC). Methods and Materials: Five independent datasets from the Oncomine database comparing gene expression in HCC compared to normal tissue were combined and specific markers associated with Wee1 sensitivity were analyzed. We then performed a series of in vitro experiments to study the effect of Wee1 inhibition on irradiated HCC cell lines with varying p53 mutational status. Clonogenic survival assays and flow cytometry using anti-γH2AX and phospho-histone H3 antibodies with propidium iodide were performed to study the effect of AZD1775 on survival, cell cycle, and DNA repair. Additionally, nucleoside enriched medium was used to examine the effect of altering nucleotide pools on Wee1 targeted radiation sensitization. Results: Our analysis of the Oncomine database found high levels of CDK1 and other cell cycle regulators indicative of Wee1 sensitivity in HCC. In our in vitro experiments, treatment with AZD1775 radiosensitized and chemosensitized Hep3B, Huh7, and HepG2 cell lines and was associated with delayed resolution of γH2AX foci and the induction of pan-nuclear γH2AX staining. Wee1 inhibition attenuated radiation-induced G{sub 2} arrest in the Hep3B (TP53 null) and Huh7 (TP53 mutant) cell lines but not in the TP53 wild-type cell line HepG2. Supplementation with nucleosides reversed the radiation-sensitizing effect of AZD1775 and reduced the amount of cells with pan-nuclear γH2AX staining after radiation. Conclusions: Radiation sensitization with Wee1 inhibition occurs in cells regardless of their p53 mutational status. In this study we show for the first time that replication stress via the overconsumption of nucleotides plays an important role in AZD1775-induced radiation sensitization.

Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity

International Nuclear Information System (INIS)

Dittmann, Klaus; Mayer, Claus; Rodemann, Hans-Peter

2005-01-01

Background and purpose: Inhibition of EGFR-function can induce radiosensitization in tumor cells. Purpose of our investigation was to identify the possible molecular mechanism of radiosensitization following treatment with anti-EGFR-antibody C225 (Cetuximab). Materials and methods: The effect of C225 on radiation response was determined in human cell lines of bronchial carcinoma (A549) and breast adenoma cells (MDA MB 231). The molecular effects of C225 on EGFR-function after irradiation were analyzed applying western blotting, immune-precipitation and kinase assays. Effects on DNA-repair were detected by quantification of γ-H2AX positive foci 24 h after irradiation. Results: The EGFR specific antibody C225 induced radiosensitization in A549 and also in MDA MB 231 cells. Radiosensitization in A549 was associated with blockage of radiation-induced EGFR transport into the nucleus, and immobilized the complex of EGFR with DNA-dependent protein kinase (DNA-PK) in the cytoplasm. As a consequence radiation-induced DNA-PK activation was abolished, a process that is essential for DNA-repair after radiation exposure. Likewise C225 treatment increased the residual amount of γ-H2AX-positive foci 24 h after irradiation in A549 and in MDA MB 231 cells. Conclusions: Our results suggest that irradiation induced DNA-PK activation-essential for DNA repair-may be hampered specifically by use of the anti-EGFR-antibody C225. This process is associated with radiosensitization

Hypoxia, Radiosensitizers and high-LET radiation - Nimorazole fragmentation using mass spectrometry

DEFF Research Database (Denmark)

Feketeova, Linda; Bassler, Niels

(s): Fragmentation experiments have been performed using a Finnigan- LTQ-FT mass spectrometer equipped with an electrospray ionisation source. Collision-induced dissociation (CID) and electron-induced dissociation (EID) have been carried out by mass selecting the desired ions and subjecting them to activation energy...... using mass spectrometry. Understanding the fragmentation of radiosensitizers is crucial in evaluating the radiosensitization potential and developing new and more effective drugs, which may improve TCP in hypoxic tumours when using ion beams such as carbon-12 along with LET-painting techniques. Method...

Chromosomal radiosensitivity of lymphocytes in South African breast ...

African Journals Online (AJOL)

radiosensitivity has been used as an indirect measure of cancer susceptibility. ... studies have shown that breast cancer patients are more sensitive to ionising radiation than healthy individuals. .... There was an effect of ER positivity on the MN.

Chromosomal radiosensitivity during the G2 cell-cycle period of skin fibroblasts from individuals with familial cancer

International Nuclear Information System (INIS)

Parshad, R.; Sanford, K.K.; Jones, G.M.

1985-01-01

The authors reported previously that human cells after neoplastic transformation in culture had acquired an increased susceptibility to chromatid damage induced by x-irradiation during the G2 phase of the cell cycle. Evidence suggested that this results from deficient DNA repair during G2 phase. Cells derived from human tumors also showed enhanced G2-phase chromosomal radiosensitivity. Furthermore, skin fibroblasts from individuals with genetic diseases predisposing to a high risk of cancer, including ataxia-telangiectasia, Bloom syndrome, Fanconi anemia, and xeroderma pigmentosum exhibited enhanced G2-phase chromosomal radiosensitivity. The present study shows that apparently normal skin fibroblasts from individuals with familial cancer--i.e., from families with a history of neoplastic disease--also exhibit enhanced G2-phase chromosomal radiosensitivity. This radiosensitivity appears, therefore, to be associated with both a genetic predisposition to cancer and a malignant neoplastic state. Furthermore, enhanced G2-phase chromosomal radiosensitivity may provide the basis for an assay to detect genetic susceptibility to cancer

On the surviving fraction in irradiated multicellular tumour spheroids: calculation of overall radiosensitivity parameters, influence of hypoxia and volume effects

International Nuclear Information System (INIS)

Horas, Jorge A; Olguin, Osvaldo R; Rizzotto, Marcos G

2005-01-01

We model the heterogeneous response to radiation of multicellular tumour spheroids assuming position- and volume-dependent radiosensitivity. We propose a method to calculate the overall radiosensitivity parameters to obtain the surviving fraction of tumours. A mathematical model of a spherical tumour with a hypoxic core and a viable rim which is a caricature of a real tumour is constructed. The model is embedded in a two-compartment linear-quadratic (LQ) model, assuming a mixed bivariated Gaussian distribution to attain the radiosensitivity parameters. Ergodicity, i.e., the equivalence between ensemble and volumetric averages is used to obtain the overall radiosensitivities for the two compartments. We obtain expressions for the overall radiosensitivity parameters resulting from the use of both a linear and a nonlinear dependence of the local radiosensitivity with position. The model's results are compared with experimental data of surviving fraction (SF) for multicellular spheroids of different sizes. We make one fit using only the smallest spheroid data and we are able to predict the SF for the larger spheroids. These predictions are acceptable particularly using bounded sensitivities. We conclude with the importance of taking into account the contribution of clonogenic hypoxic cells to radiosensitivity and with the convenience of using bounded local sensitivities to predict overall radiosensitivity parameters

Radiosensitization of human endothelial cells by IL-24

International Nuclear Information System (INIS)

Meyn, R.E.

2003-01-01

Radiation therapy remains an important cancer treatment modality but despite improvements in dose delivery many patients still fail at their primary tumor site. Therefore, new strategies designed to improve local control are needed. Protocols combining radiation with anti-angiogenic agents might be of particular advantage based on their documented low toxicity. In this regard, we have been conducting preclinical investigations of a novel cytokine, mda7/IL-24. Our collaborators have shown that mda7/IL-24 protein targets the endothelial cells of the tumor microvascular system and has potent anti-angiogenic properties in both in vitro and in vivo assays. Recently, we have demonstrated that recombinant mda7/IL-24 protein radiosensitizes human endothelial cells in vitro. Specifically, 10 ng/ml of recombinant human IL-24 protein for 12 hrs reduced the survival at 2 Gy for human umbilical vein endothelial cells (HUVECs) from 0.33 to 0.12. We are also working on understanding the molecular basis for this radiosensitizing effect. Preliminary data suggest a model whereby mda7/IL-24 engages a specific receptor on the surface of endothelial cells and initiates a signal transduction pathway that modulates the cell's propensity for radiation-induced apoptosis and capacity for repairing radiation-induced DNA double strand breaks. Mechanistic insight gained from these studies may have implications for the actions of other anti-angiogenic agents and may generally explain the regulation of radiosensitivity imparted by growth factors and cytokines

ZnFe2O4 nanoparticles for potential application in radiosensitization

International Nuclear Information System (INIS)

Hidayatullah, M; Nurhasanah, I; Budi, W S

2016-01-01

Radiosensitizer is a material that can increase the effects of radiation in radiotherapy application. Various materials with high effective atomic number have been developed as a radiosensitizer, such as metal, iron oxide and quantum dot. In this study, ZnFe 2 O 4 nanoparticles are included in iron oxide class were synthesized by precipitation method from the solution of zinc nitrate and ferrite nitrate and followed by calcination at 700° C for 3 hours. The XRD pattern shows that most of the observed peaks can be indexed to the cubic phase of ZnFe 2 O 4 with a lattice parameter of 8.424 Å. SEM image reveals that nanoparticles are the sphere-like shape with size in the range 84-107 nm. The ability of ZnFe 2 O 4 nanoparticles as radiosensitizer was examined by loading those nanoparticles into Escherichia coli cell culture which irradiated with photon energy of 6 MV at a dose of 2 Gy. ZnFe 2 O 4 nanoparticles showed ability to increase the absorbed dose by 0.5 to 1.0 cGy/g. In addition, the presence of 1 g/L ZnFe 2 O 4 nanoparticles resulted in an increase radiation effect by 6.3% higher than if exposed to radiation only. These results indicated that ZnFe 2 O 4 nanoparticles can be used as the radiosensitizer for increasing radiation effect in radiotherapy. (paper)

Biological markers as predictors of radiosensitivity in syngeneic murine tumors

International Nuclear Information System (INIS)

Chang, Sei Kyung; Shin, Hyun Soo; Seong, Jin Sil; Kim, Sung Hee

2006-01-01

We investigated whether a relationship exists between tumor control dose 50 (TCD 50 ) or tumor growth delay (TGD) and radiation induced apoptosis (RIA) in syngeneic murine tumors. Also we investigated the biological markers that can predict radiosensitivity in murine tumor system through analysis of relationship between TCD 50 , TGD, RIA and constitutive expression levels of the genetic products regulating RIA. Syngeneic murine tumors such as ovarian adenocarcinoma, mammary carcinoma, squamous cell carcinoma, fibrosarcoma, hepatocarcinoma were used in this study. C3H/HeJ mice were bred and maintained in our specific pathogen free mouse colony and were 8 ∼ 12 weeks old when used for the experiments. The tumors, growing in the right hind legs of mice, were analyzed for TCD 50 , TGD, and RIA at 8 mm in diameter. The tumors were also analyzed for the constitutive expression levels of p53, p21 WAF1/CIP1 , BAX, Bcl-2, Bcl-x L , Bcl-x S , and p34. Correlation analysis was performed whether the level of RIA were correlated with TCD 50 or TGD, and the constitutive expression levels of genetic products regulating RIA were correlated with TCD 50 , TGD, RIA. The level of RIA showed a significant positive correlation (R = 0.922, ρ = 0.026) with TGD, and showed a trend to correlation (R = -0.848), marginally significant correlation with TCD 50 (ρ = 0.070). It indicates that tumors that respond to radiation with high percentage of apoptosis were more radiosensitive. The constitutive expression levels of p21 WAF1/CIP1 and p34 showed a significant correlation either with TCD 50 (R = 0.893, ρ = 0.041 and R = 0.904, ρ = 0.035) or with TGD (R = -0.922, ρ 0.026 and R = -0.890, ρ = 0.043). The tumors with high constitutive expression levels of p21 WAF1/CIP1 or p34 were less radiosensitive than those with low expression. Radiosensitivity may be predicted with the level of RIA in murine tumors. The constitutive expression levels of p21 WAF1/CIP1 or p34 can be used as biological

Comparison of Individual Radiosensitivity to γ-Rays and Carbon Ions.

Science.gov (United States)

Shim, Grace; Normil, Marie Delna; Testard, Isabelle; Hempel, William M; Ricoul, Michelle; Sabatier, Laure

2016-01-01

Carbon ions are an up-and-coming ion species, currently being used in charged particle radiotherapy. As it is well established that there are considerable interindividual differences in radiosensitivity in the general population that can significantly influence clinical outcomes of radiotherapy, we evaluate the degree of these differences in the context of carbon ion therapy compared with conventional radiotherapy. In this study, we evaluate individual radiosensitivity following exposure to carbon-13 ions or γ-rays in peripheral blood lymphocytes of healthy individuals based on the frequency of ionizing radiation (IR)-induced DNA double strand breaks (DSBs) that was either misrepaired or left unrepaired to form chromosomal aberrations (CAs) (simply referred to here as DSBs for brevity). Levels of DSBs were estimated from the scoring of CAs visualized with telomere/centromere-fluorescence in situ hybridization (TC-FISH). We examine radiosensitivity at the dose of 2 Gy, a routinely administered dose during fractionated radiotherapy, and we determined that a wide range of DSBs were induced by the given dose among healthy individuals, with highly radiosensitive individuals harboring more IR-induced breaks in the genome than radioresistant individuals following exposure to the same dose. Furthermore, we determined the relative effectiveness of carbon irradiation in comparison to γ-irradiation in the induction of DSBs at each studied dose (isodose effect), a quality we term "relative dose effect" (RDE). This ratio is advantageous, as it allows for simple comparison of dose-response curves. At 2 Gy, carbon irradiation was three times more effective in inducing DSBs compared with γ-irradiation (RDE of 3); these results were confirmed using a second cytogenetic technique, multicolor-FISH. We also analyze radiosensitivity at other doses (0.2-15 Gy), to represent hypo- and hyperfractionation doses and determined that RDE is dose dependent: high ratios at low doses

Preferential radiosensitization of human prostatic carcinoma cells by mild hyperthermia

International Nuclear Information System (INIS)

Ryu, Samuel; Brown, Stephen L.; Kim, Sang-Hie; Khil, Mark S.; Kim, Jae Ho

1996-01-01

Purpose: Recent cell culture studies by us and others suggest that some human carcinoma cells are more sensitive to heat than are rodent cells following mild hyperthermia. In studying the cellular mechanism of enhanced thermosensitivity of human tumor cells to hyperthermia, prostatic carcinoma cells of human origin were found to be more sensitive to mild hyperthermia than other human cancer cells. The present study was designed to determine the magnitude of radiosensitization of human prostatic carcinoma cells by mild hyperthermia and to examine whether the thermal radiosensitization is related to the intrinsic thermosensitivity of cancer cells. Methods and Materials: Two human prostatic carcinoma cell lines (DU-145 and PC-3) and other carcinoma cells of human origin, in particular, colon (HT-29), breast (MCF-7), lung (A-549), and brain (U-251) were exposed to temperatures of 40-41 deg. C. Single acute dose rate radiation and fractionated radiation were combined with mild hyperthermia to determine thermal radiosensitization. The end point of the study was the colony-forming ability of single-plated cells. Results: DU-145 and PC-3 cells were found to be exceedingly thermosensitive to 41 deg. C for 24 h, relative to other cancer cell lines. Ninety percent of the prostatic cancer cells were killed by a 24 h heat exposure. Prostatic carcinoma cells exposed to a short duration of heating at 41 deg. C for 2 h resulted in a substantial enhancement of radiation-induced cytotoxicity. The thermal enhancement ratios (TERs) of single acute dose radiation following heat treatment 41 deg. C for 2 h were 2.0 in DU-145 cells and 1.4 in PC-3 cells. The TERs of fractionated irradiation combined with continuous heating at 40 deg. C were similarly in the range of 2.1 to 1.4 in prostate carcinoma cells. No significant radiosensitization was observed in MCF-7 and HT-29 cells under the same conditions. Conclusion: The present data suggest that a significant radiosensitization of

Biological markers as predictors of radiosensitivity in syngeneic murine tumors

Energy Technology Data Exchange (ETDEWEB)

Chang, Sei Kyung; Shin, Hyun Soo [Bundang CHA General Hospital, Seongnam (Korea, Republic of); Seong, Jin Sil; Kim, Sung Hee [Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (Korea, Republic of)

2006-06-15

We investigated whether a relationship exists between tumor control dose 50 (TCD{sub 50}) or tumor growth delay (TGD) and radiation induced apoptosis (RIA) in syngeneic murine tumors. Also we investigated the biological markers that can predict radiosensitivity in murine tumor system through analysis of relationship between TCD{sub 50}, TGD, RIA and constitutive expression levels of the genetic products regulating RIA. Syngeneic murine tumors such as ovarian adenocarcinoma, mammary carcinoma, squamous cell carcinoma, fibrosarcoma, hepatocarcinoma were used in this study. C3H/HeJ mice were bred and maintained in our specific pathogen free mouse colony and were 8 {approx} 12 weeks old when used for the experiments. The tumors, growing in the right hind legs of mice, were analyzed for TCD{sub 50}, TGD, and RIA at 8 mm in diameter. The tumors were also analyzed for the constitutive expression levels of p53, p21{sup WAF1/CIP1}, BAX, Bcl-2, Bcl-x{sub L}, Bcl-x{sub S}, and p34. Correlation analysis was performed whether the level of RIA were correlated with TCD{sub 50} or TGD, and the constitutive expression levels of genetic products regulating RIA were correlated with TCD{sub 50}, TGD, RIA. The level of RIA showed a significant positive correlation (R = 0.922, {rho} = 0.026) with TGD, and showed a trend to correlation (R = -0.848), marginally significant correlation with TCD{sub 50} ({rho} = 0.070). It indicates that tumors that respond to radiation with high percentage of apoptosis were more radiosensitive. The constitutive expression levels of p21{sup WAF1/CIP1} and p34 showed a significant correlation either with TCD{sub 50} (R = 0.893, {rho} = 0.041 and R = 0.904, {rho} = 0.035) or with TGD (R = -0.922, {rho} 0.026 and R = -0.890, {rho} = 0.043). The tumors with high constitutive expression levels of p21{sup WAF1/CIP1} or p34 were less radiosensitive than those with low expression. Radiosensitivity may be predicted with the level of RIA in murine tumors. The

Differences in radiosensitivity between three HER2 overexpressing cell lines

International Nuclear Information System (INIS)

Steffen, Ann-Charlott; Tolmachev, Vladimir; Stenerloew, Bo; Goestring, Lovisa; Palm, Stig; Carlsson, Joergen

2008-01-01

HER2 is a potential target for radionuclide therapy, especially when HER2 overexpressing breast cancer cells are resistant to Herceptin registered treatment. Therefore, it is of interest to analyse whether HER2 overexpressing tumour cells have different inherent radiosensitivity. The radiosensitivity of three often used HER2 overexpressing cell lines, SKOV-3, SKBR-3 and BT-474, was analysed. The cells were exposed to conventional photon irradiation, low linear energy transfer (LET), to characterise their inherent radiosensitivity. The analysis was made with clonogenic survival and growth extrapolation assays. The cells were also exposed to alpha particles, high LET, from 211 At decays using the HER2-binding affibody molecule 211 At-(Z HER2:4 ) 2 as targeting agent. Assays for studies of internalisation of the affibody molecule were applied. SKOV-3 cells were most radioresistant, SKBR-3 cells were intermediate and BT-474 cells were most sensitive as measured with the clonogenic and growth extrapolation assays after photon irradiation. The HER2 dependent cellular uptake of 211 At was qualitatively similar for all three cell lines. However, the sensitivity to the alpha particles from 211 At differed; SKOV-3 was most resistant, SKBR-3 intermediate and BT-474 most sensitive. These differences were unexpected because it is assumed that all types of cells should have similar sensitivity to high-LET radiation. The sensitivity to alpha particle exposure correlated with internalisation of the affibody molecule and with size of the cell nucleus. There can be differences in radiosensitivity, which, if they also exist between patient breast cancer cells, are important to consider for both conventional radiotherapy and for HER2-targeted radionuclide therapy. (orig.)

Determination of one-electron reduction potentials of some radiosensitive compounds by pulse radiolysis

International Nuclear Information System (INIS)

Zuo Zhihua; Yao Side; Li Hucheng; Lin Nianyun; Jin Yizun

1994-01-01

One-electron reduction potential (E 7 1 ) is one of the important parameters of radiosensitive compound with high electron affinity. In this work one-electron reduction potentials of some radiosensitizers, such as Miso, 911, CMNa, SMU-1, SMU-2, SMD, SNN, S 3 and BSO, were determined pulse radiolytically by using anthraquinone-2-sulfate (AQS), duroquinone (DQ) and methyl viologen (MV 2+ ) as references

Misonidazole radiosensitization in vivo: A therapeutic gain by penicillin pretreatment

International Nuclear Information System (INIS)

Sheldon, P.W.; Clarke, C.; Dawson, K.B.; Simpson, W.; Simmons, D.J.C.; Adams, G.E.

1984-01-01

Because intestinal microflora have the potential to metabolize nitroimidazole compounds (possibly to toxic species), the authors investigated their influence on the pharmacological, neurotoxic and radiosensitizing properties of misonidazole (MIS) in mice. This was done by comparing the responses obtained in 'normal' mice to those obtained in mice whose microflora had been depleted by pretreatment for 7-14 days with penicillin (PEN) at the rate of 0.5g/1 of drinking water. Bacteriological studies showed this treatment to C57B1 mice eliminated more than 99% of the flora from the caeca and, furthermore, this efficacy of penicillin was not interfered with by MIS administered IP at 0.3mg/g between days 7-14. This pretreatment resulted not only in the elimination of the caecal flora, but also in an increase in the pharmacokinetic exposure to MIS, an increase in Lewis lung tumour radiosensitization by MIS and a decrease in MIS-induced neurotoxicity. The authors conclude pretreatment with PEN can give a therapeutic gain with MIS radiosensitization. Further, assuming no direct interaction between the PEN and MIS, these findings indicate that the intestinal flora may produce neurotoxic species by their metabolism of MIS

Osmotic homeostasis and NKLy lymphoma cells radiosensitivity

International Nuclear Information System (INIS)

Tishchenko, V.V.; Magda, I.N.

1992-01-01

In experiments with cells of ascites NKLy lymphoma differing in ploidy and position in the cell cycle, a study was made of the radiosensitivity, osmotic homeostasis peculiarities and thermoradiation changes in potassium content. It was shown that the resistance of osmotic homeostasis of NKLy cells to thermoradiation correlated with their radioresistance

Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT

Science.gov (United States)

Leszczynska, Katarzyna B.; Foskolou, Iosifina P.; Abraham, Aswin G.; Anbalagan, Selvakumar; Tellier, Céline; Haider, Syed; Span, Paul N.; O’Neill, Eric E.; Buffa, Francesca M.; Hammond, Ester M.

2015-01-01

Restoration of hypoxia-induced apoptosis in tumors harboring p53 mutations has been proposed as a potential therapeutic strategy; however, the transcriptional targets that mediate hypoxia-induced p53-dependent apoptosis remain elusive. Here, we demonstrated that hypoxia-induced p53-dependent apoptosis is reliant on the DNA-binding and transactivation domains of p53 but not on the acetylation sites K120 and K164, which, in contrast, are essential for DNA damage–induced, p53-dependent apoptosis. Evaluation of hypoxia-induced transcripts in multiple cell lines identified a group of genes that are hypoxia-inducible proapoptotic targets of p53, including inositol polyphosphate-5-phosphatase (INPP5D), pleckstrin domain–containing A3 (PHLDA3), sulfatase 2 (SULF2), B cell translocation gene 2 (BTG2), cytoplasmic FMR1-interacting protein 2 (CYFIP2), and KN motif and ankyrin repeat domains 3 (KANK3). These targets were also regulated by p53 in human cancers, including breast, brain, colorectal, kidney, bladder, and melanoma cancers. Downregulation of these hypoxia-inducible targets associated with poor prognosis, suggesting that hypoxia-induced apoptosis contributes to p53-mediated tumor suppression and treatment response. Induction of p53 targets, PHLDA3, and a specific INPP5D transcript mediated apoptosis in response to hypoxia through AKT inhibition. Moreover, pharmacological inhibition of AKT led to apoptosis in the hypoxic regions of p53-deficient tumors and consequently increased radiosensitivity. Together, these results identify mediators of hypoxia-induced p53-dependent apoptosis and suggest AKT inhibition may improve radiotherapy response in p53-deficient tumors. PMID:25961455

Structure-function dependence and allopurinol inhibition of ratiosensitizer/nitroreductase interaction: approaches to improving therapeutic rations

International Nuclear Information System (INIS)

Raleigh, J.A.; Shum, F.Y.; Koziol, D.R.; Saunders, W.M.

1980-01-01

Normal tissue toxicity of nitroaromatic radiosensitizers may originate in radiosensitizer/nitroreductase interaction. A study of two mammalian cell nitroreductases, xanthine oxidase and NADH cytochrome c reductase, shows that the efficiency of electron transfer is dependent on sensitizer electron affinity and not lipid solubility. Misonidazole and its demethylated metabolite (RO-05-9963), for example, are equally efficient as electron acceptors from xanthine oxidase. The only exception to the electron affinity correlation is m-nitrobenzamidine hydrochloride xanthine oxidase from its cofactor, xanthine. Allopurinol inhibits electron transfer and might be a useful adjuvant to the nitroreductases in vivo is deduced from the observation that allopurinol significantly alters the serum lifetimes in mice of misonidazole and RO-05-9963

Genetic control of the radiosensitivity of lymphoid cells for antibody formation ability in mice

International Nuclear Information System (INIS)

Okumoto, Masaaki; Mori, Nobuko; Esaki, Kozaburo; Imai, Shunsuke; Haga, Satomi; Hilgers, Jo; Takamori, Yasuhiko.

1994-01-01

To analyze the genetic basis of the relationship between the radiosensitivity of the immune response and radiation lymphomagenesis, we examined the radiosensitivity of lymphoid cells for antibody formation in BALB/cHeA, STS/A, F 1 hybrids, and their recombinant inbred mouse strains. The decrease in the number of plaque-forming spleen cells in BALB/cHeA mice exposed to 3 Gy X-irradiation was more than tenfold that in STS/A mice. The phenotype of radioresistance was dominant over sensitivity. The coincidence between the strain distribution patterns of the genetic markers and radiosensitivities of antibody formation in the various recombinant inbred strains was in the region with the lgh locus on chromosome 12. There was obvious difference between the patterns in the region containing the lfa locus on chromosome 4 which has been shown to be related to the incidence of radiation-induced lymphomas. These results indicate that the region on chromosome 12 may contain major gene(s) related to radiosensitivity for antibody formation. (author)

Investigation of radiosensitivity and growth dynamics for callus tissues Crepis Capillaris, Haplopappus gracilis, Phasolium vulgaris exposed to gamma radiation

International Nuclear Information System (INIS)

Gatsek, Eh.; Glinkova, E.; Ismailova, Eh.N.

1983-01-01

Radiosensitivity of three kinds of callus tissues (Crepis capillaris, Haplopappus gracilis, Phasolium vulgaris) manifested in the change of fresh weight after γ-irradiation has been investigated. Irradiated callus arowth showed decrease with increasing doses. It is shown that the radiosensitivity of ''young'' callus tissues is determined by the kind of the plant. Callus of Phaseolis has been found to have the highest radioresistance, while that of Crepis has the lowest one. Radiosensitivity of ''old'' callus tissues is the same for all kinds. Potential mechanism of radiosensitivity of callus tissUes are discussed

The use of drugs which deplete intracellular glutathione in hypoxic cell radiosensitization

International Nuclear Information System (INIS)

Bump, E.A.; Yu, N.Y.; Brown, J.M.

1982-01-01

Diethylmaleate (DEM) is a thiol-biding reagent with specificity toward glutathione. Treatment of chinese hamster ovary (CHO) cells in vitro with 2 x 10 -4 M DEM for one hour results in a decrease in glutathione content to less than 5% of control, without cytotoxicity. This treatment results in dose-modifying sensitization to radiation under hypoxic conditions, with no effect on the shoulder of the radiation survival curve. No effect on the radiation sensitivity of oxygenated cells was seen. DEM pretreatment enhances the radiosensitization of hypoxic cells by misonidazole, as well. Similar results were obtained in vivo with EMT6 tumors in BALB/c mice. Analysis of DNA damage by the alkaline elution assay indicates that DEM enhances radiation-induced single-strand breaks, but does not significantly affect repair, while diamide and N-ethylmaleimide inhibit repair, in addition to enhancing radiation-induced single-strand breaks

Radiosensitive xrs-5 and parental CHO cells show identical DNA neutral filter elution dose-response: implications for a relationship between cell radiosensitivity and induction of DNA double-strand breaks

International Nuclear Information System (INIS)

Iliakis, George; Okayasu, Ryuichi; Seaner, Robert

1988-01-01

The purpose of this work was to investigate a possible correlation between DNA elution dose-response and cell radiosensitivity. For this purpose neutral (pH 9.6) DNA filter elution dose-response curves were measured with radiosensitive xrs-5 and the parental Chinese hamster ovary (CHO) cells in the logarithmic and plateau phase of growth. No difference was observed between the two cell types in the DNA elution dose-response curves either in logarithmic or plateau phase, despite the dramatic differences in cell radiosensitivity. This observation indicates that the shape of the DNA elution dose-response curve and the shape of the cell survival curve are not causally related. It is proposed that the shoulder observed in the DNA elution dose-response curve reflects either partial release of DNA from chromatin, or cell cycle-specific alterations in the physicochemical properties of the DNA. (author)

Small interfering RNA targeting HIF-1{alpha} reduces hypoxia-dependent transcription and radiosensitizes hypoxic HT 1080 human fibrosarcoma cells in vitro

Energy Technology Data Exchange (ETDEWEB)

Staab, Adrian [Wuerzburg Univ. (Germany). Dept. of Radiation Oncology; Paul Scherrer Institute (PSI), Villigen (Switzerland); Fleischer, Markus [Wuerzburg Univ. (Germany). Dept. of Radiation Oncology; Wuerzburg Univ. (Germany). Medical Clinic II; Loeffler, Juergen; Einsele, Herrmann [Wuerzburg Univ. (Germany). Medical Clinic II; Said, Harun M.; Katzer, Astrid; Flentje, Michael [Wuerzburg Univ. (Germany). Dept. of Radiation Oncology; Plathow, Christian [Freiburg Univ. (Germany). Dept. of Nuclear Medicine; Vordermark, Dirk [Wuerzburg Univ. (Germany). Dept. of Radiation Oncology; Halle-Wittenberg Univ. (Germany). Dept. of Radiation Oncology

2011-04-15

Background: Hypoxia inducible factor-1 has been identified as a potential target to overcome hypoxia-induced radioresistance The aim of the present study was to investigate whether selective HIF-1 inhibition via small interfering RNA (siRNA) targeting hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) affects hypoxia-induced radioresistance in HT 1080 human fibrosarcoma cells. Material and Methods: HIF-1{alpha} expression in HT 1080 human fibrosarcoma cells in vitro was silenced using HIF-1{alpha} siRNA sequence primers. Quantitative real-time polymerase chain reaction assay was performed to quantify the mRNA expression of HIF-1{alpha}. HIF-1{alpha} protein levels were studied by Western blotting at 20% (air) or after 12 hours at 0.1% O{sub 2} (hypoxia). Cells were assayed for clonogenic survival after irradiation with 2, 5, or 10 Gy, under normoxic or hypoxic conditions in the presence of HIF-1{alpha}-targeted or control siRNA sequences. A modified oxygen enhancement ratio (OER') was calculated as the ratio of the doses to achieve the same survival at 0.1% O{sub 2} as at ambient oxygen tensions. OER' was obtained at cell survival levels of 50%, 37%, and 10%. Results: HIF-1{alpha}-targeted siRNA enhanced radiation treatment efficacy under severely hypoxic conditions compared to tumor cells treated with scrambled control siRNA. OER was reduced on all survival levels after treatment with HIF-1{alpha}-targeted siRNA, suggesting that inhibition of HIF-1 activation by using HIF-1{alpha}-targeted siRNA increases radiosensitivity of hypoxic tumor cells in vitro. Conclusion: Inhibition of HIF-1 activation by using HIF-1{alpha}-targeted siRNA clearly acts synergistically with radiotherapy and increase radiosensitivity of hypoxic cells in vitro. (orig.)

Small interfering RNA targeting HIF-1α reduces hypoxia-dependent transcription and radiosensitizes hypoxic HT 1080 human fibrosarcoma cells in vitro

International Nuclear Information System (INIS)

Staab, Adrian; Fleischer, Markus; Wuerzburg Univ.; Loeffler, Juergen; Einsele, Herrmann; Said, Harun M.; Katzer, Astrid; Flentje, Michael; Plathow, Christian; Vordermark, Dirk; Halle-Wittenberg Univ.

2011-01-01

Background: Hypoxia inducible factor-1 has been identified as a potential target to overcome hypoxia-induced radioresistance The aim of the present study was to investigate whether selective HIF-1 inhibition via small interfering RNA (siRNA) targeting hypoxia-inducible factor 1α (HIF-1α) affects hypoxia-induced radioresistance in HT 1080 human fibrosarcoma cells. Material and Methods: HIF-1α expression in HT 1080 human fibrosarcoma cells in vitro was silenced using HIF-1α siRNA sequence primers. Quantitative real-time polymerase chain reaction assay was performed to quantify the mRNA expression of HIF-1α. HIF-1α protein levels were studied by Western blotting at 20% (air) or after 12 hours at 0.1% O 2 (hypoxia). Cells were assayed for clonogenic survival after irradiation with 2, 5, or 10 Gy, under normoxic or hypoxic conditions in the presence of HIF-1α-targeted or control siRNA sequences. A modified oxygen enhancement ratio (OER') was calculated as the ratio of the doses to achieve the same survival at 0.1% O 2 as at ambient oxygen tensions. OER' was obtained at cell survival levels of 50%, 37%, and 10%. Results: HIF-1α-targeted siRNA enhanced radiation treatment efficacy under severely hypoxic conditions compared to tumor cells treated with scrambled control siRNA. OER was reduced on all survival levels after treatment with HIF-1α-targeted siRNA, suggesting that inhibition of HIF-1 activation by using HIF-1α-targeted siRNA increases radiosensitivity of hypoxic tumor cells in vitro. Conclusion: Inhibition of HIF-1 activation by using HIF-1α-targeted siRNA clearly acts synergistically with radiotherapy and increase radiosensitivity of hypoxic cells in vitro. (orig.)

Autophagy influences the low-dose hyper-radiosensitivity of human lung adenocarcinoma cells by regulating MLH1.

Science.gov (United States)

Wang, Qiong; Xiao, Zhuya; Lin, Zhenyu; Zhou, Jie; Chen, Weihong; Jie, Wuyun; Cao, Xing; Yin, Zhongyuan; Cheng, Jing

2017-06-01

To investigate the impact of autophagy on the low-dose hyper-radiosensitivity (HRS) of human lung adenocarcinoma cells via MLH1 regulation. Immunofluorescent staining, Western blotting, and electron microscopy were utilized to detect autophagy in A549 and H460 cells. shRNA was used to silence MLH1 expression. The levels of MLH1, mTOR, p-mTOR, BNIP3, and Beclin-1 were measured by real-time polymerase chain reaction (PCR) and Western blotting. A549 cells, which have low levels of MLH1 expression, displayed HRS/induced radioresistance (IRR). Conversely, the radiosensitivity of H460 cells, which express high levels of MLH1, conformed to the linear-quadratic (LQ) model. After down-regulating MLH1 expression, A549 cells showed increased HRS and inhibition of autophagy, whereas H460 cells exhibited HRS/IRR. The levels of mTOR, p-mTOR, and BNIP3 were reduced in cells harboring MLH1 shRNA, and the changes in the mTOR/p-mTOR ratio mirrored those in MLH1 expression. Low MLH1-expressing A549 cells may exhibit HRS. Both the mTOR/p-mTOR and BNIP3/Beclin-1 signaling pathways were found to be related to HRS, but only mTOR/p-mTOR is involved in the regulation of HRS via MLH1 and autophagy.

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.

Quince tree (cydonia oblonga Mill.)-breeding bases:seed propagation, cytogenetics and radiosensitivity

International Nuclear Information System (INIS)

Dall'Orto, F.A.C.

1982-01-01

The following aspects of the marmeleiro, cydonia oblonga Mill., were, researched: media nad periods to supply the seed chilling requirement in moist cold storage (5-10 0 c); quince seeds viability prepared by several extraction processes; seed germination and seedling development; cytogenetic aspects; seeds viability influenced by storage conditions and periods of time for storage; preliminary determination of seed radiosensitivity; concentrations of some macro and micronutrients in quince seedlings obtained from irradiated seeds, and radiosensitivity and interphasic nuclear volumes. (MAC) [pt

The radiosensitivity of nile tilapia (Oreochromis niloticus) fingerlings

International Nuclear Information System (INIS)

Reyes, Michael Joseph T.; Velasco, Pia Victoria V.

2000-04-01

The nile tilapia (Oreochromis niloticus), a very popular fish commercially in the Philippines, was studied to determine its radiosensitivity and to see its potential as a biological indicator in aquatic ecosystems. Nile tilapia was seen to be radiosensitive. The fish were exposed to gamma-irradiation and chromosomal aberrations were induced. The various types of aberrations seen were chromatid gaps, chromosome gaps, chromatid fragments, dicentric rings, fusions, despiralizations and translocations. Among the aberrations observed, dicentric rings, fusions and chromosome gaps were strongly correlated with dosage, with only the dicentric rings increasing steadily with increasing dosage. In the course of the study, the lethal dosage 50 for nile tilapia with 18 days was determined and it was observed at 2.0 krad. The modal chromosome number was also established at 2n=44 with a karyotype exhibiting 22 pairs of acrocentric chromosomes with 2 pairs of marker chromosomes present. (Author)

The radiosensitivity of nile tilapia (Oreochromis niloticus) fingerlings

Energy Technology Data Exchange (ETDEWEB)

Reyes, Michael Joseph T; Velasco, Pia Victoria V

2000-04-01

The nile tilapia (Oreochromis niloticus), a very popular fish commercially in the Philippines, was studied to determine its radiosensitivity and to see its potential as a biological indicator in aquatic ecosystems. Nile tilapia was seen to be radiosensitive. The fish were exposed to gamma-irradiation and chromosomal aberrations were induced. The various types of aberrations seen were chromatid gaps, chromosome gaps, chromatid fragments, dicentric rings, fusions, despiralizations and translocations. Among the aberrations observed, dicentric rings, fusions and chromosome gaps were strongly correlated with dosage, with only the dicentric rings increasing steadily with increasing dosage. In the course of the study, the lethal dosage{sub 50} for nile tilapia with 18 days was determined and it was observed at 2.0 krad. The modal chromosome number was also established at 2n=44 with a karyotype exhibiting 22 pairs of acrocentric chromosomes with 2 pairs of marker chromosomes present. (Author)

Sensory and cross-network contributions to response inhibition in patients with schizophrenia

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Matthew J. Hoptman

Full Text Available Patients with schizophrenia show response inhibition deficits equal to or greater than those seen in impulse-control disorders, and these deficits contribute to poor outcome. However, little is known about the circuit abnormalities underlying this impairment. To address this, we examined stop signal task performance in 21 patients with schizophrenia and 21 healthy controls using event related potential (ERP and resting state functional connectivity. Patients showed prolonged stop signal reaction time (SSRT and reduced N1, N2, and P3 amplitudes compared to controls. Across groups, P3 amplitudes were maximal after SSRT (i.e., after the time associated with the decision to stop occurred, suggesting that this component indexed response monitoring. Multiple regression analyses showed that longer SSRTs were independently related to 1 patient status, 2 reduced N1 amplitude on successful stop trials and 3 reduced anticorrelated resting state functional connectivity between visual and frontoparietal cortical networks. This study used a combined multimodal imaging approach to better understand the network abnormalities that underlie response inhibition in schizophrenia. It is the first of its kind to specifically assess the brain's resting state functional architecture in combination with behavioral and ERP methods to investigate response inhibition in schizophrenia. Keywords: EEG, Stop signal task, Impulsivity, Schizophrenia, Resting state functional connectivity

Effects of heat-shock treatment and genotype on radiosensitivity of maize seeds

International Nuclear Information System (INIS)

Yamagata, Hirotada; Tanisaka, Takatoshi; Harima, Kunio

1975-01-01

In order to clarify the internal and external factors responsible for radiosensitivity of seed, and to induce mutations more effectively, two experiments were conducted using maize. (1) Seeds of an inbred line were irradiated with γ rays at an extremely low temperature (-70 0 C) and then dipped in hot water (60 0 C, 30 sec.). Through such heat-shock treatment the radiosensitivity of maize seeds was remarkably reduced: LD 50 and RD 50 for growth rose as high as about three times and about twice, respectively. (2) Seeds of seven strains including four inbred lines, two single-cross hybrids and one double-cross hybrid were exposed to γ rays by the ordinary procedure. Hybrids, regardless of whether they were single cross or double cross, were clearly proved to surpass their parental strains in radiation tolerance, both in survival rate and in culm length. These descents of radiosensitivity were considered to be due mainly to the increased heterozygosity. (auth.)

Radiosensitivity of pulmonary alveolar macrophages in rats exposed to local X-irradiation

International Nuclear Information System (INIS)

Gong Yifen; Fei Lihua; Wu Dechang

1987-01-01

The radiosensitivity of pulmonary alveolar macrophages (PAMs) in rats exposed to local thoracic X-irradiatoin was studied. The percentages of mitotic and labeling cells were used as biological endpoints. The parameters of radiosensitivity of PAMs obtained on the second day after local exposure are as follows: D 0 = 0.68 Gy, Dq = 0.06 Gy, n = 1.1 for mitotic cells and D 0 = 1.04 Gy, Dq = 0.12 Gy, n = 1.12 for labeling cells. The parameters of radiosensitivity of PAMs in bronchical lavage obtained immediately after X-irradiation are: D 0 = 3.56 Gy, Dq = 0.77 Gy, n = 1.24 for labeling cells and D 0 = 3.69 Gy, Dq = 0.35 Gy, n = 1.1 for mitotic cells. The comparison of thses results indicates that the radiation effect on PAMs obtained immediately after X-irradiation is less severe than that of PAMs obtained 2 days later. It might be caused by the delay of cell cycle within 2 days after X-irradiation

Chromosomal radiosensitivity in patients with multiple sclerosis

International Nuclear Information System (INIS)

Milenkova, Maria; Milanov, Ivan; Kmetska, Ksenia; Deleva, Sofia; Popova, Ljubomira; Hadjidekova, Valeria; Groudeva, Violeta; Hadjidekova, Savina; Domínguez, Inmaculada

2013-01-01

Highlights: • We studied radiosensitivity to in vitro γ-irradiated lymphocytes from MS patients. • Immunotherapy in RRMS patients reduced the yield of radiation induced MN. • The group of treated RRMS accounts for the low radiosensitivity in MS patients. • Spontaneous yield of MN was similar in treated and untreated RRMS patients. - Abstract: Multiple sclerosis is a clinically heterogeneous autoimmune disease leading to severe neurological disability. Although during the last years many disease-modifying agents as treatment options for multiple sclerosis have been made available, their mechanisms of action are still not fully determined. In the present study radiosensitivity in lymphocytes of patients with relapsing–remitting multiple sclerosis, secondary progressive multiple sclerosis and healthy controls was investigated. Whole blood cultures from multiple sclerosis patients and healthy controls were used to analyze the spontaneous and radiation-induced micronuclei in binucleated lymphocytes. A subgroup of patients with relapsing–remitting multiple sclerosis was treated with immunomodulatory agents, interferon β or glatiramer acetate. The secondary progressive multiple sclerosis patients group was not receiving any treatment. Our results reveal that the basal DNA damage was not different between relapsing–remitting and secondary progressive multiple sclerosis patients, and healthy controls. No differences between gamma-irradiation induced micronuclei frequencies in binucleated cells from relapsing–remitting and secondary progressive multiple sclerosis patients, and healthy controls were found either. Nevertheless, when we compared the radiation induced DNA damage in binucleated cells from healthy individuals with the whole group of patients, a reduction in the frequency of micronuclei was obtained in the patients group. Induced micronuclei yield was significantly lower in the irradiated samples from treated relapsing–remitting multiple

Chromosomal radiosensitivity in patients with multiple sclerosis

Energy Technology Data Exchange (ETDEWEB)

Milenkova, Maria; Milanov, Ivan; Kmetska, Ksenia [III Neurological Clinic, University Hospital Saint Naum, Sofia (Bulgaria); Deleva, Sofia; Popova, Ljubomira; Hadjidekova, Valeria [Laboratory of Radiation Genetics, NCRRP, Sofia (Bulgaria); Groudeva, Violeta [Department of Diagnostic Imaging, University Hospital St. Ekaterina, Sofia (Bulgaria); Hadjidekova, Savina [Department of Medical Genetics, Medical University, Sofia (Bulgaria); Domínguez, Inmaculada, E-mail: idomin@us.es [Department of Cell Biology, Faculty of Biology, University of Seville, Avda. Reina Mercedes 6, 41012 (Spain)

2013-09-15

Highlights: • We studied radiosensitivity to in vitro γ-irradiated lymphocytes from MS patients. • Immunotherapy in RRMS patients reduced the yield of radiation induced MN. • The group of treated RRMS accounts for the low radiosensitivity in MS patients. • Spontaneous yield of MN was similar in treated and untreated RRMS patients. - Abstract: Multiple sclerosis is a clinically heterogeneous autoimmune disease leading to severe neurological disability. Although during the last years many disease-modifying agents as treatment options for multiple sclerosis have been made available, their mechanisms of action are still not fully determined. In the present study radiosensitivity in lymphocytes of patients with relapsing–remitting multiple sclerosis, secondary progressive multiple sclerosis and healthy controls was investigated. Whole blood cultures from multiple sclerosis patients and healthy controls were used to analyze the spontaneous and radiation-induced micronuclei in binucleated lymphocytes. A subgroup of patients with relapsing–remitting multiple sclerosis was treated with immunomodulatory agents, interferon β or glatiramer acetate. The secondary progressive multiple sclerosis patients group was not receiving any treatment. Our results reveal that the basal DNA damage was not different between relapsing–remitting and secondary progressive multiple sclerosis patients, and healthy controls. No differences between gamma-irradiation induced micronuclei frequencies in binucleated cells from relapsing–remitting and secondary progressive multiple sclerosis patients, and healthy controls were found either. Nevertheless, when we compared the radiation induced DNA damage in binucleated cells from healthy individuals with the whole group of patients, a reduction in the frequency of micronuclei was obtained in the patients group. Induced micronuclei yield was significantly lower in the irradiated samples from treated relapsing–remitting multiple

Low-Dose Radiation Cataract and Genetic Determinants of Radiosensitivity

Energy Technology Data Exchange (ETDEWEB)

Kleiman, Norman Jay [Columbia University

2013-11-30

The lens of the eye is one of the most radiosensitive tissues in the body. Ocular ionizing radiation exposure results in characteristic, dose related, progressive lens changes leading to cataract formation. While initial, early stages of lens opacification may not cause visual disability, the severity of such changes progressively increases with dose until vision is impaired and cataract extraction surgery may be required. Because of the transparency of the eye, radiation induced lens changes can easily be followed non-invasively over time. Thus, the lens provides a unique model system in which to study the effects of low dose ionizing radiation exposure in a complex, highly organized tissue. Despite this observation, considerable uncertainties remain surrounding the relationship between dose and risk of developing radiation cataract. For example, a growing number of human epidemiological findings suggest significant risk among various groups of occupationally and accidentally exposed individuals and confidence intervals that include zero dose. Nevertheless, questions remain concerning the relationship between lens opacities, visual disability, clinical cataract, threshold dose and/or the role of genetics in determining radiosensitivity. Experimentally, the response of the rodent eye to radiation is quite similar to that in humans and thus animal studies are well suited to examine the relationship between radiation exposure, genetic determinants of radiosensitivity and cataractogenesis. The current work has expanded our knowledge of the low-dose effects of X-irradiation or high-LET heavy ion exposure on timing and progression of radiation cataract and has provided new information on the genetic, molecular, biochemical and cell biological features which contribute to this pathology. Furthermore, findings have indicated that single and/or multiple haploinsufficiency for various genes involved in DNA repair and cell cycle checkpoint control, such as Atm, Brca1 or Rad9

Radiosensitizing effect of nitric oxide in tumor cells and experimental tumors irradiated with gamma rays and proton beams

International Nuclear Information System (INIS)

Policastro, Lucia L.; Duran, Hebe; Molinari, Beatriz L.; Somacal, Hector R.; Valda, Alejandro A.

2003-01-01

Nitric oxide (NO) has been reported to be a radiosensitizer of mammalian cells under hypoxic conditions. In a previous study, we demonstrated an enhancement in radiation response induced by NO in mouse tumor cells under aerobic conditions, with an increasing effect as a function of malignancy. The aim of the present study was to evaluate the effect of NO in tumor cells and in experimental tumors irradiated with γ rays and proton beams. Irradiations were performed with a 137 Cs γ source and with proton beams generated by the TANDAR accelerator. Tumor cells were treated with the NO donor DETA-NO and the sensitizer enhancement ratio (SER) was calculated using the α parameter of the survival curve fitted to the linear-quadratic model. Tumor cells irradiated with protons were radio sensitized by DETA-NO only in the more malignant cells irradiated with low LET protons (2.69±0.08 keV/μm). For higher LET protons there were no radiosensitizing effect. For human tumor cells pre-treated with DETA-NO and irradiated with γ rays, a significantly greater effect was demonstrated in the malignant cells (MCF-7) as compared with the near normal cells (HBL-100). Moreover, a significant decrease in tumor growth was demonstrated in mice pre-treated with the NO donor spermine and irradiated with γ rays and low LET protons as compared with mice irradiated without pre-treatment with the NO donor. In conclusion, we demonstrated a differential effect of NO as a radiosensitizer of malignant cells, both with γ rays and low LET protons. This selectivity, coupled to the in vivo inhibition of tumor growth, is of great interest for the potential use of NO releasing agents in radiotherapy. (author)

Radiosensitivity of drug-resistant human tumour xenografts

International Nuclear Information System (INIS)

Mattern, J.; Bak, M. Jr.; Volm, M.; Hoever, K.H.

1989-01-01

The radiosensitivity of three drug-resistant sublines of a human epidermoid lung carcinoma growing as xenografts in nude mice was investigated. Drug resistance to vincristine, actinomycin D and cisplatin was developed in vivo by repeated drug treatment. It was found that all three drug-resistant tumour lines were not cross-resistant to irradiation. (orig.) [de

Whole brain radiotherapy with radiosensitizer for brain metastases

Directory of Open Access Journals (Sweden)

Viani Gustavo

2009-01-01

Full Text Available Abstract Purpose To study the efficacy of whole brain radiotherapy (WBRT with radiosensitizer in comparison with WBRT alone for patients with brain metastases in terms of overall survival, disease progression, response to treatment and adverse effects of treatment. Methods A meta-analysis of randomized controlled trials (RCT was performed in order to compare WBRT with radiosensitizer for brain metastases and WBRT alone. The MEDLINE, EMBASE, LILACS, and Cochrane Library databases, in addition to Trial registers, bibliographic databases, and recent issues of relevant journals were researched. Significant reports were reviewed by two reviewers independently. Results A total of 8 RCTs, yielding 2317 patients were analyzed. Pooled results from this 8 RCTs of WBRT with radiosensitizer have not shown a meaningful improvement on overall survival compared to WBRT alone OR = 1.03 (95% CI0.84–1.25, p = 0.77. Also, there was no difference in local brain tumor response OR = 0.8(95% CI 0.5 – 1.03 and brain tumor progression (OR = 1.11, 95% CI 0.9 – 1.3 when the two arms were compared. Conclusion Our data show that WBRT with the following radiosentizers (ionidamine, metronidazole, misonodazole, motexafin gadolinium, BUdr, efaproxiral, thalidomide, have not improved significatively the overall survival, local control and tumor response compared to WBRT alone for brain metastases. However, 2 of them, motexafin- gadolinium and efaproxiral have been shown in recent publications (lung and breast to have positive action in lung and breast carcinoma brain metastases in association with WBRT.

A study on the toxicity of three radiosensitizers on retinoblastoma cells by MTT assay

International Nuclear Information System (INIS)

Yi Xianjin; Jin Yizun; Ding Li; Ni Zhou; Wang Wenji

1994-01-01

The toxicity of three radiosensitizers BSO, CM and RSU-1069 on retinoblastoma cells was determined and the efficiency of in vitro MTT assay on drug-screening for retinoblastoma was also evaluated. The results showed that the MTT assay is very useful. The toxicity of radiosensitizers on retinoblastoma cells is dependent on cell line characteristics, drug concentration and time of exposure to it

Effect of radiation on immunity and immunological methods of radiosensitivity modifications

International Nuclear Information System (INIS)

Ivanov, A.A.

1987-01-01

Immunity system is shown to be heterogeneous as to its radiosensitivity, but injury of one of its most radiosensitive links results in the violation of the whole system functioning already at the level of sublethal radiation doses. Injury processes and disbalance in the immunity system play important role in the realization of radiobiological effects at the level of the whole organism starting from the period of primary reaction to irradiation and ending with the period of remote consequences. The process of radiation injury can be considerably modified by actively affecting cell and humoral factors of immunologic reactivity

Comparison of radiosensitivity of bacteria isolated from given radiation exposure history

International Nuclear Information System (INIS)

Kim, K.S.; Min, B.H.; Rhee, K.S.

1974-01-01

This experiment was carried out to identify and to compare the radiosensitivities of bacteria isolated from the sources of different radiation exposure histories. Among 10 strains isolated in this investigation, 4 strains of bacteria, Bacillus firmus, Bacillus brevis, Bacillus subtilis and Bacillus sphaericus were isolated from high- and low-radioactive sites simultaneously. Bacterial strains isolated from radioactive sources such as reactor and isotope production rooms were more resistant to irradiation than the microorganisms from medical products and laboratories, however, there was no significance in radiosensitivity in the same species of bacteria, even if they were isolated from different radiation exposure histories. (author)

Dynamic telomerase gene suppression via network effects of GSK3 inhibition.

Directory of Open Access Journals (Sweden)

Alan E Bilsland

2009-07-01

Full Text Available Telomerase controls telomere homeostasis and cell immortality and is a promising anti-cancer target, but few small molecule telomerase inhibitors have been developed. Reactivated transcription of the catalytic subunit hTERT in cancer cells controls telomerase expression. Better understanding of upstream pathways is critical for effective anti-telomerase therapeutics and may reveal new targets to inhibit hTERT expression.In a focused promoter screen, several GSK3 inhibitors suppressed hTERT reporter activity. GSK3 inhibition using 6-bromoindirubin-3'-oxime suppressed hTERT expression, telomerase activity and telomere length in several cancer cell lines and growth and hTERT expression in ovarian cancer xenografts. Microarray analysis, network modelling and oligonucleotide binding assays suggested that multiple transcription factors were affected. Extensive remodelling involving Sp1, STAT3, c-Myc, NFkappaB, and p53 occurred at the endogenous hTERT promoter. RNAi screening of the hTERT promoter revealed multiple kinase genes which affect the hTERT promoter, potentially acting through these factors. Prolonged inhibitor treatments caused dynamic expression both of hTERT and of c-Jun, p53, STAT3, AR and c-Myc.Our results indicate that GSK3 activates hTERT expression in cancer cells and contributes to telomere length homeostasis. GSK3 inhibition is a clinical strategy for several chronic diseases. These results imply that it may also be useful in cancer therapy. However, the complex network effects we show here have implications for either setting.

Directional spike propagation in a recurrent network: dynamical firewall as anisotropic recurrent inhibition.

Science.gov (United States)

Samura, Toshikazu; Hayashi, Hatsuo

2012-09-01

It has been demonstrated that theta rhythm propagates along the septotemporal axis of the hippocampal CA1 of the rat running on a track, and it has been suggested that directional spike propagation in the hippocampal CA3 is reflected in CA1. In this paper, we show that directional spike propagation occurs in a recurrent network model in which neurons are connected locally and connection weights are modified through STDP. The recurrent network model consists of excitatory and inhibitory neurons, which are intrinsic bursting and fast spiking neurons developed by Izhikevich, respectively. The maximum length of connections from excitatory neurons is shorter in the horizontal direction than the vertical direction. Connections from inhibitory neurons have the same maximum length in both directions, and the maximum length of inhibitory connections is the same as that of excitatory connections in the vertical direction. When connection weights between excitatory neurons (E→E) were modified through STDP and those from excitatory neurons to inhibitory neurons (E→I) were constant, spikes propagated in the vertical direction as expected from the network structure. However, when E→I connection weights were modified through STDP, as well as E→E connection weights, spikes propagated in the horizontal direction against the above expectation. This paradoxical propagation was produced by strengthened E→I connections which shifted the timing of inhibition forward. When E→I connections are enhanced, the direction of effective inhibition changes from horizontal to vertical, as if a gate for spike propagation is opened in the horizontal direction and firewalls come out in the vertical direction. These results suggest that the advance of timing of inhibition caused by potentiation of E→I connections is influential in network activity and is an important element in determining the direction of spike propagation. Copyright © 2012 Elsevier Ltd. All rights reserved.

Impairment of GABA transporter GAT-1 terminates cortical recurrent network activity via enhanced phasic inhibition

Directory of Open Access Journals (Sweden)

Daniel Simon Razik

2013-09-01

Full Text Available In the central nervous system, GABA transporters (GATs very efficiently clear synaptically released GABA from the extracellular space, and thus exert a tight control on GABAergic inhibition. In neocortex, GABAergic inhibition is heavily recruited during recurrent phases of spontaneous action potential activity which alternate with neuronally quiet periods. Therefore, such activity should be quite sensitive to minute alterations of GAT function. Here, we explored the effects of a gradual impairment of GAT-1 and GAT-2/3 on spontaneous recurrent network activity – termed network bursts and silent periods – in organotypic slice cultures of rat neocortex. The GAT-1 specific antagonist NO-711 depressed activity already at nanomolar concentrations (IC50 for depression of spontaneous multiunit firing rate of 42 nM, reaching a level of 80% at 500-1000 nM. By contrast, the GAT-2/3 preferring antagonist SNAP-5114 had weaker and less consistent effects. Several lines of evidence pointed towards an enhancement of phasic GABAergic inhibition as the dominant activity-depressing mechanism: network bursts were drastically shortened, phasic GABAergic currents decayed slower, and neuronal excitability during ongoing activity was diminished. In silent periods, NO-711 had little effect on neuronal excitability or membrane resistance, quite in contrast to the effects of muscimol, a GABA mimetic which activates GABAA receptors tonically. Our results suggest that an enhancement of phasic GABAergic inhibition efficiently curtails cortical recurrent activity and may mediate antiepileptic effects of therapeutically relevant concentrations of GAT-1 antagonists.

Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo

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Zwicker, F.; Roeder, F.; Debus, J.; Huber, P.E. [University Hospital Center Heidelberg, Heidelberg (Germany). Dept. of Radiation Oncology; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany). Clinical Cooperation Unit Molecular Radiation Oncology; Kirsner, A.; Weber, K.J. [University Hospital Center Heidelberg, Heidelberg (Germany). Dept. of Radiation Oncology; Peschke, P. [Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany). Clinical Cooperation Unit Molecular Radiation Oncology

2013-08-15

Background: Inhibition of pyruvate dehydrogenase kinase (PDK) by dichloroacetate (DCA) can shift tumor cell metabolism from anaerobic glycolysis to glucose oxidation, with activation of mitochondrial activity and chemotherapy-dependent apoptosis. In radiotherapy, DCA could thus potentially enhance the frequently moderate apoptotic response of cancer cells that results from their mitochondrial dysfunction. The aim of this study was to investigate tumor-specific radiosensitization by DCA in vitro and in a human tumor xenograft mouse model in vivo. Materials and methods: The interaction of DCA with photon beam radiation was investigated in the human tumor cell lines WIDR (colorectal) and LN18 (glioma), as well as in the human normal tissue cell lines HUVEC (endothelial), MRC5 (lung fibroblasts) and TK6 (lymphoblastoid). Apoptosis induction in vitro was assessed by DAPI staining and sub-G1 flow cytometry; cell survival was quantified by clonogenic assay. The effect of DCA in vivo was investigated in WIDR xenograft tumors growing subcutaneously on BALB/c-nu/nu mice, with and without fractionated irradiation. Histological examination included TUNEL and Ki67 staining for apoptosis and proliferation, respectively, as well as pinomidazole labeling for hypoxia. Results: DCA treatment led to decreased clonogenic survival and increased specific apoptosis rates in tumor cell lines (LN18, WIDR) but not in normal tissue cells (HUVEC, MRC5, TK6). However, this significant tumor-specific radiosensitization by DCA in vitro was not reflected by the situation in vivo: The growth suppression of WIDR xenograft tumors after irradiation was reduced upon additional DCA treatment (reflected by Ki67 expression levels), although early tumor cell apoptosis rates were significantly increased by DCA. This apparently paradoxical effect was accompanied by a marked DCA-dependent induction of hypoxia in tumor-tissue. Conclusion: DCA induced tumor-specific radiosensitization in vitro but not in vivo

Individual radiosensitivity measured with lymphocytes can be used to predict the risk of fibrosis after radiotherapy of breast cancer patients

International Nuclear Information System (INIS)

Hoeller, U.; Borgmann, K.; Alberti, W.; Dikomey, E.

2003-01-01

To analyse the relationship of individual cellular radiosensitivity and fibrosis after breast conserving therapy. A new model was used describing the percentage of patients developing fibrosis per year per patients at risk . In a retrospective study, 86 patients were included, who had undergone breast conserving surgery and irradiation of the breast with a median dose of 55 Gy (54-55Gy), 2.5 Gy/fraction (n=57) or 2 Gy/fraction (n=29). Median age was 62 years (range: 44-86) and median follow up was 7.5 years (range 5-16). Patients were examined for fibrosis according to the LENT/SOMA score. For analysis, fibrosis was classified as none (G0-1) or present (G2-3). The time to complete development of fibrosis was determined by analysis of yearly mammograms. Individual cellular radiosensitivity was determined by scoring lethal chromosomal aberrations in in vitro irradiated (6 Gy) lymphocytes using metaphase technique. Patients with low/intermediate cellular radiosensitivity were compared with patients with high cellular radiosensitivity with actuarial methods. Ten patients developed fibrosis at 1-8 years after radiotherapy. Individual cellular radiosensitivity was described by normal distribution of lethal chromosomal aberrations, average 5.47 lethal aberrations per cell (standard deviation 0.71). Cellular radiosensitivity was defined as low/intermediate (le 6.18 lethal aberrations) in 73 patients and as high (> 6.18 lethal aberrations ) in 13 patients. In both groups the actuarial rate of fibrosis-free patients declined exponentially with time after radiotherapy. Patients with high cellular radiosensitivity showed a 2.3 fold higher annual rate for fibrosis than patients with intermediate and low radiosensitivity (3.6±0.1 vs. 1.6±0.3). In breast cancer patients, high individual cellular radiosensitivity as determined by the number of lethal chromosome aberrations in in vitro irradiated lymphocytes was correlated with an enhanced annual rate of fibrosis

Differential radiosensitivity among B cell subpopulations

International Nuclear Information System (INIS)

Riggs, J.E.

1988-01-01

The selective radiosensitivity of sIgM >> sIgD marginal zone B cells is associated with the selective loss of B cell function. The simultaneous restoration of impaired function and recovery of these cells with time supports this premise. B cell recovery, delayed one week after irradiation, is in progress at two weeks, and virtually complete by three weeks. XID mice reveal similar recovery kinetics although there are fewer recovering cells and these bear reduced levels of Ia. This observation represents additional evidence that xid B cells are distinct from those of normal mice. The simultaneous loss, and concurrent recovery, of sIgM >> sIgD B cells and TI-2 responsiveness in irradiated mice suggests the existence of a unique B cell subpopulation possessing both phenotypes. Additional support for this hypothesis is provided by demonstrating that splenocytes, depleted of IgD + cells adoptively reconstitute this response in XID mice. The peritoneal B cell pool, which, compared to the spleen, consist of increased numbers of sIgM >> sIgD B cells, is shown to be a source of radiosensitive B cells that are TI-2 responsive. These observations represent additional evidence for an association between sIgM >> sIgD B cells and TI-2 responsiveness

LET effects on normal and radiosensitive cell lines

International Nuclear Information System (INIS)

Geard, C.R.; Travisano, M.

1986-01-01

Charged particles in the track segment mode were produced by the RARAF Van de Graaff accelerator and used to irradiate two CHO cell lines, a radiosensitive hypermutable line EM9 and its normal parent AA8. Asynchronous cells were irradiated attached to 6 micrometer thick Mylar with protons, deuterons and helium-3 particles at LETs ranging from 10 to 150 keV per micrometer. A 50 kVp x-ray tube integrated into the track segment facility provided a low LET comparison. Following irradiation cells were monitored for clonogenicity, and in a separate series of experiments frequencies of sister chromatid exchanges. Up to 9 experiments were carried out at each LET, with a total of 8 radiations of different LETs being compared. The optimally effective LET for cell survival was between 80 and 120 keV per micrometer, with the 150 keV per micrometer particles indicating energy wastage. The differential between the normal and radiosensitive cell lines was maintained at all LETs

Radiosensitization of nitroindazole derivatives on HeLa cells

International Nuclear Information System (INIS)

Wang Hao; Shi Peiji; Zhou Xiaoliang; Wang Yan; Tang Weisheng

2010-01-01

Objective: To investigate the cytotoxicity and radiosensitization of 5-nitroindazole-3-formyliminodiacetic acid on HeLa cells. Methods: HeLa cells in exponential growth phase were incubated in culture media with different doses and the survival rate was determined by MTT assay. The survival rate of cells receiving radiation combined with different doses of medicine was compared with that of the control.Results: The cytotoxicity of S-nitroindazole-3-formyliminodiacetic acid on HeLa cells was very low. The drug had hypoxia radiosensitizing effect on HeLa cells. At doses of 0, 6, 12, 24, 48 and 96 μg/ml under hypoxia, the survival rate were 0.91 , 0.87, 0.84, 0.81, 0.76 and 0.60, respectively. At the dosage of 48 and 96 μg/ml, the survival rate were 0.85 and 0.73 under oxygenous). Conclusions: 5-Nitroindazole-3-formyliminodiacetic acid has low cytotoxicity and rediosensitizing effect on HeLa cells. (authors)

Individual radiosensitivity measured with lymphocytes may be used to predict the risk of fibrosis after radiotherapy for breast cancer

International Nuclear Information System (INIS)

Hoeller, Ulrike; Borgmann, Kerstin; Bonacker, Michael; Kuhlmey, Antje; Bajrovic, Amira; Jung, Horst; Alberti, Winfried; Dikomey, Ekkehard

2003-01-01

Background and purpose: To analyse the relationship of individual cellular radiosensitivity and fibrosis after breast conserving therapy. A new model was used describing the percentage of patients developing fibrosis per year and per patient at risk. Patients and methods: In a retrospective study, 86 patients were included, who had undergone breast conserving surgery and irradiation of the breast with a median dose of 55 Gy (54-55 Gy) given at 2.5 Gy/fraction (n=57) or 2 Gy/fraction (n=29). Median age was 62 years (range 44-86) and median follow-up was 7.5 years (range 5-17). Patients were examined for fibrosis according to the LENT/SOMA score. For analysis, fibrosis was classified as grade 0 and grade 1 (G0-1) or present grade 2 and grade 3 (G2-3). The time to complete development of fibrosis was determined by analysis of yearly mammograms. Individual cellular radiosensitivity was determined by scoring lethal chromosomal aberrations in in vitro irradiated (6 Gy) lymphocytes using metaphase technique. Patients with low/intermediate cellular radiosensitivity were compared with patients with high cellular radiosensitivity using actuarial methods. Results: Ten patients developed fibrosis at 1-8 years after radiotherapy. Individual cellular radiosensitivity was described by normal distribution of lethal chromosomal aberrations, the average was 5.47 lethal aberrations per cell (standard deviation (SD) 0.71). Cellular radiosensitivity was defined as low/intermediate (≤6.18 lethal aberrations) in 73 patients and high (>6.18 lethal aberrations; mean+SD) in 13 patients. In both groups, the actuarial rate of fibrosis-free patients decreased exponentially with time after radiotherapy. Patients with high cellular radiosensitivity showed a 2.3-fold higher annual rate for fibrosis than patients with intermediate and low radiosensitivity (3.6 versus 1.6% per year). Conclusions: In breast cancer patients, high individual cellular radiosensitivity as determined by the number of

Genetic control of yeast cell radiosensitivity modification by oxygen and hypoxic sensitizers

International Nuclear Information System (INIS)

Zhuranovskaya, G.P.; Petin, V.G.

1984-01-01

Diploid yeast cells Saccharomyces cerevisiae ''of the wild type'', individual mutants, homozygous in rad 2 and rad 54 and double mutants, containing both these loci in homozygous state are considered to prove genetic determination of radiosensitivity modification of hypoxic cells by oxygen and electron acceptor compounds previously demonstrated on yeast cells of other genotypes. It is shown that both ''oxygen effect'' and the effect of hypoxic sensitizers depend on the activity of repair systems. The possible mechanism of participation of post-radiation restoration processes in the modification of cell radiosensitivity, is discussed

Integrin inhibitor (Cilengitide) as radiosensitization strategy for malignant tumors; Inibidor de integrina (Cilengitida) como estratégia de radiossensibilização de tumores malignos

Energy Technology Data Exchange (ETDEWEB)

Silva, Felipe Henrique de Souza

2017-07-01

Radiotherapy is effective in tumor control, but several tumors have molecular characteristics that lead to radioresistance and possible posttreatment recurrence. Many tumors have overexpression of integrin receptors. Integrins play a central role in growth, motility, regulation of adhesion and survival, leading to increased proliferation, invasion and metastasis of tumors, making these receptors excellent targets for the development of new therapies. Studies have shown that inhibiting the interaction of matrix proteins with integrin receptors may increase the cytotoxic effect of ionizing radiation by demonstrating the radiosensitizing potential of combination therapy in tumoral lines. Cilengitide an inhibitor of integrins receptors α Vβ3 and αVβ5 stands out for its great antitumor potential against gliomas. Thus, the combination of ionizing radiation with cilengitide is an alternative therapeutic strategy. However, the effect of this combination is little studied in Glioblastomas (U87 and T98) and not studied in melanoma (UACC). The objective of this study was to evaluate the radiosensitising potential of the RGD molecule cilengitida by means of the combined treatment with gamma radiation in different tumor lines, as well as to compare the effect of this combination therapy with cisplatin, a molecule already used in clinical practice. Our panel of tumor cell lines was composed of U87 (wild-type p53 malignant glioblastoma) T98 (malignant glioblastoma mutant p53), MCF7 (mammary carcinoma) and UACC (melanoma). The radiosensitizer effect of cilengitide was evaluated by the quantification of metabolic cell viability through the MTT assay. Inhibition of colony formation was investigated in clonogenicity assays. The flow cytometer was used to investigate cell cycle distribution and the type of cell death induced. We observed that in all cell lines examined, cilengitida promoted detachment, metabolic alterations and reduction of proliferation, as well as alteration of

Efficacy of radiosensitizing doped titania nanoparticles under hypoxia and preparation of an embolic microparticle

Directory of Open Access Journals (Sweden)

Morrison RA

2017-05-01

Full Text Available Rachel A Morrison,1,* Malgorzata J Rybak-Smith,1,* James M Thompson,2 Bénédicte Thiebaut,3 Mark A Hill,2 Helen E Townley1,4 1Department of Engineering Science, 2Gray Laboratories, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, 3Johnson Matthey, Technology Centre, Reading, Berkshire, 4Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford, UK *These authors have contributed equally to this work Abstract: The aim of this study was to develop a manufacturing protocol for large-scale production of doped titania radiosensitizing nanoparticles (NPs to establish their activity under hypoxia and to produce a multimodal radiosensitizing embolic particle for cancer treatment. We have previously shown that radiosensitizing NPs can be synthesized from titania doped with rare earth elements, especially gadolinium. To translate this technology to the clinic, a crucial step is to find a suitable, scalable, high-throughput method. Herein, we have described the use of flame spray pyrolysis (FSP to generate NPs from titanium and gadolinium precursors to produce titania NPs doped with 5 at% gadolinium. The NPs were fully characterized, and their capacity to act as radiosensitizers was confirmed by clonogenic assays. The integrity of the NPs in vitro was also ascertained due to the potentially adverse effects of free gadolinium in the body. The activity of the NPs was then studied under hypoxia since this is often a barrier to effective radiotherapy. In vitro radiosensitization experiments were performed with both the hypoxia mimetics deferoxamine and cobalt chloride and also under true hypoxia (oxygen concentration of 0.2%. It was shown that the radiosensitizing NPs were able to cause a significant increase in cell death even after irradiation under hypoxic conditions such as those found in tumors. Subsequently, the synthesized NPs were used to modify polystyrene embolization

Radiosensitization of hypoxic bacterial cells by nitroimidazoles of low lipophilicity: steady-state and rapid-mix studies

International Nuclear Information System (INIS)

Anderson, R.F.; Patel, K.B.; Sehmi, D.S.

1981-01-01

Radiosensitization of hypoxic bacterial cells by five 2-nitroimidazoles, with similar reduction potentials to misonidazole but having lower lipophilicites, has been measured in Escherichia coli AB 1157 and Streptococcus lactis 712. Sensitization efficiency progressively decreased with decreasing lepophilicity in E. coli but not in S. lactis. This difference is discussed in terms of the differing membrane properties of the two bacteria; E. coli resembled a multicompartment model, as would also be expected with mammalian cells. Rapid-mix experiments are described which show that the radiosensitization observed after experiments are described which show that the radiosensitization observed after preirradiation contact times between ca. 3 and 30 msec is dependent on the lipophilicity of the sensitizer, higher lipophilicity resulting in a lower contact time being required for radiosensitization. This result and the observation that a highly lipophilic compound affects only half the full oxygen enhancement level after short contact times suggest that part of the sensitization process occurs in a lipophilic compartment of the cell

Enhancement of P53-Mutant Human Colorectal Cancer Cells Radiosensitivity by Flavonoid Fisetin

International Nuclear Information System (INIS)

Chen Wenshu; Lee Yijang; Yu Yichu; Hsaio Chinghui

2010-01-01

Purpose: The aim of this study was to investigate whether fisetin is a potential radiosensitizer for human colorectal cancer cells, which are relatively resistant to radiotherapy. Methods and Materials: Cell survival was examined by clonogenic survival assay, and DNA fragmentation was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The effects of treatments on cell cycle distribution and apoptosis were examined by flow cytometry. Western blot analysis was performed to ascertain the protein levels of γ-H2AX, phospho-Chk2, active caspase-3, PARP cleavage, phospho-p38, phospho-AKT, and phospho-ERK1/2. Results: Fisetin pretreatment enhanced the radiosensitivity of p53-mutant HT-29 human colorectal cancer cells but not human keratocyte HaCaT cells; it also prolonged radiation-induced G 2 /M arrest, enhanced radiation-induced cell growth arrest in HT-29 cells, and suppressed radiation-induced phospho-H2AX (Ser-139) and phospho-Chk2 (Thr-68) in p53-mutant HT-29 cells. Pretreatment with fisetin enhanced radiation-induced caspase-dependent apoptosis in HT-29 cells. Fisetin pretreatment augmented radiation-induced phosphorylation of p38 mitogen-activated protein kinase, which is involved in caspase-mediated apoptosis, and SB202190 significantly reduced apoptosis and radiosensitivity in fisetin-pretreated HT-29 cells. By contrast, both phospho-AKT and phospho-ERK1/2, which are involved in cell proliferation and antiapoptotic pathways, were suppressed after irradiation combined with fisetin pretreatment. Conclusions: To our knowledge, this study is the first to provide evidence that fisetin exerts a radiosensitizing effect in p53-mutant HT-29 cells. Fisetin could potentially be developed as a novel radiosensitizer against radioresistant human cancer cells.

Use of radiosensitivity to identify irradiated fresh poultry products

International Nuclear Information System (INIS)

Copin, M.P.; Bourgeois, C.M.

1991-01-01

Microbiological comparison between irradiated and non-irradiated foodstuff has been studied for a long time as a way to detect whether a foodstuff has been irradiated or not. Generally, the proposed methods are based on the fact that ionization select species of bacteria which are recognized to be radioresistant. So reduction or elimination of known radiation sensitive microbes from the normal endogenous microflora could give an indication that the foodstuff has been irradiated, predominance of known radioresistant bacteria should be another indication. In the present work, we try to develop a test based on the radiosensitivity of the bacteria independently of their place. These first experiments show that the determination of radiosensitivity of strains isolated from a product or even of global radioresistance of mesophilic microflora could indicate if this product has been previously submitted to ionizing radiations. (4 tabs)

Change in radiosensitivity of sea-urchin eggs during early cleavage stages

International Nuclear Information System (INIS)

Nakamura, I.

1977-01-01

When sea-urchin eggs were irradiated with 137 Cs γ-rays, their radiosensitivity, expressed by the percentage which formed pluteus larvae, fluctuated during the early cleavage cycle. Split-dose irradiations were made both in the sensitive and resistant phases. For eggs in the sensitive phase, the effect of the first exposure of 500 rad was not diminished during the interval before the second exposure. Eggs irradiated in the resistant phase were only slightly damaged. Results implied that fluctuations in radiosensitivity of sea-urchin eggs were caused mainly by different degrees of non-repairable damage in each phase of cleavage rather than by different recovery abilities. (author)

Effect of anemia on tumor radiosensitivity under normo and hyperbaric conditions

International Nuclear Information System (INIS)

Rojas, A.; Stewart, F.A.; Smith, K.A.; Soranson, J.A.; Randhawa, V.S.; Stratford, M.R.; Denekamp, J.

1987-01-01

The effect of chronic anemia on tumor radiosensitivity in a murine tumor has been investigated. Anemia was induced by bilateral kidney irradiation given several months before tumor implantation. Anemic, anemic transfused, and normal non-anemic age-matched tumor bearing animals were irradiated with X rays (2 F/24 hr) either in air, air plus misonidazole, or under hyperbaric oxygen. The most resistant response was that of tumors grown in normal mice treated in air. Anemia produced an increase in radiosensitivity which was further enhanced by red blood cell replacement. The most sensitive overall response was seen in the anemic-transfused group treated with HBO

Acute LSD effects on response inhibition neural networks.

Science.gov (United States)

Schmidt, A; Müller, F; Lenz, C; Dolder, P C; Schmid, Y; Zanchi, D; Lang, U E; Liechti, M E; Borgwardt, S

2017-10-02

Recent evidence shows that the serotonin 2A receptor (5-hydroxytryptamine2A receptor, 5-HT2AR) is critically involved in the formation of visual hallucinations and cognitive impairments in lysergic acid diethylamide (LSD)-induced states and neuropsychiatric diseases. However, the interaction between 5-HT2AR activation, cognitive impairments and visual hallucinations is still poorly understood. This study explored the effect of 5-HT2AR activation on response inhibition neural networks in healthy subjects by using LSD and further tested whether brain activation during response inhibition under LSD exposure was related to LSD-induced visual hallucinations. In a double-blind, randomized, placebo-controlled, cross-over study, LSD (100 µg) and placebo were administered to 18 healthy subjects. Response inhibition was assessed using a functional magnetic resonance imaging Go/No-Go task. LSD-induced visual hallucinations were measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) questionnaire. Relative to placebo, LSD administration impaired inhibitory performance and reduced brain activation in the right middle temporal gyrus, superior/middle/inferior frontal gyrus and anterior cingulate cortex and in the left superior frontal and postcentral gyrus and cerebellum. Parahippocampal activation during response inhibition was differently related to inhibitory performance after placebo and LSD administration. Finally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive impairments and visual imagery. Our findings show that 5-HT2AR activation by LSD leads to a hippocampal-prefrontal cortex-mediated breakdown of inhibitory processing, which might subsequently promote the formation of LSD-induced visual imageries. These findings help to better understand the neuropsychopharmacological mechanisms of visual hallucinations in LSD-induced states and neuropsychiatric disorders.

Genotype dependent radiosensitivity of autotetraploids in Trigonella foenum-graecum L

Energy Technology Data Exchange (ETDEWEB)

Raghuvanshi, S S; Singh, A K

1980-01-01

Different diploids of Trigonella foenum-graecum L. and their corresponding autotetraploids were seedtreated with 40 krad of ..gamma..-rays, and parameters such as germination, survival, growth reduction, pollen fertility, pod setting, etc. were recorded. A stimulation of seed germination due to the irradiation could be observed. Contrary to the general rule that polyploids are more radioresistant than their corresponding diploids, one 4x strain was completely killed while the 2x version survived comparatively well. Apparently gene reduplication is not the overall protective mechanism as was once earlier believed. The importance of genotypic influence on radiosensitivity was demonstrated at both the 2x and 4x level. The limitation of interphase chromosome volume and degree of ploidy in predicting radiosensitivity is discussed.

Application of rosula-formation tests for determining man lymphocyte radiosensitivity

International Nuclear Information System (INIS)

Shchilik, Ts.; Krushevskij, E.; Endrzhejchak, V.

1982-01-01

Radiosensitivity of subpopulation of lymphocytes-T-lymphocytes and B-lymphocytes was studied to diagnose acute radiation disease as well as if radiosensitivity of any of them is more effective indication of irradiation as compared with absolute lymphocyte quantity. The investigations were carried on in vitro using blood of healthy men-donors at the age of 21-25. It is shown that absolute quantity of cells forming AE rosette in perapheral blood is a much better indication of irradiation as compared with absolute quantity of lymphocytes. Considerable significance of tests of rosette formation especially AE test is underlined. High test sensitivity and relative simplicity of accomplishment permit authors to recommend it for diagnostic purposes when revealing acute radiation disease including the stages of medicinal evacuation

Radio-sensitizing effect of ethyl caffeate on nasopharyngeal ...

African Journals Online (AJOL)

3Department of Clinical Laboratory, The 5th People's Hospital of Ji'nan, Ji'nan ... Purpose: To investigate the radio-sensitizing effect of ethyl caffeate (ETF) on naso-pharyngeal ... malignant solid tumors of head and neck which ... Excess irradiation could result in severe side .... protein bands were probed with corresponding.

Evaluation of the effect of three monazite constituents on the radiosensitivity of human osteoblasts

International Nuclear Information System (INIS)

Iwahara, Lucas Kiyoshi da Fonseca; Oliveira, Monica Stuck de; Alencar, Marcus Alexandre Vallim de

2017-01-01

Thorium has gained notoriety in recent years, as a potential source of nuclear energy, substituting uranium in power plants. Monazite is an important font of thorium, as well of uranium and rare earths elements. Professionals involved in the extraction and manipulation of this mineral are occupationally exposed to aerosols containing metals and to ionizing radiation. This paper analyzed the effects of thorium, cerium and lanthanum on cell radiosensitivity. As an osteotropic substance, thorium is mostly deposited in bone tissue and may interfere in cellular radiosensitivity. A human osteoblast cell line was used to evaluate the effects of thorium, cerium and lanthanum on cell radiosensitivity, using proliferation as indicator. Assays were performed using cell cultures exposed to metals and to ionizing radiation. As a result, metals in combination with ionizing radiation induced changes on cell proliferation, in a concentration-dependent manner, in comparison with the exposure to metals alone. That suggests the possibility of combination interfering with radiosensitivity of osteoblasts, indicating an enhancement in occupational risk for workers that manipulate monazite byproducts and are subject to radiation in the environment. Thus, the development of risk assessment models that include the evaluation of metal-radiation mixtures and their cytotoxic and radiotoxic effects on tissues and organs must be highlighted. (author)

Understanding the radiosensitivity of hematopoietic stem cells through CDNA micro-arrays profiling

Energy Technology Data Exchange (ETDEWEB)

Pawlik, A.; Cebo, Ch.; Vaigot, P.; Tronik-Le Roux, D. [Evry Univ., Lab. de Genomique et Radiobiologie de l' Hematopoiese, Service de Genomique Fonctionnelle, CEA, 91 (France)

2006-07-01

individually, since a large percentage of the identified genes have not been yet attributed to a particular function. To determine whether expression modulations of these genes could be associated with changes in the cell radiosensitivity, we have constructed vectors containing either cDNA s encoding four transcription factors or specific siRNA. Transfections in different cell lines are currently performed to assess whether overexpression or inhibition o f these factors might modify the radiosensitivity of the cell. To determine whether the in vivo transcriptional changes in gene expression triggered by ionizing radiation exposure were dependent on the microenvironment, the effect of IR exposure was monitored in the murine E.M.L. cell line. These cells were defined as possessing a Sca 'B220{sup -} Lin{sup lo} stem-like phenotype and can be potentially differentiated onto both lymphoid and myeloid lineages. Similarities of the in vivo and in vitro responses might be considered mostly as cell autonomous. Altogether this approach has the potential for unraveling molecular networks and finding novel and specific actors participating to the early response o f hematopoietic cells to radiation exposure. The outcome of this research might lead to the identification of molecules that ultimately modify the radiosensitivity of a cell and facilitate the derivation of clinically useful targets for rational therapeutic decisions. (N.C.)

Use of a temperature-sensitive p53 mutant to evaluate mechanisms of 5-fluorodeoxyuridine-mediated radiosensitization

International Nuclear Information System (INIS)

Naida, J.D.; Davis, M.A.; Lawrence, T.S.

1996-01-01

Purpose/Objective: Evidence exists that fluorodeoxyuridine (FdUrd)-mediated radiosensitization occurs in HT29 human colon carcinoma cells (which are p53 mutant) when these cells progress past the G 1 /S boundary in the presence of the drug. It has been demonstrated that wild type p53 levels increase following fluoropyrimidine treatment and that G 1 arrest is associated with increased p53 levels. We hypothesized that the restoration of wild type p53 function might restore G 1 /S arrest after FdUrd treatment, and that this would prevent FdUrd-mediated radiosensitization. Similarly, we hypothesized that cells containing wild type p53 would not be radiosensitized by FdUrd. Materials and Methods: Two clones of HT29 human colon cancer cells (ts29-A and ts29-G) containing murine temperature-sensitive p53 were constructed using electroporation and Geneticin selection. Incubation of these cells at the permissive temperature of 32 deg. C produces wild type p53 function and at the non permissive temperature of 38 deg. C causes mutant p53 function. A G418 resistant control cell line was also constructed (HT29neo). Cells were incubated at either 32 deg. C or 38 deg. C for 24 hours prior to irradiation and with FdUrd (100 nM) or medium only during the last 14 hours of the temperature shift. To assess progression into S phase, single-parameter (propidium iodide (PI)) and two-parameter (PI and bromodeoxyuridine) flow cytometry were performed at the end of drug exposure. A standard clonogenic assay was used. Results: We found that when ts29-A and ts29-G cells were incubated at the non-permissive (inactive p53 conformation) temperature, they progressed into S phase following exposure to FdUrd and were radiosensitized (enhancement ratio 1.5) to a degree similar to that seen in parental HT29 cells. Cells incubated at the permissive (wild-type p53 conformation) temperature demonstrated G 1 arrest, S phase depletion, and G2 arrest. In addition, FdUrd-mediated radiosensitization was

DNA repair , cell repair and radiosensitivity

International Nuclear Information System (INIS)

Zhestyanikov, V.D.

1983-01-01

Data obtained in laboratory of radiation cytology and literature data testifying to a considerable role of DNA repair in cell sensitivity to radiation and chemical DNA-tropic agents have been considered. Data pointing to the probability of contribution of inducible repair of DNA into plant cells sensitivity to X-rays are obtained. Certain violations of DNA repair do not result in the increase of radiosensitivity. It is assumed that in the cases unknown mechanisms of DNA repair operate

Loss of inhibition in sensorimotor networks in focal hand dystonia

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Cecile Gallea

2018-01-01

Interpretation: Impairments of GABAergic neurotransmission in the cerebellum and the sensorimotor cortical areas could explain different aspects of loss of inhibitory control in FHD, the former being involved in maladaptive plasticity, the latter in surround inhibition. Reorganization of the inferior prefrontal cortices, part of the associative network, might be compensatory for the loss of inhibitory control in sensorimotor circuits. These findings suggest that cerebellar and cerebral GABAergic abnormalities could play a role in the functional imbalance of striato-cerebello-cortical loops in dystonia.

Radiosensitivity of hemopoietic stem cells on cloning in bone marrow and spleen

International Nuclear Information System (INIS)

Shvets, V.N.; Shafirkin, A.V.

1979-01-01

It was shown that population of stem cells from bone marrow of mice is heterogenous by radiosensitivity. A 55%-survival of CFU is exponential function of radiation dose (D 0 -9 rad). A dose-effect curve for radioresistant part of the population (D 0 =180 rad) is sygmoid (Dsub(q)=130 rad). Radiosensitive CFU are suggested to represent a primarily committed fraction of half-semi cells, and radioresistant CFU are referable to a pool of pluripotent stem cells. Heterogenous nature of CFU population is proved with different modifications of radiation effect and interactions of CFU with T-lymphocytes

Omega-3 fatty acid supplementation in cancer therapy. Does eicosapentanoic acid influence the radiosensitivity of tumor cells?

Energy Technology Data Exchange (ETDEWEB)

Manda, Katrin; Kriesen, Stephan; Hildebrandt, Guido [Rostock Univ. (Germany). Dept. of Radiotherapy; Fietkau, Rainer; Klautke, Gunther [Univ. Hospital Erlangen, Erlangen (Germany). Dept. of Radiation Oncology

2011-02-15

Purpose: The aim of this study was to evaluate whether the omega-3 polyunsaturated fatty acid cis-5,8,11,14,17-eicosapentanoic acid (EPA) can enhance the radiosensitivity of different human tumor cell lines. Materials and Methods: Colon adenocarcinoma cells HT-29, and two glioblastoma multiforme tumor cells T98G and U251 were cultured under standard conditions. Cell growth was observed during administration with different concentrations of EPA, using it as the free fatty acid dissolved in ethanol or bound to bovine serum albumin. To investigate the influence of EPA (free and bound) on radiosensitivity, tumor cells were pretreated 30 minutes or 24 hours prior to irradiation with the fatty acid. Cell survival was measured by colony-forming assays. Results: When combined with irradiation, incubation with EPA was found to result in enhanced radiosensitivity with substantial variation: while there was strong radiosensitization for HT-29 and U251 cells, almost no effect for T98G cells was observed. A marked radiosensitization was clearly dependent on the treatment schedule. Conclusion: The observations suggest that EPA is not only a nutritional adjuvant but also may be a potential candidate to enhance the efficacy of irradiation on human cancer cells. (orig.)

Inhibition of the mitotic exit network in response to damaged telomeres.

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Mauricio Valerio-Santiago

Full Text Available When chromosomal DNA is damaged, progression through the cell cycle is halted to provide the cells with time to repair the genetic material before it is distributed between the mother and daughter cells. In Saccharomyces cerevisiae, this cell cycle arrest occurs at the G2/M transition. However, it is also necessary to restrain exit from mitosis by maintaining Bfa1-Bub2, the inhibitor of the Mitotic Exit Network (MEN, in an active state. While the role of Bfa1 and Bub2 in the inhibition of mitotic exit when the spindle is not properly aligned and the spindle position checkpoint is activated has been extensively studied, the mechanism by which these proteins prevent MEN function after DNA damage is still unclear. Here, we propose that the inhibition of the MEN is specifically required when telomeres are damaged but it is not necessary to face all types of chromosomal DNA damage, which is in agreement with previous data in mammals suggesting the existence of a putative telomere-specific DNA damage response that inhibits mitotic exit. Furthermore, we demonstrate that the mechanism of MEN inhibition when telomeres are damaged relies on the Rad53-dependent inhibition of Bfa1 phosphorylation by the Polo-like kinase Cdc5, establishing a new key role of this kinase in regulating cell cycle progression.

Cabazitaxel-induced stabilization of microtubules enhances radiosensitivity in ovarian cancer cells

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Charles eKunos

2013-09-01

Full Text Available Background: Up to 40% of women with ovarian cancer have short disease-free intervals due to molecular mechanisms of chemotherapy resistance. New therapeutic strategies are sought. Ovarian cancers are sensitive to radiochemotherapy. The taxane cabazitaxel (XRP6258, Jevtana promotes tubulin assembly and stabilizes microtubules against depolymerization in cells, acting similarly in mechanism to paclitaxel. Here, sequences of cabazitaxel-radiation co-administration are tested for drug-alone cytotoxicity and optimal radiosensitization.Methods: SKOV3, OVCAR3, and TOV-112D ovarian cancer cells were administered cabazitaxel 24 h before (first, 18 h before (second, together (third, or 24 h after (fourth a single radiation dose, and then, investigated by clonogenic assay and flow cytometric assays. Radiation dose-cell survival data were fitted by two-stage multivariate analyses of variance. High content flow cytometry partitioned cabazitaxel effects into G2-phase versus M-phase events by DNA content, cyclin A2, and phospho-S10-histone H3 (PHH3. Paclitaxel served as a comparator. Findings: Cabazitaxel cytotoxicity and radiosensitization were dose dependent. Cabazitaxel added 24 h before radiation was the most lethal schedule. DNA content measurements by flow cytometry showed that cabazitaxel-treated cells accumulated in the radiosensitive G2/M 4C DNA complement compartment. Cytometry also showed that surviving cabazitaxel-induced cell cycle arrested cells resolve the arrest by entering 4C or by 8C DNA complement cell cycles.Interpretation: The radiosensitizing effect of cabazitaxel was schedule dependent, due to cell cycle redistribution, and best when cabazitaxel was given 24 h before radiation. Clinical trials of administering both cabazitaxel and radiation should be explored in women with chemoresistant ovarian cancer. Funding: Case Comprehensive Cancer Center and Sanofi-Aventis

Dosimetry using radiosensitive gels in radiotherapy: significance and methods

International Nuclear Information System (INIS)

Gibon, D.; Bourel, P.; Castelain, B.; Marchandise, X.; Rousseau, J.

2001-01-01

The goal of conformal radiotherapy is to concentrate the dose in a well-defined volume by avoiding the neighbouring healthy structures. This technique requires powerful treatment planning software and a rigorous control of estimated dosimetry. The usual dosimetric tools are not adapted to visualize and validate complex 3D treatment. Dosimetry by radiosensitive gel permits visualization and measurement of the three-dimensional dose distribution. The objective of this work is to report on current work in this field and, based on our results and our experience, to draw prospects for an optimal use of this technique. Further developments will relate to the realization of new radiosensitive gels satisfying, as well as possible, cost requirements, easy realization and use, magnetic resonance imagery (MRI) sensitivity, tissue equivalence, and stability. Other developments focus on scanning methods, especially in MRI to measure T1 and T2. (author)

Regional differences in radiosensitivity across the rat cervical spinal cord

International Nuclear Information System (INIS)

Bijl, Hendrik P.; Luijk, Peter van; Coppes, Rob P.; Schippers, Jacobus M.; Konings, Antonius W.T.; Kogel, Albert J. van der

2005-01-01

Purpose: To study regional differences in radiosensitivity within the rat cervical spinal cord. Methods and materials: Three types of inhomogeneous dose distributions were applied to compare the radiosensitivity of the lateral and central parts of the rat cervical spinal cord. The left lateral half of the spinal cord was irradiated with two grazing proton beams, each with a different penumbra (20-80% isodoses): lateral wide (penumbra = 1.1 mm) and lateral tight (penumbra = 0.8 mm). In the third experiment, the midline of the cord was irradiated with a narrow proton beam with a penumbra of 0.8 mm. The irradiated spinal cord length (CT-2) was 20 mm in all experiments. The animals were irradiated with variable single doses of unmodulated protons (150 MeV) with the shoot-through method, whereby the plateau of the depth-dose profile is used rather than the Bragg peak. The endpoint for estimating isoeffective dose (ED 50 ) values was paralysis of fore and/or hind limbs within 210 days after irradiation. Histology of the spinal cords was performed to assess the radiation-induced tissue damage. Results: High-precision proton irradiation of the lateral or the central part of the spinal cord resulted in a shift of dose-response curves to higher dose values compared with the homogeneously irradiated cervical cord to the same 20-mm length. The ED 50 values were 28.9 Gy and 33.4 Gy for the lateral wide and lateral tight irradiations, respectively, and as high as 71.9 Gy for the central beam experiment, compared with 20.4 Gy for the homogeneously irradiated 20-mm length of cervical cord. Histologic analysis of the spinal cords showed that the paralysis was due to white matter necrosis. The radiosensitivity was inhomogeneously distributed across the spinal cord, with a much more radioresistant central white matter (ED 50 = 71.9 Gy) compared with lateral white matter (ED 50 values = 28.9 Gy and 33.4 Gy). The gray matter did not show any noticeable lesions, such as necrosis or

TU-F-CAMPUS-T-03: Enhancing the Tumor Specific Radiosensitization Using Molecular Targeted Gold Nanorods

International Nuclear Information System (INIS)

Diagaradjane, P; Deorukhkar, A; Sankaranarayanapillai, M; Singh, P; Manohar, N; Tailor, R; Cho, S; Goodrich, G; Krishnan, S

2015-01-01

Purpose: Gold nanoparticle (GNP) mediated radiosensitization has gained significant attention in recent years. However, the widely used passive targeting strategy requires high concentration of GNPs to induce the desired therapeutic effect, thus dampening the enthusiasm for clinical translation. The purpose of this study is to utilize a molecular targeting strategy to minimize the concentration of GNPs injected while simultaneously enhancing the tumor specific radiosensitization for an improved therapeutic outcome. Methods: Cetuximab (antibody specific to the epidermal growth factor receptor that is over-expressed in tumors) conjugated gold nanorods (cGNRs) was used for the tumor targeting. The binding affinity, internalization, and in vitro radiosensitization were evaluated using dark field microscopy, transmission electron microscopy, and clonogenic cell survival assay, respectively. In vivo biodistribution in tumor (HCT116-colorectal cancer cells) bearing mice were quantified using inductively coupled plasma mass spectrometry. In vivo radiosensitization potential was tested using 250-kVp x-rays and clinically relevant 6-MV radiation beams. Results: cGNRs displayed excellent cell-surface binding and internalization (∼31,000 vs 12,000/cell) when compared to unconjugated GNRs (pGNRs). In vitro, the dose enhancement factor at 10% survival (DEF10) was estimated as 1.06 and 1.17, respectively for both 250-kVp and 6-MV beams. In vivo biodistribution analysis revealed enhanced uptake of cGNRs in tumor (1.3 µg/g of tumor tissue), which is ∼1000-fold less than the reported values using passive targeting strategy. Nonetheless, significant radiosensitization was observed in vivo with cGNRs when compared to pGNRs, when irradiated with 250-kVp (tumor volume doubling time 35 days vs 25 days; p=0.002) and 6 MV (17 days vs 13 days; p=0.0052) beams. Conclusion: The enhanced radiosensitization effect observed with very low intratumoral concentrations of gold and megavoltage x

TU-F-CAMPUS-T-03: Enhancing the Tumor Specific Radiosensitization Using Molecular Targeted Gold Nanorods

Energy Technology Data Exchange (ETDEWEB)

Diagaradjane, P [M.D. Anderson Cancer Center, Houston, TX (United States); Deorukhkar, A; Sankaranarayanapillai, M; Singh, P [The UT MD Anderson Cancer Center, Houston, TX (United States); Manohar, N; Tailor, R; Cho, S [UT MD Anderson Cancer Center, Houston, TX (United States); Goodrich, G [Nanospectra Biosciences Inc, Houston, TX (United States); Krishnan, S [The University of Texas MD Anderson Cancer Center, Houston, TX (United States)

2015-06-15

Purpose: Gold nanoparticle (GNP) mediated radiosensitization has gained significant attention in recent years. However, the widely used passive targeting strategy requires high concentration of GNPs to induce the desired therapeutic effect, thus dampening the enthusiasm for clinical translation. The purpose of this study is to utilize a molecular targeting strategy to minimize the concentration of GNPs injected while simultaneously enhancing the tumor specific radiosensitization for an improved therapeutic outcome. Methods: Cetuximab (antibody specific to the epidermal growth factor receptor that is over-expressed in tumors) conjugated gold nanorods (cGNRs) was used for the tumor targeting. The binding affinity, internalization, and in vitro radiosensitization were evaluated using dark field microscopy, transmission electron microscopy, and clonogenic cell survival assay, respectively. In vivo biodistribution in tumor (HCT116-colorectal cancer cells) bearing mice were quantified using inductively coupled plasma mass spectrometry. In vivo radiosensitization potential was tested using 250-kVp x-rays and clinically relevant 6-MV radiation beams. Results: cGNRs displayed excellent cell-surface binding and internalization (∼31,000 vs 12,000/cell) when compared to unconjugated GNRs (pGNRs). In vitro, the dose enhancement factor at 10% survival (DEF10) was estimated as 1.06 and 1.17, respectively for both 250-kVp and 6-MV beams. In vivo biodistribution analysis revealed enhanced uptake of cGNRs in tumor (1.3 µg/g of tumor tissue), which is ∼1000-fold less than the reported values using passive targeting strategy. Nonetheless, significant radiosensitization was observed in vivo with cGNRs when compared to pGNRs, when irradiated with 250-kVp (tumor volume doubling time 35 days vs 25 days; p=0.002) and 6 MV (17 days vs 13 days; p=0.0052) beams. Conclusion: The enhanced radiosensitization effect observed with very low intratumoral concentrations of gold and megavoltage x

Profound radiosensitivity in leukemic T-cell lines and T-cell-type acute lymphoblastic leukemia demonstrated by sodium [51Cr]chromate labeling

International Nuclear Information System (INIS)

Nakazawa, S.; Minowada, J.; Tsubota, T.; Sinks, L.F.

1978-01-01

Radiation sensitivity was determined by measuring spontaneous release from 51 Cr-labeled cells in various lymphoid cell populations. Among six leukemia T-cell lines originating from acute lymphoblastic leukemia, four such lines were found to be highly radiosensitive. In contrast, two of the leukemic T-cell lines and four normal control B-cell lines were not radiosensitive. Thymocytes from six patients and leukemia T-cell blasts from three patients with T-cell leukemia were likewise found to be highly radiosensitive, whereas leukemic blasts from six patients with null-cell (non-T, non-B-cell) acute lymphoblastic leukemia were not radiosensitive. Normal peripheral blood lymphocytes and mitogen-induced normal lymphoblasts were found not to be radiosensitive. The results indicate that measurement of the radiation sensitivity of acute leukemic blasts may have a therapeutic significance in coping with the heterogeneous nature of individual leukemia cases

MicroRNA-449a enhances radiosensitivity in CL1-0 lung adenocarcinoma cells.

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Yi-Jyun Liu

Full Text Available Lung cancer is the leading cause of cancer-related mortality worldwide. Radiotherapy is often applied for treating lung cancer, but it often fails because of the relative non-susceptibility of lung cancer cells to radiation. MicroRNAs (miRNAs have been reported to modulate the radiosensitivity of lung cancer cells and have the potential to improve the efficacy of radiotherapy. The purpose of this study was to identify a miRNA that can adjust radiosensitivity in lung adenocarcinoma cells. Two lung adenocarcinoma cell lines (CL1-0 and CL1-5 with different metastatic ability and radiosensitivity were used. In order to understand the regulatory mechanisms of differential radiosensitivity in these isogenic tumor cells, both CL1-0 and CL1-5 were treated with 10 Gy radiation, and were harvested respectively at 0, 1, 4, and 24 h after radiation exposure. The changes in expression of miRNA upon irradiation were examined using Illumina Human microRNA BeadChips. Twenty-six miRNAs were identified as having differential expression post-irradiation in CL1-0 or CL1-5 cells. Among these miRNAs, miR-449a, which was down-regulated in CL1-0 cells at 24 h after irradiation, was chosen for further investigation. Overexpression of miR-449a in CL1-0 cells effectively increased irradiation-induced DNA damage and apoptosis, altered the cell cycle distribution and eventually led to sensitization of CL1-0 to irradiation.

Enhanced apoptosis and radiosensitization by combined 13-CIS-retinoic acid and interferon-α2a; role of RAR-β gene

International Nuclear Information System (INIS)

Ryu, Samuel; Stein, Joseph P.; Chung, Chung T.; Lee, Yong J.; Kim, Jae Ho

2001-01-01

Purpose: Combined use of 13-cis-retinoic acid (cRA) and interferon-α2a (IFNα) induced significant radiosensitization in human cervical cancer ME-180 cell line, whereas it failed to achieve similar radiation enhancement in HeLa cells. The differential radiosensitization could be from the difference of retinoic acid receptor (RAR) expression because RAR-β was highly expressed in ME-180 cells in contrast to the HeLa cells where RAR-β was not detectable. We examined the role of this gene in mediating radiosensitization by cRA and IFNα, and explored the mechanism of radiation-induced cell killing. Methods and Materials: Human cervical cancer cell lines, ME-180 and HeLa, were treated with cRA and IFNα followed by radiation. Apoptosis and radiosensitization were quantitated by TUNEL assay (in situ DNA nick end labeling) and colony-forming ability of surviving cells. The cells were transfected with bcl-2 gene and RAR-β gene to test the role of these genes in mediating radiosensitization and apoptosis. Results: Synergistic radiosensitization and apoptosis was observed by combined use of cRA and IFNα with radiation in ME-180 cells which express high level of RAR-β mRNA, whereas these were not seen in HeLa cells where RAR-β mRNA is not detectable. Both radiosensitization and apoptosis were abolished by bcl-2 gene in ME-180 cells. RAR-β gene transfection induced similar radiation enhancement and apoptosis in HeLa cells. Conclusion: Apoptosis and radiation response were enhanced in the cells with high level of RAR-β mRNA expression. The RAR-β gene appears to mediate the radiation-induced apoptosis by cRA and IFNα. These findings indicate that presence of RAR-β in the cancer cells could be exploited for patient selection in using these drugs for apoptosis and radiosensitization

Strain differences in the radiosensitivity of mouse spermatogonia

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Bianchi, M; Hurtado de Catalfo, G; Hendry, J H

1985-01-01

The radiosensitivity of spermatogonia was found to be greater by up to a factor of 2 in C3H mice than in B6D2F1 mice, whether assessed for the highly sensitive spermatogonia (types A2 to In) or the much more resistant clonogenic spermatogonia which repopulate tubules. The latter were similarly resistant in the B6D2F1 hybrid and in the DBA2 parent, but were much more sensitive in the C57BL parent strain. A difference in sensitivity by up to a factor of 2 results in a variation by a factor of 10 or more in the level of survival of clonogenic cells after high doses. This variation is also observed when comparing data in the literature from different authors using various strains of mice. Using the radiosensitizer misonidazole, it was shown that hypoxia did not play a major role in the lesser sensitivity demonstrated in B6D2F1 mice. The variation in sensitivity is similar to the range reported in the literature for reciprocal translocations.

Clinical experience with intravenous radiosensitizers in unresectable sarcomas

International Nuclear Information System (INIS)

Kinsella, T.J.; Glatstein, E.

1987-01-01

Traditionally, adult bone and soft tissue sarcomas have been considered to be ''radioresistant.'' Because of this philosophy, patients who present with locally advanced, unresectable sarcomas often are treated in a palliative fashion, usually with low-dose radiotherapy. Over the last 6 years, 29 patients with unresectable primary or metastatic sarcomas were treated using a combination of intravenous chemical radiosensitizers and high-dose irradiation. Twenty-two of 29 patients achieved clinical local control, with six patients having a complete clinical response. The time to tumor response is often several months or longer, which is in contrast to other tumor histologies (carcinomas, lymphomas), where tumor response usually occurs over several weeks. Several large tumors have shown only a minimal tumor response, yet were found to be sterilized in posttreatment biopsy or autopsy examination. Of 15 patients with primary sarcomas without metastases, 11 patients (73%) remain free of local tumor progression from 12 to 83 months. Adult high-grade sarcomas can be controlled with high-dose radiotherapy and intravenous radiosensitizers, although the precise role of these agents is unclear

Effect of 17-AAG on radio-sensitivity of HeLa and V79 cells

International Nuclear Information System (INIS)

Pan Yanling; Hong Chengjiao; Zhang Baoguo

2010-01-01

In order to investigate the radio-sensitizing effect of 17-AAG, an inhibitor of Heat Shock Protein 90, on human Uterine Cervix Cancer HeLa and V79 cells, Clonogenic assay was used to observe the cell survival rate. The results show that 17-AAG can decrease obviously (p 0.05). This indicates that 17-AAG may enhance the radio-sensitivity of the HeLa cell line and has no effect on the V79 cell line. (authors)

Modification of γ-irradiation damaging effect on the seeds of radiosensitive and radioresistant plants

International Nuclear Information System (INIS)

Kaplan, I.S.; Tikhomirov, F.A.; Khvostova, V.V.; AN SSSR, Novosibirsk. Inst. Tsitologii i Genetiki)

1975-01-01

Low and high temperature treatment of seeds during irradiation has shown to result in a decrease of the general deleterious effect of radiation in both relatively radiosensitive (bean) and radioresistant (flax, mustard) species. The protective effect of the treatment is supposed to be due to its influence on short-half-life radicals and this is supportted by experiments with storage of irradiated seeds. The treatment allows to obtain high mutation frequencies in both radiosensitive and radioresistant plants

Mean-field analysis of orientation selectivity in inhibition-dominated networks of spiking neurons.

Science.gov (United States)

Sadeh, Sadra; Cardanobile, Stefano; Rotter, Stefan

2014-01-01

Mechanisms underlying the emergence of orientation selectivity in the primary visual cortex are highly debated. Here we study the contribution of inhibition-dominated random recurrent networks to orientation selectivity, and more generally to sensory processing. By simulating and analyzing large-scale networks of spiking neurons, we investigate tuning amplification and contrast invariance of orientation selectivity in these networks. In particular, we show how selective attenuation of the common mode and amplification of the modulation component take place in these networks. Selective attenuation of the baseline, which is governed by the exceptional eigenvalue of the connectivity matrix, removes the unspecific, redundant signal component and ensures the invariance of selectivity across different contrasts. Selective amplification of modulation, which is governed by the operating regime of the network and depends on the strength of coupling, amplifies the informative signal component and thus increases the signal-to-noise ratio. Here, we perform a mean-field analysis which accounts for this process.

Curcumin and trans-resveratrol exert cell cycle-dependent radioprotective or radiosensitizing effects as elucidated by the PCC and G2-assay

Energy Technology Data Exchange (ETDEWEB)

Sebastià, N., E-mail: natividad.sebastia@uv.es [Radiation Protection Service, IIS La Fe, Health Research Institute La Fe, Valencia (Spain); Montoro, A. [Radiation Protection Service, Universitary and Politechnic Hospital La Fe, Valencia (Spain); Grupo de Investigación Biomédica en Imagen GIBI230, IIS La Fe, Health Research Institute La Fe, Valencia (Spain); Unidad Mixta de Investigación en Endocrinología, Nutrición y Dietética Clínica, IIS La Fe, Health Research Institute La Fe, Valencia (Spain); Hervás, D. [Biostatistics Unit, IIS La Fe, Health Research Institute La Fe, Valencia (Spain); Pantelias, G.; Hatzi, V.I. [Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety, National Centre for Scientific Research “Demokritos”, Aghia Paraskevi, Athens (Greece); Soriano, J.M. [Grupo de Investigación Biomédica en Imagen GIBI230, IIS La Fe, Health Research Institute La Fe, Valencia (Spain); Unidad Mixta de Investigación en Endocrinología, Nutrición y Dietética Clínica, IIS La Fe, Health Research Institute La Fe, Valencia (Spain); Department of Preventive Medicine and Public Health, Faculty of Pharmacy, University of Valencia, Burjassot, Valencia (Spain); Villaescusa, J.I. [Radiation Protection Service, Universitary and Politechnic Hospital La Fe, Valencia (Spain); and others

2014-08-15

Highlights: • Curcumin and trans-resveratrol can exert radioprotective or radiosensitizing effects. • The mechanisms underlying such dual action were elucidated using the PCC and G2-assay. • Radioprotection occurs in non-cycling cells exposed to curcumin and resveratrol. • Radiosensitization occurs in cycling cells exposed to the chemicals. • G2-checkpoint abrogation by the chemicals underlies the radiosensitizing mechanism. - Abstract: Curcumin and trans-resveratrol are well-known antioxidant polyphenols with radiomodulatory properties, radioprotecting non-cancerous cells while radiosensitizing tumor cells. This dual action may be the result of their radical scavenging properties and their effects on cell-cycle checkpoints that are activated in response to radiation-induced chromosomal damage. It could be also caused by their effect on regulatory pathways with impact on detoxification enzymes, the up-regulation of endogenous protective systems, and cell-cycle-dependent processes of DNA damage. This work aims to elucidate the mechanisms underlying the dual action of these polyphenols and investigates under which conditions they exhibit radioprotecting or radiosensitizing properties. The peripheral blood lymphocyte test system was used, applying concentrations ranging from 1.4 to 140 μM curcumin and 2.2 to 220 μM trans-resveratrol. The experimental design focuses first on their radioprotective effects in non-cycling lymphocytes, as uniquely visualized using cell fusion-mediated premature chromosome condensation, excluding, thus, cell-cycle interference to repair processes and activation of checkpoints. Second, the radiosensitizing potential of these chemicals on the induction of chromatid breaks in cultured lymphocytes following G2-phase irradiation was evaluated by a standardized G2-chromosomal radiosensitivity predictive assay. This assay uses caffeine for G2-checkpoint abrogation and it was applied to obtain an internal control for radiosensitivity

Curcumin and trans-resveratrol exert cell cycle-dependent radioprotective or radiosensitizing effects as elucidated by the PCC and G2-assay

International Nuclear Information System (INIS)

Sebastià, N.; Montoro, A.; Hervás, D.; Pantelias, G.; Hatzi, V.I.; Soriano, J.M.; Villaescusa, J.I.

2014-01-01

Highlights: • Curcumin and trans-resveratrol can exert radioprotective or radiosensitizing effects. • The mechanisms underlying such dual action were elucidated using the PCC and G2-assay. • Radioprotection occurs in non-cycling cells exposed to curcumin and resveratrol. • Radiosensitization occurs in cycling cells exposed to the chemicals. • G2-checkpoint abrogation by the chemicals underlies the radiosensitizing mechanism. - Abstract: Curcumin and trans-resveratrol are well-known antioxidant polyphenols with radiomodulatory properties, radioprotecting non-cancerous cells while radiosensitizing tumor cells. This dual action may be the result of their radical scavenging properties and their effects on cell-cycle checkpoints that are activated in response to radiation-induced chromosomal damage. It could be also caused by their effect on regulatory pathways with impact on detoxification enzymes, the up-regulation of endogenous protective systems, and cell-cycle-dependent processes of DNA damage. This work aims to elucidate the mechanisms underlying the dual action of these polyphenols and investigates under which conditions they exhibit radioprotecting or radiosensitizing properties. The peripheral blood lymphocyte test system was used, applying concentrations ranging from 1.4 to 140 μM curcumin and 2.2 to 220 μM trans-resveratrol. The experimental design focuses first on their radioprotective effects in non-cycling lymphocytes, as uniquely visualized using cell fusion-mediated premature chromosome condensation, excluding, thus, cell-cycle interference to repair processes and activation of checkpoints. Second, the radiosensitizing potential of these chemicals on the induction of chromatid breaks in cultured lymphocytes following G2-phase irradiation was evaluated by a standardized G2-chromosomal radiosensitivity predictive assay. This assay uses caffeine for G2-checkpoint abrogation and it was applied to obtain an internal control for radiosensitivity

HAP1 gene expression is associated with radiosensitivity in breast cancer cells

International Nuclear Information System (INIS)

Wu, Jing; Zhang, Jun-ying; Yin, Li; Wu, Jian-zhong; Guo, Wen-jie; Wu, Jian-feng; Chen, Meng; Xia, You-you; Tang, Jin-hai; Ma, Yong-chao; He, Xia

2015-01-01

Highlights: • Overexpression of HAP1 gene promotes apoptosis in MCF-7 cells after irradiation. • HAP1 reduces tumor volume in nude mice xenograft models after irradiation. • HAP1 increases radiosensitivity of breast cancer cells in vitro and vivo. - Abstract: Objectives: The purpose of this study was to investigate the relationship between huntingtin-associated protein1 (HAP1) gene and radiation therapy of breast cancer cells. Methods: HAP1 gene was transfected into breast cancer MCF-7 cells, which was confirmed by quantitative reverse transcription-polymerase chain reaction analysis (qRT-PCR) and Western blot in vitro. The changes of cell radiosensitivity were assessed by colony formation assay. Apoptosis were examined by flow cytometry. The expressions of two radiation-induced genes were evaluated by Western blot. Tumor growth was investigated in nude mice xenograft models in vivo. Results: Our data showed that HAP1 gene expression was significantly increased in HAP1-transfected MCF-7 cells in comparison with the parental cells or negative control cells. The survival rate in MCF-7/HAP1 cells was significantly decreased after irradiation (0, 2, 4, 6, 8 Gy), compared to cells in MCF-7 and MCF-7/Pb groups in vitro. HAP1 gene increased apoptosis in MCF-7 cells after irradiation. Additionally, the tumor volume and weight in MCF-7/HAP1 + RT group were observably lower than in MCF-7/HAP1 group and MCF-7/Pb + RT group. Conclusion: The present study indicated that HAP1 gene expression was related to the radiosensitivity of breast cancer cells and may play an important role in the regulation of cellular radiosensitivity

Procedures for increasing the radiosensitivity of malignant tumors with special regard to synchronized radiotherapy

Energy Technology Data Exchange (ETDEWEB)

Guenther, W

1975-01-01

Two principal ways to increase the radiosensitivity of malignant tumours are described: to begin with, both the use of highly ionizing corpuscular radiation - e.g. in neutron therapy - and the simultaneous application of photons and high-pressure oxygen heighten radiosensitivity by increasing the number of secondary hit events. The second principal direction - in which the radiation intervals are timed in dependence of lifetime and division rhythm of the tumour cells - is described and illustrated by results of 5-fluorouracil and /sup 60/Co irradiation of 71 patients. The results show a particularly good response of carcinomas of the ENT region and the breast. Questions of the radiosensitive stage, the time of infusion, the influence of the generation cycle and the influence of oxygen-starved cells on the results are major points for future studies on synchronized radiotherapy. Mathematical calculations are carried out concerning the time of infusion and the influence of the generation cycle. Some consequences are mentioned which had not been dealt with so far in synchronized radiotherapy: high single doses and short intervals between sessions for tumours with short generation and duplication times, and low doses and long intervals for small tumours with slow growth rates. There is no principal difference between oxygen-starved and oxygen-rich cells as far as the dependence of radiosensitivity on the generation cycle - i.e. the starting point of synchronized radiotherapy - is concerned.

Differential Radiosensitizing Effect of Valproic Acid in Differentiation Versus Self-Renewal Promoting Culture Conditions

International Nuclear Information System (INIS)

Debeb, Bisrat G.; Xu Wei; Mok, Henry; Li Li; Robertson, Fredika; Ueno, Naoto T.; Reuben, Jim; Lucci, Anthony; Cristofanilli, Massimo; Woodward, Wendy A.

2010-01-01

Purpose: It has been shown that valproic acid (VA) enhances the proliferation and self-renewal of normal hematopoietic stem cells and that breast cancer stem/progenitor cells can be resistant to radiation. From these data, we hypothesized that VA would fail to radiosensitize breast cancer stem/progenitor cells grown to three-dimensional (3D) mammospheres. Methods and Materials: We used the MCF7 breast cancer cell line grown under stem cell-promoting culture conditions (3D mammosphere) and standard nonstem cell monolayer culture conditions (two-dimensional) to examine the effect of pretreatment with VA on radiation sensitivity in clonogenic survival assays and on the expression of embryonic stem cell transcription factors. Results: 3D-cultured MCF-7 cells expressed higher levels of Oct4, Nanog, and Sox2. The 3D passage enriched self-renewal and increased radioresistance in the 3D mammosphere formation assays. VA radiosensitized adherent cells but radioprotected 3D cells in single-fraction clonogenic assays. Moreover, fractionated radiation sensitized VA-treated adherent MCF7 cells but did not have a significant effect on VA-treated single cells grown to mammospheres. Conclusion: We have concluded that VA might preferentially radiosensitize differentiated cells compared with those expressing stem cell surrogates and that stem cell-promoting culture is a useful tool for in vitro evaluation of novel cancer therapeutic agents and radiosensitizers.

Different radiosensitivities of mast-cell precursors in the bone marrow and skin of mice

International Nuclear Information System (INIS)

Kitamura, Y.; Yokoyama, M.; Sonoda, T.; Mori, K.J.

1983-01-01

Although tissue mast cells are derived from the bone marrow, some descendants of bone marrow-derived precursors retain the ability to proliferate and differentiate into mast cells even after localization in the skin. The purpose of the present study was to determine the D0 values for mast-cell precursors in the bone marrow and those localized in the skin. Bone marrow cells were removed from (WB X C57BL/6)F1-+/+ mice after various doses of irradiation and injected into the skin of the congenic W/Wv mice which were genetically without mast cells. Radiosensitivity of mast-cell precursors in the bone marrow was evaluated by determining the proportion of the injection sites at which mast cells did not appear. For the assay of the radiosensitivity of mast-cell precursors localized in the skin, pieces of skin were removed from beige C57BL/6 (bgJ/bgJ. Chediak-Higashi syndrome) mice after various doses of irradiation and grafted onto the back of the normal C57BL/6 mice. Radiosensitivity of mast-cell precursors in the skin was evaluated by determining the decrease of beige-type mast cells which possessed giant granules. Mast-cell precursors in the bone marrow were much more radiosensitive than those localized in the skin. D0 value was about 100 rad for the former and about 800 rad for the latter

Differences in heat-induced cell killing as determined in three mammalian cell lines do not correspond with the extent of heat radiosensitization

International Nuclear Information System (INIS)

Kampinga, H.H.; Jorritsma, J.B.M.; Burgman, P.; Konings, A.W.T.

1986-01-01

Three different cell lines, Ehrlich ascites tumour (EAT) cells, HeLa S 3 cells and LM mouse fibroblasts, were used to investigate whether or not the extent of heat killing (44 0 C) and heat radio-sensitization (44 0 C before 0-6 Gy X-irradiation) are related. Although HeLa cells were the most heat-resistant cell line and showed the least heat radiosensitization, we found that the most heat-sensitive EAT cells (D 0 , EAT = 8.0 min; D 0 , LM = 10.0 min; D 0 , HeLa = 12.5 min) showed less radiosensitization than the more heat-resistant LM fibroblasts (TERsub(HeLa)< TERsub(EAT)< TERsub(LM)). Therefore, it is concluded that the routes leading to heat-induced cell death are not identical to those determining heat radiosensitization. Furthermore the inactivation of DNA polymerase α and β activities by heat seemed not to correlate with heat survival alone but showed a positive relationship to heat radiosensitization. The possibility of these enzymes being a determinant in heat radiosensitization is discussed. (author)

Radiosensitivity of str.fecalis in presence of some substances being contained in meat cans

International Nuclear Information System (INIS)

Stojchev, M.; Brankova, G.; Dzhezheva, G.

1974-01-01

This study was designed to assess the effects of some organic and inorganic substances present in canned meats on the radiosensitivity of Streptococcus faecalis exposed to different doses of gamma rays. It was found that the death rate of irradiated S.faecalis depends on the radiation dose, the time elapsed after irradiation, and the medium in which the cells are suspended. Adding lactic and ascorbic acids and glucose to the model solution decreased the radiosensitivity and increased the post-irradiation effects. (E.T.)

Early childhood behavioral inhibition, adult psychopathology and the buffering effects of adolescent social networks: a twenty-year prospective study.

Science.gov (United States)

Frenkel, Tahl I; Fox, Nathan A; Pine, Daniel S; Walker, Olga L; Degnan, Kathryn A; Chronis-Tuscano, Andrea

2015-10-01

We examined whether the temperament of behavioral inhibition is a significant marker for psychopathology in early adulthood and whether such risk is buffered by peer social networks. Participants (N = 165) were from a prospective study spanning the first two decades of life. Temperament was characterized during infancy and early childhood. Extent of involvement in peer social networks was measured during adolescence, and psychopathology was assessed in early adulthood. Latent Class Analyses generated comprehensive variables at each of three study time-points. Regressions assessed (a) the direct effect of early behavioral inhibition on adult psychopathology (b) the moderating effect of adolescent involvement in social peer networks on the link between temperamental risk and adult psychopathology. Stable behavioral inhibition in early childhood was negatively associated with adult mental health (R(2 ) = .07, p = .005, β = -.26), specifically increasing risk for adult anxiety disorders (R(2) = .04, p = .037, β = .19). These temperament-pathology relations were significantly moderated by adolescent peer group social involvement and network size (Total R(2) = .13, p = .027, β = -.22). Temperament predicted heightened risk for adult anxiety when adolescent social involvement was low (p = .002, β = .43), but not when adolescent social involvement was high. Stable behavioral inhibition throughout early childhood is a risk factor for adult anxiety disorders and interacts with adolescent social involvement to moderate risk. This is the first study to demonstrate the critical role of adolescent involvement in socially active networks in moderating long-lasting temperamental risk over the course of two decades, thus informing prevention/intervention approaches. © 2015 Association for Child and Adolescent Mental Health.

Radiosensitivity of mice and its modifiers based on the endogeneous spleen colony formation

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Kobayashi, Jindo; Wagatuma, Kaoru

1987-02-01

In irradiated mouse hematopoietic tissue, there is a group of cells which can proliferate and form macroscopic colonies. In the spleen, the colonies formed in this manner are discrete and easy to count. In order to look into a difference of radiosensitivity between male and female and the mechanisms of the modification, such as protective agent and hormones on radiosensitivity, the spleen colony forming (SCF) is used as an indicator of reactions in the x-rays irradiated mice. A linear decrease was found in SCF depended on x-rays dose. From the colony forming after irradiation the male was more radiosensitive than female. AET protected from the injury depended on the radiation dose in male mice, but in female mice, protection effects were not observed. Gonatropin showed protective effects for radiation injury on high dose irradiation both in male and female mice. Adrenaline showed similar effects as Gonatropin. Insuline showed a negative effects of protection on 400 R irradiation, while on 600 R irradiation, protective effects were observed.

BMI-1 suppression increases the radiosensitivity of oesophageal carcinoma via the PI3K/Akt signaling pathway.

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Yang, Xing-Xiao; Ma, Ming; Sang, Mei-Xiang; Zhang, Xue-Yuan; Liu, Zhi-Kun; Song, Heng; Zhu, Shu-Chai

2018-02-01

BMI-1 knockdown, while the kinase agonist IGF-1 reversed the effects of BMI-1 knockdown on cell viability and radiosensitivity. Taken together, BMI-1 knockdown induces radiosensitivity in ESCC and significantly inhibits cell viability, which may contribute to an increased proportion of cells in the G0/G1 phase and cell apoptosis via suppression of the PI3K/Akt signalling pathway.

Radiosensitivity related to neuroendocrine and endodermal differentation in lung carcinoma lines

International Nuclear Information System (INIS)

Duchesne, G.; Casoni, A.; Pera, M.

1988-01-01

A panel of human lung carcinoma lines was studied with respect to hormone production and intermediate filament expression to distinguish between endodermal and neuroendocrine differentation. An index of the degree of neuroendocrine differentiation of each line was derived from the presence or absence of hormone production, cytokeratins, neurofilaments and an embryonic endodermal cell marker, which allowed identification of three groups showing high, intermediate or low neuroendocrine expression. This grouping correlated well with the in vitro radiosensitivity of the lines, those expressing pure neuroendocrine features being significantly more radiosensitive than those with an endodermal phenotype, with the intermediate group having intermediate sensitivity. Use of such an index might predict those patients likely to benefit from the use of radiotherapy in their management. 30 refs.; 3 figs.; 3 tabs

Evaluation of nitrobenzimidazoles as hypoxic cell radiosensitizers

International Nuclear Information System (INIS)

Wright, J.; Frank, L.R.; Bush, D.; Harrison, G.H.

1983-01-01

Radiobiological and pharmacokinetic assays were performed to determine the potential of 2-nitrobenzimidazole (NBI) as a hypoxic cell radiosensitizing agent. As judged by comparing survival curve slopes of Serratia marcescens irradiated under aerated and hypoxic conditions, the NBI enhancement ratio (ER) at 2 mM concentration was 2.4 +- 0.2, compared with an oxygen enhancement ratio of 3.3 +- 0.3. 2,5-Dinitrobenzimidazole (DNBI) was investigated in vitro; its ER was 3.0 +- 0.3 at 4 mM concentration. Very poor tissue penetration of DNBI precluded further testing in vivo. Acute toxic signs appeared in C3H/HeJ mice following ip injection of NBI at 100 mg/kg. These would be partly attributable to the stress caused by the high pH of the injection vehicle. The LD 50 was estimated to be 125 to 150 mg/kg. Mammary adenocarcinoma tumors grown in the flanks of these mice exhibited maximum NBI levels at 5 min postinjection (ip). Peak tumor radiosensitization occurred in the interval between 5 and 10 min postinjection. The ER for tumor regrowth delay was 2.1 +- 0.3 following 50 mg/kg injected into mice 5 min before irradiation. Functional evaluation up to 40 days after treatment revealed no evidence of neurological deficit

Evaluation of nitrobenzimidazoles as hypoxic cell radiosensitizers

International Nuclear Information System (INIS)

Wright, J.; Frank, L.R.; Bush, D.; Harrison, G.H.

1983-01-01

Radiobiological and pharmacokinetic assays were performed to determine the potential of 2-nitrobenzimidazole (NBI) as a hypoxic cell radiosensitizing agent. As judged by comparing survival curve slopes of Serratia marcescens irradiated under aerated and hypoxic conditions, the NBI enhancement ratio (ER) at 2 mM concentration was 2.4 +/- 0.2, compared with an oxygen enhancement ratio of 3.3 +/- 0.3. 2,5-Dinitrobenzimidazole (DNBI) was investigated in vitro; its ER was 3.0 +/- 0.3 at 4 mM concentration. Very poor tissue penetration of DNBI precluded further testing in vivo. Acute toxic signs appeared in C3H/HeJ mice following ip injection of NBI at 100 mg/kg. These would be partly attributable to the stress caused by the high pH of the injection vehicle. The LD50 was estimated to be 125-150 mg/kg. Mammary adenocarcinoma tumors grown in the flanks of these mice exhibited maximum NBI levels at 5 min postinjection (ip). Peak tumor radiosensitization occurred in the interval between 5 and 10 min postinjection. The ER for tumor regrowth delay was 2.1 +/- 0.3 following 50 mg/kg injected into mice 5 min before irradiation. Functional evaluation up to 40 days after treatment revealed no evidence of neurological deficit

Molecular mechanism of radiosensitization by nitro compounds

International Nuclear Information System (INIS)

Kagiya, T.; Wada, T.; Nishimoto, S.I.

1984-01-01

In this chapter a molecular mechanism of radiosensitization by electron-affinic nitro compounds is discussed, mainly on the basis of the results of the radiation-induced chemical studies of DNA-related compounds in aqueous solutions. In Section II the general aspects of the radiation chemistry of organic compounds in the absence and presence of oxygen in aqueous solution are shown in order to demonstrate characteristic differences between radiation chemical reactions in hypoxic and oxic cells. The effects of nitro compounds on the radiolysis yields of DNA-related compounds in aqueous solutions are described in Section III. In Section IV the retardation effects of misonidazole on the radiation chemical processes of DNA-related compounds are shown along with the reaction characteristics of misonidazole with hydroxyl radical ( . OH) and hydrated electron (e/sub aq/-bar) produced by the radiolysis of water. The promotion of radiation-induced oxidation of thymine into thymine glycol (TG) by nitro radiosensitizers in deoxygenated solution and the relations between the activity of nitro compound for the thymine glycol formation and the enhancement activity measured in vitro are described in Section V. Finally, the protection against radiation-induced damage of thymine by a sulfhydryl compound of glutathione and the ability of electron-affinic compounds to decompose the intracellular radioprotector are described in Section VI

Differential Radiosensitizing Potential of Temozolomide in MGMT Promoter Methylated Glioblastoma Multiforme Cell Lines

International Nuclear Information System (INIS)

Nifterik, Krista A. van; Berg, Jaap van den; Stalpers, Lukas J.A.; Lafleur, M. Vincent M.; Leenstra, Sieger; Slotman, Ben J.; Hulsebos, Theo J.M.; Sminia, Peter

2007-01-01

Purpose: To investigate the radiosensitizing potential of temozolomide (TMZ) for human glioblastoma multiforme (GBM) cell lines using single-dose and fractionated γ-irradiation. Methods and Materials: Three genetically characterized human GBM cell lines (AMC-3046, VU-109, and VU-122) were exposed to various single (0-6 Gy) and daily fractionated doses (2 Gy per fraction) of γ-irradiation. Repeated TMZ doses were given before and concurrent with irradiation treatment. Immediately plated clonogenic cell-survival curves were determined for both the single-dose and the fractionated irradiation experiments. To establish the net effect of clonogenic cell survival and cell proliferation, growth curves were determined, expressed as the number of surviving cells. Results: All three cell lines showed MGMT promoter methylation, lacked MGMT protein expression, and were sensitive to TMZ. The isotoxic TMZ concentrations used were in a clinically feasible range of 10 μmol/L (AMC-3046), 3 μmol/L (VU-109), and 2.5 μmol/L (VU-122). Temozolomide was able to radiosensitize two cell lines (AMC 3046 and VU-122) using single-dose irradiation. A reduction in the number of surviving cells after treatment with the combination of TMZ and fractionated irradiation was seen in all three cell lines, but only AMC 3046 showed a radiosensitizing effect. Conclusions: This study on TMZ-sensitive GBM cell lines shows that TMZ can act as a radiosensitizer and is at least additive to γ-irradiation. Enhancement of the radiation response by TMZ seems to be independent of the epigenetically silenced MGMT gene

Alterations in growth phenotype and radiosensitivity after fractionated irradiation of breast carcinoma cells from a single patient

International Nuclear Information System (INIS)

Wazer, D.E.; Joyce, M.; Jung, L.; Band, V.

1993-01-01

The purpose was to investigate growth regulation and radiosensitivity in surviving clonogens after fractionated irradiation. Four breast carcinoma cell lines isolated from the primary tumor (21NT, 21PT) and metastases (21MT-1, 21MT-2) of a single patient were exposed to cumulative radiation doses of 30 Gy yielding cell lines designated -IR with respect to their parent. The irradiated lines were then compared to their parent for serum- and growth factor-requirements under defined media conditions, ability to proliferate in soft agar, concentration of TGF-alpha in conditioned medium, and radiosensitivity. The irradiated lines showed no change in proliferative doubling times under serum- and growth factor-supplemented media conditions. A single line, 21MT-1-IR, acquired a limited ability to proliferate in serum- and growth factor-deplete medium with a day 2-4 doubling time of 44.5 hr. Three lines, 21MT-1-IR, 21MT-2-IR, and 21NT-IR, formed colonies in soft agar in contrast to none of the unirradiated parent lines. There were significant 6-8 fold increases in conditioned media TGF-alpha concentrations for 21MT-2-IR and 21NT-IR cells. The 21MT-1-IR and 21NT-IR cells were significantly less radiosensitive than their respective parent lines. This decrease in radiosensitivity appeared to be at least partially mediated by a released factor as the radiosensitivity of 21MT-1 cells was significantly decreased by pre-incubation with conditioned medium from 21MT-1-IR cells. Radiation-induced changes in growth phenotype vary with respect to clonal origin of the cell line and may influence the radiosensitivity of surviving clonogens after fractionated treatment. 18 refs., 4 figs., 3 tabs

Evaluation of different biomarkers to predict individual radiosensitivity in an inter-laboratory comparison--lessons for future studies.

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Burkhard Greve

Full Text Available Radiotherapy is a powerful cure for several types of solid tumours, but its application is often limited because of severe side effects in individual patients. With the aim to find biomarkers capable of predicting normal tissue side reactions we analysed the radiation responses of cells from individual head and neck tumour and breast cancer patients of different clinical radiosensitivity in a multicentric study. Multiple parameters of cellular radiosensitivity were analysed in coded samples of peripheral blood lymphocytes (PBLs and derived lymphoblastoid cell lines (LCLs from 15 clinical radio-hypersensitive tumour patients and compared to age- and sex-matched non-radiosensitive patient controls and 15 lymphoblastoid cell lines from age- and sex- matched healthy controls of the KORA study. Experimental parameters included ionizing radiation (IR-induced cell death (AnnexinV, induction and repair of DNA strand breaks (Comet assay, induction of yH2AX foci (as a result of DNA double strand breaks, and whole genome expression analyses. Considerable inter-individual differences in IR-induced DNA strand breaks and their repair and/or cell death could be detected in primary and immortalised cells with the applied assays. The group of clinically radiosensitive patients was not unequivocally distinguishable from normal responding patients nor were individual overreacting patients in the test system unambiguously identified by two different laboratories. Thus, the in vitro test systems investigated here seem not to be appropriate for a general prediction of clinical reactions during or after radiotherapy due to the experimental variability compared to the small effect of radiation sensitivity. Genome-wide expression analysis however revealed a set of 67 marker genes which were differentially induced 6 h after in vitro-irradiation in lymphocytes from radio-hypersensitive and non-radiosensitive patients. These results warrant future validation in larger

Radiosensitivity of fibroblasts obtained from a cafe-au-lait spot and normal-appearing skin of a patient with neurofibromatosis (NF-6)

International Nuclear Information System (INIS)

Hannan, M.A.; Smith, B.P.; Sigut, D.; Sackey, K.

1990-01-01

Fibroblast cells derived from a cafe-au-lait spot and normal-appearing skin of a neurofibromatosis (NF-6) patient were studied for radiosensitivity in comparison with two normal cell lines used as controls. No difference in radiosensitivity was observed between the patient's cell lines and the controls using acute gamma-irradiation. However, a markedly increased radiosensitivity of the fibroblasts obtained from the patient's skin of normal appearance was demonstrated after chronic gamma-irradiation. The cells from the cafe-au-lait spot showed intermediate sensitivity to chronic irradiation as compared with the control cell lines and the fibroblasts derived from the normal skin of the patient. These results showed the usefulness of chronic irradiation in detecting increased cellular radiosensitivity which may result from a unique DNA repair defect in an NF patient. We suggest that enhanced genetic changes in radiosensitive NF patients may lead to formation of cafe-au-lait lesions and certain tumors. Such a transformation may be associated with production of radiotolerant cells

DNA-AuNP networks on cell membranes as a protective barrier to inhibit viral attachment, entry and budding.

Science.gov (United States)

Li, Chun Mei; Zheng, Lin Ling; Yang, Xiao Xi; Wan, Xiao Yan; Wu, Wen Bi; Zhen, Shu Jun; Li, Yuan Fang; Luo, Ling Fei; Huang, Cheng Zhi

2016-01-01

Viral infections have caused numerous diseases and deaths worldwide. Due to the emergence of new viruses and frequent virus variation, conventional antiviral strategies that directly target viral or cellular proteins are limited because of the specificity, drug resistance and rapid clearance from the human body. Therefore, developing safe and potent antiviral agents with activity against viral infection at multiple points in the viral life cycle remains a major challenge. In this report, we propose a new modality to inhibit viral infection by fabricating DNA conjugated gold nanoparticle (DNA-AuNP) networks on cell membranes as a protective barrier. The DNA-AuNPs networks were found, via a plaque formation assay and viral titers, to have potent antiviral ability and protect host cells from human respiratory syncytial virus (RSV). Confocal immunofluorescence image analysis showed 80 ± 3.8% of viral attachment, 91.1 ± 0.9% of viral entry and 87.9 ± 2.8% of viral budding were inhibited by the DNA-AuNP networks, which were further confirmed by real-time fluorescence imaging of the RSV infection process. The antiviral activity of the networks may be attributed to steric effects, the disruption of membrane glycoproteins and limited fusion of cell membrane bilayers, all of which play important roles in viral infection. Therefore, our results suggest that the DNA-AuNP networks have not only prophylactic effects to inhibit virus attachment and entry, but also therapeutic effects to inhibit viral budding and cell-to-cell spread. More importantly, this proof-of-principle study provides a pathway for the development of a universal, broad-spectrum antiviral therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Radiosensitivity of red flour beetle tribolium castaneum

International Nuclear Information System (INIS)

Sattar, A.; Khattak, S.; Hamed, M.

1992-07-01

In this report radiosensitivity of red beetle has been discussed. Red flour beetle is the most injurious pest causing great losses to stored grain. Radiation is one of the best tools of insect control. Different radiation doses (50 to 200 krads) were employed for different age groups from 1 to 60 days. It is concluded from these results that 200 krad radiation dose caused 100% mortality in red beetle in all age group. (A.B.)

Radiosensitization, mutagenicity, and toxicity of Escherichia coli by several nitrofurans and nitroimidazoles. [X radiation

Energy Technology Data Exchange (ETDEWEB)

Chessin, H.; McLaughlin, T.; Mroczkowski, Z.; Rupp, W.D.; Low, K.B.

1978-08-01

Representative nitrofurans (nitrofurantoin, nifuroxime, NF-167, NF-269) and nitroimidazoles (metronidazole, misonidazole) were found to sensitize hypoxic RecA/sup -/ Escherichia coli cells to X irradiation. These compounds were also mutagenic to E. coli using a UvrA/sup -/ strain as a test system, and toxic at high concentrations, using several strains differing in their repair capacity. However, the relative degrees of radiosensitization, mutagenicity, and toxicity, for the various compounds, were not simply correlated, suggesting that potential radiosensitizers with fewer side effects could be screened using bacteria.

Uroporphyrinogen decarboxylase is a radiosensitizing target for head and neck cancer.

Science.gov (United States)

Ito, Emma; Yue, Shijun; Moriyama, Eduardo H; Hui, Angela B; Kim, Inki; Shi, Wei; Alajez, Nehad M; Bhogal, Nirmal; Li, Guohua; Datti, Alessandro; Schimmer, Aaron D; Wilson, Brian C; Liu, Peter P; Durocher, Daniel; Neel, Benjamin G; O'Sullivan, Brian; Cummings, Bernard; Bristow, Rob; Wrana, Jeff; Liu, Fei-Fei

2011-01-26

Head and neck cancer (HNC) is the eighth most common malignancy worldwide, comprising a diverse group of cancers affecting the head and neck region. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, thereby underscoring a need to develop novel therapeutic approaches in HNC treatment. Uroporphyrinogen decarboxylase (UROD), a key regulator of heme biosynthesis, was identified from an RNA interference-based high-throughput screen as a tumor-selective radiosensitizing target for HNC. UROD knockdown plus radiation induced caspase-mediated apoptosis and cell cycle arrest in HNC cells in vitro and suppressed the in vivo tumor-forming capacity of HNC cells, as well as delayed the growth of established tumor xenografts in mice. This radiosensitization appeared to be mediated by alterations in iron homeostasis and increased production of reactive oxygen species, resulting in enhanced tumor oxidative stress. Moreover, UROD was significantly overexpressed in HNC patient biopsies. Lower preradiation UROD mRNA expression correlated with improved disease-free survival, suggesting that UROD could potentially be used to predict radiation response. UROD down-regulation also radiosensitized several different models of human cancer, as well as sensitized tumors to chemotherapeutic agents, including 5-fluorouracil, cisplatin, and paclitaxel. Thus, our study has revealed UROD as a potent tumor-selective sensitizer for both radiation and chemotherapy, with potential relevance to many human malignancies.

Comparison of microwave and magnetic nanoparticle hyperthermia radiosensitization in murine breast tumors

Science.gov (United States)

Giustini, Andrew J.; Petryk, Alicia A.; Hoopes, Paul J.

2011-03-01

Hyperthermia has been shown to be an effective radiosensitizer. Its utility as a clinical modality has been limited by a minimally selective tumor sensitivity and the inability to be delivered in a tumor-specific manner. Recent in vivo studies (rodent and human) have shown that cancer cell-specific cytotoxicity can be effectively and safely delivered via iron oxide magnetic nanoparticles (mNP) and an appropriately matched noninvasive alternating magnetic field (AMF). To explore the tumor radiosensitization potential of mNP hyperthermia we used a syngeneic mouse breast cancer model, dextran-coated 110 nm hydrodynamic diameter mNP and a 169 kHz / 450 Oe (35.8 kA/m) AMF. Intradermally implanted (flank) tumors (150 +/- 40 mm3) were treated by injection of 0.04 ml mNP (7.5 mg Fe) / cm3 into the tumor and an AMF (35.8 kA/m and 169 kHz) exposure necessary to achieve a CEM (cumulative equivalent minute) thermal dose of 60 (CEM 60). Tumors were treated with mNP hyperthermia (CEM 60), radiation alone (15 Gy, single dose) and in combination. Compared to the radiation and heat alone treatments, the combined treatment resulted in a greater than two-fold increase in tumor regrowth tripling time (tumor treatment efficacy). None of the treatments resulted in significant normal tissue toxicity or morbidity. Studies were also conducted to compare the radiosensitization effect of mNP hyperthermia with that of microwave-induced hyperthermia. The effects of incubation of nanoparticles within tumors (to allow nanoparticles to be endocytosed) before application of AMF and radiation were determined. This preliminary information suggests cancer cell specific hyperthermia (i.e. antibody-directed or anatomically-directed mNP) is capable of providing significantly greater radiosensitization / therapeutic ratio enhancement than other forms of hyperthermia delivery.

Radiosensitizing Effects of Ectopic miR-101 on Non–Small-Cell Lung Cancer Cells Depend on the Endogenous miR-101 Level

International Nuclear Information System (INIS)

Chen, Susie; Wang Hongyan; Ng, Wooi Loon; Curran, Walter J.; Wang Ya

2011-01-01

Purpose: Previously, we showed that ectopic miR-101 could sensitize human tumor cells to radiation by targeting ATM and DNA-PK catalytic subunit (DNA-PKcs) to inhibit DNA repair, as the endogenous miR-101 levels are low in tumors in general. However, the heterogeneity of human cancers may result in an exception. The purpose of this study was to test the hypothesis that a few tumor cell lines with a high level of endogenous miR-101 would prove less response to ectopic miR-101. Methods and Materials: Fourteeen non–small-cell lung cancer (NSCLC) cell lines and one immortalized non-malignant lung epithelial cell line (NL20) were used for comparing endogenous miR-101 levels by real-time reverse transcription–polymerase chain reaction. Based on the different miR-101 levels, four cell lines with different miR-101 levels were chosen for transfection with a green fluorescent protein–lentiviral plasmid encoding miR-101. The target protein levels were measured by using Western blotting. The radiosensitizing effects of ectopic miR-101 on these NSCLC cell lines were determined by a clonogenic assay and xenograft mouse model. Results: The endogenous miR-101 level was similar or lower in 13 NSCLC cell lines but was 11-fold higher in one cell line (H157) than in NL20 cells. Although ectopic miR-101 efficiently decreased the ATM and DNA-PKcs levels and increased the radiosensitization level in H1299, H1975, and A549 cells, it did not change the levels of the miR-101 targets or radiosensitivity in H157 cells. Similar results were observed in xenograft mice. Conclusions: A small number of NSCLC cell lines could have a high level of endogenous miR-101. The ectopic miR-101 was able to radiosensitize most NSCLC cells, except for the NSCLC cell lines that had a much higher endogenous miR-101 level. These results suggest that when we choose one miRNA as a therapeutic tool, the endogenous level of the miRNA in each tumor should be considered.

Radiosensitizing Effects of Ectopic miR-101 on Non-Small-Cell Lung Cancer Cells Depend on the Endogenous miR-101 Level

Energy Technology Data Exchange (ETDEWEB)

Chen, Susie; Wang Hongyan; Ng, Wooi Loon; Curran, Walter J. [Department of Radiation Oncology, School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, GA (United States); Wang Ya, E-mail: ywang94@emory.edu [Department of Radiation Oncology, School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, GA (United States)

2011-12-01

Purpose: Previously, we showed that ectopic miR-101 could sensitize human tumor cells to radiation by targeting ATM and DNA-PK catalytic subunit (DNA-PKcs) to inhibit DNA repair, as the endogenous miR-101 levels are low in tumors in general. However, the heterogeneity of human cancers may result in an exception. The purpose of this study was to test the hypothesis that a few tumor cell lines with a high level of endogenous miR-101 would prove less response to ectopic miR-101. Methods and Materials: Fourteeen non-small-cell lung cancer (NSCLC) cell lines and one immortalized non-malignant lung epithelial cell line (NL20) were used for comparing endogenous miR-101 levels by real-time reverse transcription-polymerase chain reaction. Based on the different miR-101 levels, four cell lines with different miR-101 levels were chosen for transfection with a green fluorescent protein-lentiviral plasmid encoding miR-101. The target protein levels were measured by using Western blotting. The radiosensitizing effects of ectopic miR-101 on these NSCLC cell lines were determined by a clonogenic assay and xenograft mouse model. Results: The endogenous miR-101 level was similar or lower in 13 NSCLC cell lines but was 11-fold higher in one cell line (H157) than in NL20 cells. Although ectopic miR-101 efficiently decreased the ATM and DNA-PKcs levels and increased the radiosensitization level in H1299, H1975, and A549 cells, it did not change the levels of the miR-101 targets or radiosensitivity in H157 cells. Similar results were observed in xenograft mice. Conclusions: A small number of NSCLC cell lines could have a high level of endogenous miR-101. The ectopic miR-101 was able to radiosensitize most NSCLC cells, except for the NSCLC cell lines that had a much higher endogenous miR-101 level. These results suggest that when we choose one miRNA as a therapeutic tool, the endogenous level of the miRNA in each tumor should be considered.

Radiosensitization by overexpression of the nonphosphorylation form of IκB-α in human glioma cells

International Nuclear Information System (INIS)

Honda, Naoko; Yagi, Kasumi; Ding, Gui-Rong; Miyakoshi, Junji

2002-01-01

To assess the role of NF-κB in cellular radiosensitivity, we constructed mutated IκB expression plasmids for SY-IκB (with mutations at residues of 32, 36 and 42) expression in human malignant glioma cells (radiosensitive MO54 and radioresistant T98 cells), giving respective cell types referred to as MO54-SY4 and T98-SY14. Both of the clones expressing SY-IκB became radiosensitive, compared with the parental MO54 and T98 cells. A treatment with herbimycin A or genistein did not change the radiosensitivity of cells expressing SY-IκB, but made both the MO54 and T98 parental cells more sensitive to ionizing radiation. A treatment with TNF-α induced DNA fragmentation and apoptosis in cells expressing SY-IκB, but not in MO54 and T98 cells. The survival after X-ray exposure of the parental MO54 cells was slightly increased by a TNF-α treatment, but that of the parental T98 cells did not change. The change in sensitivity to ultra-violet (UV) radiation and adriamycin in MO54-SY4 cells was very similar to that for X-ray sensitivity, but no change was observed in T98-SY14 cells. Significant sublethal damage repair was observed in T98 cells, whereas MO54 cells showed little repair activity. The expression of p53 was enhanced in the parental MO54 cells, while the p53 levels in the MO54-SY4, and in the parent and clonal T98 cells, did not change. Our data suggest that the serine and tyrosine phosphorylation of IκB-α may play a role in determining the radiosensitivity of malignant glioma cells. (author)

Optimal energy for cell radiosensitivity enhancement by gold nanoparticles using synchrotron-based monoenergetic photon beams.

Science.gov (United States)

Rahman, Wan Nordiana; Corde, Stéphanie; Yagi, Naoto; Abdul Aziz, Siti Aishah; Annabell, Nathan; Geso, Moshi

2014-01-01

Gold nanoparticles have been shown to enhance radiation doses delivered to biological targets due to the high absorption coefficient of gold atoms, stemming from their high atomic number (Z) and physical density. These properties significantly increase the likelihood of photoelectric effects and Compton scattering interactions. Gold nanoparticles are a novel radiosensitizing agent that can potentially be used to increase the effectiveness of current radiation therapy techniques and improve the diagnosis and treatment of cancer. However, the optimum radiosensitization effect of gold nanoparticles is strongly dependent on photon energy, which theoretically is predicted to occur in the kilovoltage range of energy. In this research, synchrotron-generated monoenergetic X-rays in the 30-100 keV range were used to investigate the energy dependence of radiosensitization by gold nanoparticles and also to determine the photon energy that produces optimum effects. This investigation was conducted using cells in culture to measure dose enhancement. Bovine aortic endothelial cells with and without gold nanoparticles were irradiated with X-rays at energies of 30, 40, 50, 60, 70, 81, and 100 keV. Trypan blue exclusion assays were performed after irradiation to determine cell viability. Cell radiosensitivity enhancement was indicated by the dose enhancement factor which was found to be maximum at 40 keV with a value of 3.47. The dose enhancement factor obtained at other energy levels followed the same direction as the theoretical calculations based on the ratio of the mass energy absorption coefficients of gold and water. This experimental evidence shows that the radiosensitization effect of gold nanoparticles varies with photon energy as predicted from theoretical calculations. However, prediction based on theoretical assumptions is sometimes difficult due to the complexity of biological systems, so further study at the cellular level is required to fully characterize the effects

Correlation between residual level of DNA double-strand breaks and the radiosensitivity of cancer cells

International Nuclear Information System (INIS)

Sun Jianxiang; Sun Weijian; Sui Jianli; Zhou Pingkun

2008-01-01

Objective: To understand the variation of the DNA double-strand break rejoining capacity among different cultured cancer cell lines and the primary cancer cells from brain cancer patients, and to explore the predictor of radiotherapy responses of cancers. Methods: DNA double-strand breaks (DSBs) were induced by 60 Co γ-irradiation. Pulsed-field gel electrophoresis was used to analyze the initial production and rejoining of DNA DSBs. Radiosensitivity was determined by in vitro assay of clonogenic-forming capacity. Results: A wide variation of radiosensitivity, e.g. the survival parameter of Do varied from 0.65 to 2.15 Gy, was displayed among the eight cell lines derived from different type of cancers. Although differential level of initial DNA DSBs induced by 20 Gy γ-rays was observed among various cell lines, it was not correlated with the radiosensitivity. The deficiency of DNA DSB rejoining in radiosensitive cell lines was shown either in the early rapid-rejoining phase (SX-10 cells) or in the late slow-rejoining phase (A2780 cells). A significant relationship was observed between the residual level of DNA DSBs measured at 2 h post-20 Gy irradiation and the cellular radiosensitivity (D 0 or SF 2 ). The kinetic curves of rejoining DNA DSBs in the primary human brain tumor cells indicated a variation on DSB rejoining capacity among different individual tumor. The residual level of DNA DSBs after 2 h of rejoining post 20 Gy irradiation in primary human brain tumor cells is compatible to the results obtained in vitro culture cancer cell lines. Conclusions: The residual level of DNA DSBs is correlated with radioresistance of cancer cells, and the residual DNA damage is a useful parameter in predicting the response of tumor tissue to radiotherapy. (authors)

Ectopic expression of miR-34a enhances radiosensitivity of non-small cell lung cancer cells, partly by suppressing the LyGDI signaling pathway

International Nuclear Information System (INIS)

Duan Weiming; Xu Yaxiang; Dong Yujin; Cao Lili; Tong Jian; Zhou Xinwen

2013-01-01

miR-34a is transcriptionally induced by the tumor suppressor gene p53, which is often downregulated in non-small cell lung cancer (NSCLC). To address whether the downstream signal of miR-34a is sufficient to induce apoptosis and to alter cellular radiosensitivity, a chemical synthetic miR-34a mimic was delivered into A549 and H1299 cells, with or without co-treatment of γ-irradiation. Results showed that ectopic expression of miR-34a induced dose-dependent cell growth inhibition and apoptosis in a p53-independent manner in both NSCLC cell lines. Interestingly, LyGDI was discovered as a new target gene of miR-34a, and downregulation of LyGDI promoted Rac1 activation and membrane translocation, resulting in cell apoptosis. Furthermore, restoration of miR-34a indirectly reduced cyclooxygenase-2 (COX-2) expression. Taken together, these results demonstrate that restoration of miR-34a expression enhances radiation-induced apoptosis, partly by suppressing the LyGDI signaling pathway, and miR-34a could possibly be used as a radiosensitizer for non-small cell lung cancer therapy. (author)

The discussion of method for survey the radiosensitivity of human glioma cell line SHG-44

International Nuclear Information System (INIS)

Li Li; Xu Changshao; Zhou Juying; Xu Xiaoting; Luo Jialin

2005-01-01

Objective: To investigate if thiazolyl blue colorimetric assay (MTT) and cell counting kit-8 (CCK-8) can replace clone forming assay for survey the radiosensitivity of SHG-44. Methods; Three assays was applied to examine the growth inhibition of human glioma cell line SHG-44 in eight dose groups of 0, 1, 2, 3, 4, 6, 8 and 10 Gy, and statistical research was applied to analyze the correlation between survival fraction and various doses. Results: Dose was associated with survival fraction in these three assays at some range of irradiation doseage (dose≤3 Gy). If out of the range, the relation is poor. CCK-8 has no rather superiority than MTT. Conclusion: By now clone forming assay is still the 'gold standard'. In some cases, MTT and other assays can give us some reference, but these assays still can not replace clone forming assay. (authors)

Characteristics of fluorinated nitroazoles as hypoxic cell radiosensitizers

International Nuclear Information System (INIS)

Shibamoto, Y.; Nishimoto, S.; Shimokawa, K.

1989-01-01

Types of 2-nitroimidazoles and 3-nitro-1,2,4-triazoles bearing one or two fluorine atoms on their side chains were synthesized to evaluate their physicochemical properties, radiosensitizing effects, and toxicity. The reduction potential of the compounds containing one fluorine was similar to that of misonidazole (MISO), whereas that of the difluorinated compounds was slightly higher. Both mono- and difluorinated compounds had an in vitro sensitizing activity comparable to or slightly higher than that of MISO. The fluorinated 3-nitrotriazoles were almost as efficient as the 2-nitroimidazoles with the same substituent. In vivo, some of the compounds were up to twice more efficient than MISO, whereas others were as efficient as MISO. Toxicity in terms of LD50/7 in mice was quite variable depending on the side-chain structure; the amide derivatives were less toxic than MISO, whereas the alcohol and ether derivatives were more toxic. In view of the radiosensitizing effect and toxicity in vivo, at least one compound, KU-2285 (a 2-nitroimidazole with an N1-substituent of: CH2CF2CONHCH2CH2OH) has been found to be as useful a hypoxic cell sensitizer as SR-2508

Rockets, radiosensitizers, and RRx-001: an origin story part I.

Science.gov (United States)

Oronsky, Bryan; Scicinski, Jan; Ning, Shoucheng; Peehl, Donna; Oronsky, Arnold; Cabrales, Pedro; Bednarski, Mark; Knox, Susan

2016-03-01

From Adam and Eve, to Darwinism, origin stories attempt to fill in the blanks, connect the dots, and define the turning points that are fundamental to subsequent developments. The purpose of this review is to present the origin story of a one-of-a-kind anticancer agent, RRx-001, which emerged from the aerospace industry as a putative radiosensitizer; not since the dynamite-to-dilator transformation of nitroglycerin in 1878 or the post-World War II explosive-to-elixir conversion of hydralazine, an ingredient in rocket fuel, to an antihypertensive, an antidepressant and an antituberculant, has energetic chemistry been harnessed for therapeutic purposes. This is Part 1 of the radiosensitization story; Parts 2 and 3, which detail the crossover activity of RRx-001 as a chemosensitizer in multiple tumor types and disease states including malaria, hemorrhagic shock and sickle cell anemia, are the subject of future reviews.

Neoplasms radiosensitivity: how to increase the efficiency of radiotherapy

International Nuclear Information System (INIS)

Calais, G.

1991-01-01

The hypoxia in the neoplasms is a radioresistance factor. This article is about the methods able to reduce the hypoxia in tumors: use of hyperbaric oxygen, radiosensitizers (as metronidazole), hyperthermia and modification of oxygen release in the tissues in modifying the blood flow and in reducing the hemoglobin affinity for oxygen [fr

Radiosensitivity of neuroblastoma

International Nuclear Information System (INIS)

Deacon, J.M.; Wilson, P.; Steel, G.G.

1985-01-01

Neuroblastoma is known to be clinically radioresponsive: it is possible to obtain local tumour control with relatively small doses of radiation. The main therapeutic problem, however, is one of metastatic disease, where in spite of modern combination chemotherapy, the prognosis remains poor. Systemic therapy with either drugs or radiation is dose-limited by toxicity to bone marrow stem cells. However, the advent of new technology which enables tumour cells to be removed from infiltrated marrow prior to autologous bone marrow ''rescue'' allows dose escalation, and makes the use of systemic irradiation in the treatment of stage IV disease feasible. The objective of this study was to investigate the radiobiology of neuroblastoma in detail, including intrinsic cellular radiosensitivity, repair capacity, and extrinsic dose-modifying factors which may affect tumour response in vivo. Cells at three levels of organisation were used: single cell suspensions multicellular tumour spheroids; and xenografts grown in immune-suppressed mice

Periodic Forcing of Inhibition-Stabilized Networks: Nonlinear Resonances and Phase-Amplitude Coupling

OpenAIRE

Veltz, Romain; Sejnowski, Terrence J.

2015-01-01

International audience; Inhibition stabilized networks (ISNs) are neural architectures with strong positive feedback among pyramidal neurons balanced by strong negative feedback from in-hibitory interneurons, a circuit element found in the hippocampus and the primary vi-sual cortex. In their working regime, ISNs produce damped oscillations in the γ-range in response to inputs to the inhibitory population. In order to understand the proper-ties of interconnected ISNs, we investigated periodic ...

Effects of taurolidine on radiosensitivity of murine melanoma cells and its mechanism

International Nuclear Information System (INIS)

Sun Baosheng; Liu Shixin; Wang Tiejun; Liu Linlin; Huang Guomin; Gong Shouliang

2008-01-01

Objective: To observe the effects of taurolidine on radiosensitivity of B16-F10 cells of murine melanoma via the enhancement of Bax and Bad proteins and induction of Bcl-2 protein. Methods: The apoptosis of B16-F10 cells was assessed after treated with 0, 10, 25, 50, 100 and 150 μmol·L -1 taurolidine, clone survival assay was used to detect the radiosensitivity of B16-F10 cells, and protein expressions were determined by Western blotting. Results: The apoptosis of 5% cells was induced in a dose-and time-dependent manner after B16-F10 cells were treated with 50 μmol·L -1 taurolidine. The survival rate decreased after treated with tautolidine in combination with 2 Gy X-irradiation with the increase of taurolidine concentration and doses of irradiation (P 0 and SER D q ) also increased with the increase of its concentration, there was significant difference between 50 μmol·L -1 taurolidine group and 10 μmol·L -1 taurolidine group (P<0.05); meantime, the level of proapototic protein Bax and Bad increased and the level of antiapoptotic protein Bcl-2 reduced. Conclusion: Taurolidine in combination with irradiation can enhance the radiosensitivity by the mediation of Bcl-2 family protein. (authors)

The merits of DNA content and cell kinetic parameters for the assessment of intrinsic cellular radiosensitivity to photon and high-LET neutron irradiation

International Nuclear Information System (INIS)

Theron, C.S.; Serafin, A.; Bohm, L.; Slabbert, J.P.

1997-01-01

Differences of the intrinsic cellular radiosensitivity between tumours make the selection of patients for specific radiation schedules very difficult. The reasons for these variations are still unclear, but are thought to be due to genomic and cellular characteristics. Radiosensitivities vary between cell cycle stages, with S-phase cells being most radioresistant and G2/M phase cells most radiosensitive. It is also well established that most tumour cells have an abnormal ploidy. DNA content and cellular proliferation kinetics therefore could influence the intrinsic radiosensitivity. This prompted us to assess the merits of these parameters as predictors of radiation response. (authors)

Diagnosis and therapy of cutaneous radiation syndrome. Individual radiosensitivity assessment in patients undergoing medical exposures presenting severe cutaneous radiation induced lesions

International Nuclear Information System (INIS)

Di Giorgio, Marina; Vallerga, Maria B.; Perez, Maria R.; Portas, Mercedes

2007-01-01

Hospital de Quemados del Gobierno de la Ciudad de Buenos Aires (Burn Center) is one of the reference hospitals of the Medical Radiological Emergency Response Network of Argentina. In the frame of an agreement between the Burn Center and the Nuclear Regulatory Authority of Argentina, a research project for an approach based on diagnosis and therapy of cutaneous radiation induced lesions is in progress. Individual radiosensitivity assessment was conducted in patients included in this research protocol that showed acute and/or late cutaneous reactions with grades 3 and 4 of the Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European organization for research and treatment of cancer (EORTC). DNA repair capacity and its kinetics were evaluated in human peripheral blood lymphocytes using alkaline comet assay and micronucleus test. In this paper, two representative cases, in which the research protocol was applied, are presented. Therapeutic response and its correlation with radiosensitivity test results are described. Case 1: female patient undergoing external radiotherapy for invasive ductal breast cancer that presented acute cutaneous radiotoxicity, grade 3 (confluent moist epithelitis, )that led to treatment break. Case 2: male patient undergoing coronary angioplasty (interventional radiology), which developed late cutaneous radiotoxicity, grade 4 (ulceration at the dorsal region). Patients were treated with: topic administration of trolamine and silver sulfadiazine with lidocaine, associated with systemic administration of pentoxiphiline and anti-oxidants. The therapeutic response was evaluated through clinical follow-up, serial photographic record and complementary tests (tele thermography and high frequency ultrasonography). Case 1 response was positive (favorable) with early local recovery and complete remission of signs and symptoms after 5 months. Both MN frequencies and comet assay showed values compatible with normal radiosensitivity