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Sample records for cduprt increases radiosensitization

  1. Expression of the bifunctional suicide gene CDUPRT increases radiosensitization and bystander effect of 5-FC in prostate cancer cells

    International Nuclear Information System (INIS)

    Purpose: To test the hypothesis that, with 5-fluorocytosine (5-FC) treatment, the co-expression of cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) can lead to greater radiosensitization and bystander effect than CD-expression alone. Methods and materials: R3327-AT cell lines stably expressing CD or CDUPRT were generated. The 5-FC and 5-FU cytotoxicity, and the radiosensitivity with/without 5-FC treatment, of these cells were evaluated under both aerobic and hypoxic conditions. The bystander effect was assessed by apoptosis staining and clonogenic survival. The pharmacokinetics of 5-FU and 5-FC metabolism was monitored in mice bearing CD- or CDUPRT-expressing tumors using 19F MR spectroscopy (MRS). Results: CDUPRT-expressing cells were more sensitive to 5-FC and 5-FU than CD-expressing cells. CDUPRT-expression further enhanced the radiosensitizing effect of 5-FC, relative to that achieved by CD-expression alone. A 25-fold lower dose of 5-FC resulted in the same magnitude of radiosensitization in CDUPRT-expressing cells, relative to that in CD-expressing cells. The 5-FC cytotoxicity in co-cultures of parental cells mixed with 10-20% CDUPRT cells was similar to that in 100% CDUPRT cells. 19F MRS measurements showed that expression of CDUPRT leads to enhanced accumulation of fluorine nucleotide (FNuc), relative to that associated with CD-expression alone. Conclusion: Our study suggests that CDUPRT/5-FC strategy may be more effective than CD/5-FC, especially when used in combination with radiation.

  2. Pharmacokinetics and the bystander effect in CD::UPRT/5-FC bi-gene therapy of glioma

    Institute of Scientific and Technical Information of China (English)

    SHI De-zhi; HU Wei-xing; LI Li-xin; CHEN Gong; WEI Dong; GU Pei-yuan

    2009-01-01

    , reached a maximum at around 160 minutes, and was detectable for several hours. At a 10% ratio of C6-CD::UPRT cells, the survival rate was (79.55±0.88)% (P <0.01). As the C6-CD::UPRT ratio increased, the survival rate of the cells decreased.19F-MRS showed that the signals for 5-FU and F-Nuctd in the culture medium increased as the ratio of C6-CD::UPRT in the mixture increased.Conclusions 19F-MRS studies indicated that C6-CD::UPRT cells could effectively express CD and UPRT enzymes.The CD::UPRT/5-FC system showed an obvious bystander effect. This study demonstrated that CD::UPRT/5-FC gene therapy is suitable for 5-FC to F-Nuctd metabolism; and 19F-MRS can monitor transferred CD::UPRT gene expression and catalysis of substrates noninvasively, dynamically and quantitatively.

  3. Autophagy Inhibition to Increase Radiosensitization in Breast Cancer

    OpenAIRE

    Liang, Diana Hwang; El-Zein, Randa; Dave, Bhuvanesh

    2015-01-01

    Currently, many breast cancer patients with localized breast cancer undergo breast-conserving therapy, consisting of local excision followed by radiation therapy. Following radiation therapy, breast cancer cells are noted to undergo induction of autophagy, development of radioresistance, and enrichment of breast cancer stem cell subpopulations. It is hypothesized that inhibition of the cytoprotective autophagy that arises following radiation therapy increases radiosensitivity and confers long...

  4. HMGB1increases radiosensitivity by interacting with HDAC1%HMGB1 increases radiosensitivity by interacting with HDAC1

    Institute of Scientific and Technical Information of China (English)

    He Xin; Meng Qinghui; Meng Aimin; Liu Qiang; Wang Haichao; Fan Saijun

    2015-01-01

    Objective To study the nuclear protein association of high-mobility group box-1 (HMGB1) and histone deacetylase 1 (HDAC1),and the effect of interaction on radiosensitivity in human breast cancer cells.Methods The protein-protein interaction was determined by immunoprecipitationWestern blot and glutathione-S-transferase capture assays.Cell growth was examined by MTT (methyl thiazolyl tetrazolium)assay and clonogenic assay.Histone deacetylase activity was analyzed by histone deacetylase assay.Results A significant increase of HMGB1 protein and radiosensitivity was observed in MDA-MB-231 and MDA-MB-468 cells transfected with a pCMV-Tag2B expression vector carrying with a full-length of HMGB1 cDNA.HMGB1 binding to HDAC1 was demonstrated as GST (glutathione Stransferase)-pull down and immunoprecipitation Western blot assay,and the association was elevated by irradiation.An LXCXE motif was required for the HMGB1-HADC1 interaction and HMGB1 radiosensitization.A significant difference of IC50 value was observed,for example,1.8 and 2.2 Gy (wtHMGB1 transfectants,P < 0.05),3.6 and 3.8 Gy (HMGB1/C103F transfectants,P > 0.05),both compared with 3.9 and 4.1 Gy (pCMV-Tag2B transfectants) in MDA-MB-231 and MDA-MB-468 cells,respectively.A specific HDAC1 inhibitor trichostatin A markedly reduced the HMGB1-mediated radiosensitivity,0.5 Gy in the presence of trichostatin A versus 1.8 Gy in absence of trichostatin A in MDA-MB-231 transfectants,1.2 Gy (with trichostatin A) versus 2.2 Gy (without trichostatin A) in MDA-MB-468 transfectants,P < 0.05.Histone deacetylase activity was also detected in immunoprecipitates prepared from these cells with antibodies to HMGB1,and this activity was abolished by the histone trichostatin A.Conclusions These results suggest a previous unanticipated role for HDAC1 in modification of HMGB1-mediated radiosensitivity by its direct interaction with HMGB1.

  5. Autophagy involved in resveratrol increased radiosensitivity in glioma stem cells

    International Nuclear Information System (INIS)

    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)

  6. Zidovudine, abacavir and lamivudine increase the radiosensitivity of human esophageal squamous cancer cell lines.

    Science.gov (United States)

    Chen, Xuan; Wang, Cong; Guan, Shanghui; Liu, Yuan; Han, Lihui; Cheng, Yufeng

    2016-07-01

    Telomerase is a type of reverse transcriptase that is overexpressed in almost all human tumor cells, but not in normal tissues, which provides an opportunity for radiosensitization targeting telomerase. Zidovudine, abacavir and lamivudine are reverse transcriptase inhibitors that have been applied in clinical practice for several years. We sought to explore the radiosensitization effect of these three drugs on human esophageal cancer cell lines. Eca109 and Eca9706 cells were treated with zidovudine, abacavir and lamivudine for 48 h before irradiation was administered. Samples were collected 1 h after irradiation. Clonal efficiency assay was used to evaluate the effect of the combination of these drugs with radiation doses of 2, 4, 6 and 8 Gy. DNA damage was measured by comet assay. Telomerase activity (TA) and relative telomere length (TL) were detected and evaluated by real-time PCR. Apoptosis rates were assessed by flow cytometric analysis. The results showed that all the drugs tested sensitized the esophageal squamous cell carcinoma (ESCC) cell lines to radiation through an increase in radiation-induced DNA damage and cell apoptosis, deregulation of TA and decreasing the shortened TL caused by radiation. Each of the drugs investigated (zidovudine, abacavir and lamivudine) could be used for sensitizing human esophageal cancer cell lines to radiation. Consequently, the present study supports the potential of these three drugs as therapeutic agents for the radiosensitization of esophageal squamous cell cancer. PMID:27220342

  7. Partial knockdown of TRF2 increase radiosensitivity of human mesenchymal stem cells.

    Science.gov (United States)

    Orun, O; Tiber, P Mega; Serakinci, N

    2016-09-01

    Telomere repeat binding factor TRF2 is a member of shelterin complex with an important role in protecting and stabilizing chromosomal ends. In the present study, we investigated the effect of partial knockdown of TRF2 on radiosensitivity of telomerase immortalized human mesenchymal stem cells (hMSC-telo1), which have a higher radioresistance compared to non telomerized counterpart. Partial knockdown of the protein achieved 15-20% reduction in TRF2 protein levels. The study compared the effect of 2.5Gy radiation in two-four days after irradiation for hMSC-telo1 cells and the cells transfected with siTRF2 and null control vector. Radio-response of the cells were examined using senescence associated β-Gal assay (β-Gal), colony forming assay (CFU) and γ-H2AX phosphorylation. TRF2 deficiency substantially increased radiosensitivity of cells compared to controls in both proliferation and senescence assay (2.4 fold increase in β-Gal, 1.6 fold decrease in CFU). In addition, it increased the γ-H2AX foci as revealed by both immunfluorescence and Western blot analysis. Our data suggests that partial knockdown of TRF2 in hMSC-telo1 cells cause increased γ-H2AX foci which led to fail TRF2 to protect telomeres from radiation thus TRF2 deficiency led to a 1,5-2 fold increase in the radiosensitivity of hMSC-telo1 cells through telomere destabilization. PMID:26598048

  8. Growth suppression and radiosensitivity increase by HMGB1 in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Yang JIAO; Hai-chao WANG; Sai-jun FAN

    2007-01-01

    Aim: HMGB 1 (high-mobility group box-1) is a nuclear protein containing a con- sensus RB (retinoblastoma)-binding LXCXE motif. In this study, we studied the potential association of HMGB 1 and RB and the in vitro and in vivo activities of HMGB 1 in human breast cancer cells. Methods: The protein-protein interaction was determined by immunoprecipitation-Western blotting and glutathione-S-trans- ferase capture assays; cell growth and radiosensitivity were examined by cell counts, MTT assay, and clonogenic assay; cell cycle progression and apoptosis were evaluated using flow cytometry; and the antitumor activity of HMGB 1 was examined with tumor xenografts in nude mice. Results: HMGB 1 was associated with RB via a LXCXE motif-dependent mechanism. HMGB 1 enhanced the ability of RB for E2F and cyclin A transcription repression. The increased expression of HMGB 1 conferred an altered phenotypes characterized by the suppression of cell growth; G12 arrest and apoptosis was induced in MCF-7 cells containing the wild- type retinoblastoma (Rb) gene, but showed no activities in BT-549 cells contain- ing the Rb gene deletion. The HMGB 1-induced apoptosis accompanied by caspase 3 activation and PARP (poly(ADP-ribose)polymerase) cleavage. HMGB 1 elevated the radiosensitivity of breast cancer cells in both the MCF-7 and BT-549 cell lines. The enhanced expression of HMGB 1 caused a suppression of growth of MCF-7 tumor xenografts in nude mice, while LXCXE-defective HMGB 1 completely lost antitumor growth activity. Conclusion: HMGB 1 functions as a tumor suppressor and radiosensitizer in breast cancer. A HMGB 1-RB interaction is critical for the HMGB1-mediated transcriptional repression, cell growth inhibition, G12 cell cycle arrest, apoptosis induction, and tumor growth suppression, but is not required for radiosensitization. Therefore, it may be possible to design new therapies for the treatment of breast cancer that exert their effects by modulating the HMGB 1 and RB regulatory

  9. Slug inhibition increases radiosensitivity of oral squamous cell carcinoma cells by upregulating PUMA.

    Science.gov (United States)

    Jiang, Fangfang; Zhou, Lijie; Wei, Changbo; Zhao, Wei; Yu, Dongsheng

    2016-08-01

    As a new strategy, radio-gene therapy was widely used for the treatment of cancer patients in recent few years. Slug was involved in the radioresistance of various cancers and has been found to have an anti-apoptotic effect. This study aims to investigate whether the modulation of Slug expression by siRNA affects oral squamous cell carcinoma sensitivity to X-ray irradiation through upregulating PUMA. Two oral squamous cell carcinoma cell lines (HSC3 and HSC6) were transfected with small interfering RNA (siRNA) targeting Slug and subjected to radiotherapy in vitro. After transfection with Slug siRNA, both HSC3 and HSC6 cells showed relatively lower expression of Slug and higher expression of PUMA. The Slug siRNA transfected cells showed decreased survival and proliferation rates, an increased apoptosis rate and enhanced radiosensitivity to X-ray irradiation. Our results revealed that Slug siRNA transfection in combination with radiation increased the expression of PUMA, which contributed to radiosensitivity of oral squamous cell carcinoma cells. Thus, controlling the expression of Slug might contribute to enhance sensitivity of HSC3 and HSC6 cells toward X-ray irradiation in vitro by upregulating PUMA. PMID:27277529

  10. Increased Chromosomal Radiosensitivity in Women Carrying BRCA1/BRCA2 Mutations Assessed With the G2 Assay

    International Nuclear Information System (INIS)

    Purpose: Several in vitro studies suggest that BRCA1 and BRCA2 mutation carriers present increased sensitivity to ionizing radiation. Different assays for the assessment of deoxyribonucleic acid double-strand break repair capacity have been used, but results are rather inconsistent. Given the concerns about the possible risks of breast screening with mammography in mutation carrier women and the potentially damaging effects of radiotherapy, the purpose of this study was to further investigate the radiosensitivity of this population. Methods and Materials: The G2 chromosomal radiosensitivity assay was used to assess chromosomal breaks in lymphocyte cultures after exposure to 1 Gy. A group of familiar breast cancer patients carrying a mutation in the BRCA1 or BRCA2 gene (n = 15) and a group of healthy mutation carriers (n = 5) were investigated and compared with a reference group of healthy women carrying no mutation (n = 21). Results: BRCA1 and BRCA2 mutation carriers had a significantly higher number of mean chromatid breaks per cell (p = 0.006) and a higher maximum number of breaks (p = 0.0001) as compared with their matched controls. Both healthy carriers and carriers with a cancer history were more radiosensitive than controls (p = 0.002 and p = 0.025, respectively). Age was not associated with increased radiosensitivity (p = 0.868). Conclusions: Our results indicate that BRCA1 and BRCA2 mutation carriers show enhanced radiosensitivity, presumably because of the involvement of the BRCA genes in deoxyribonucleic acid repair and cell cycle control mechanisms.

  11. Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft.

    Science.gov (United States)

    Senra, Joana M; Telfer, Brian A; Cherry, Kim E; McCrudden, Cian M; Hirst, David G; O'Connor, Mark J; Wedge, Stephen R; Stratford, Ian J

    2011-10-01

    PARP-1 is a critical enzyme in the repair of DNA strand breaks. Inhibition of PARP-1 increases the effectiveness of radiation in killing tumor cells. However, although the mechanism(s) are well understood for these radiosensitizing effects in vitro, the underlying mechanism(s) in vivo are less clear. Nicotinamide, a drug structurally related to the first generation PARP-1 inhibitor, 3-aminobenzamide, reduces tumor hypoxia by preventing transient cessations in tumor blood flow, thus improving tumor oxygenation and sensitivity to radiotherapy. Here, we investigate whether olaparib, a potent PARP-1 inhibitor, enhances radiotherapy, not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non-small cell lung carcinoma (NSCLC). In irradiated Calu-6 and A549 cells, olaparib enhanced the cytotoxic effects of radiation (sensitizer enhancement ratio at 10% survival = 1.5 and 1.3) and DNA double-strand breaks persisted for at least 24 hours after treatment. Combination treatment of Calu-6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression (P = 0.007) relative to radiotherapy alone. To determine whether this radiosensitization was solely due to effects on DNA repair, we used a dorsal window chamber model to establish the drug/radiation effects on vessel dynamics. Olaparib alone, when given as single or multiple daily doses, or in combination with fractionated radiotherapy, increased the perfusion of tumor blood vessels. Furthermore, an ex vivo assay in phenylephrine preconstricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide. This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC. PMID:21825006

  12. Upregulation of microRNA-98 increases radiosensitivity in esophageal squamous cell carcinoma

    Science.gov (United States)

    Jin, Ying-Ying; Chen, Qing-Juan; Wei, Yang; Wang, Ya-Li; Wang, Zhong-Wei; Xu, Kun; He, Yun; Ma, Hong-Bing

    2016-01-01

    Although radiation resistance is a common challenge in the clinical treatment of esophageal squamous cell carcinoma (ESCC), an effective treatment strategy has yet to be developed. Aberrant expression of microRNAs (miRNAs) is responsible for cancer sensitivity to radiation. In this study, we aimed to identify the miRNAs that are associated with radioresistance in ESCC. We used a miRNA microarray to perform a comparison of miRNA expression in both ESCC parental and acquired radioresistance cell lines. qRT-PCR was used to confirm the alterations. Cell radiosensitivity was determined with a survival fraction assay. Functional analyses of the identified miRNA in ESCC cells with regard to metastasis and apoptosis were performed by transwell assays and flow cytometry. The miRNA targets were identified with pathway analysis and confirmed with a luciferase assay. miR-98 was recognized as the most downregulated miRNA in established radioresistant cell line. AmiR-98 mimic enforced the expression of miRNA-98 and made ESCC cells sensitive to radiotherapy, while anti-miR-98 reversed this process. Optimal results were achieved by decreasing cellular proliferation, decreasing cell migration and inducing apoptosis. The luciferase target gene analysis results showed that the overexpression of miRNA-98 inhibited tumor growth and resistance tolerance by directly binding to the BCL-2 gene. Our study indicated that increasing miRNA-98 expression can be used as a potential radiosensitive therapeutic strategy for treating esophageal cancer cells. PMID:27422937

  13. Changes in epidermal radiosensitivity with time associated with increased colony numbers

    NARCIS (Netherlands)

    G.J.M.J. van den Aardweg (Gerard J. M.); G.M. Morris; A. Bywaters; E.J. Bakker (Erik Jan); W.J. Mooi (Wolter)

    2001-01-01

    textabstractEpidermal clonogenic cell survival and colony formation following irradiation were investigated and related to radiosensitivity. A rapid in vivo/in vitro assay was developed for the quantification of colonies arising from surviving clonogenic cells in pig ep

  14. Inhibitory Effect of Pulmonary Carcinoma by Adenovirus-Mediated CD/UPRT Gene

    Institute of Scientific and Technical Information of China (English)

    HUANG Qi; CHEN Dayu; FU Xiangning; ZU Yukun

    2006-01-01

    The cell killing effects and bystander effects of double suicide gene on pulmonary carcinoma cells were explored. Lung adenocarcinoma cells (A549) were transfected with different titers of adenovirus vector and followed with different concentrations of 5-FC after a recombinant adenovirus vector carrying CD/UPRT gene (Ad-CD/UPRT) was constructed. The cell viability was measured by MTT assay 4 days later. The cell viability was dropped to 30.57 %-8.62 % after 10 MOI of Ad-CD/UPRT transfected and 5-FC (10-1000 μg/mL) administration. Furthermore, Ad-CD/UPRT-infected A549 cells showed a profound neighbor cell killing effect in the same methods. These results suggested that Ad-CD/UPRT/5-FC system can effectively suppress growth of lung adenocarcinoma cells, which may provide a novel and powerful candidate for lung cancer gene therapy strategies.

  15. Downregulation of high mobility group box 1 modulates telomere homeostasis and increases the radiosensitivity of human breast cancer cells.

    Science.gov (United States)

    Ke, Shaobo; Zhou, Fuxiang; Yang, Hui; Wei, Yuehua; Gong, Jun; Mei, Zijie; Wu, Lin; Yu, Haijun; Zhou, Yunfeng

    2015-03-01

    The functions of the high mobility group box 1 (HMGB1) in tumor cells include replenishing telomeric DNA and maintaining cell immortality. There is a negative correlation between human telomerase reverse transcriptase (hTERT) and radiosensitivity in tumor cells. Our aim was to elucidate the relationship among HMGB1, telomere homeostasis and radiosensitivity in MCF-7 cells. In this study, we established stably transfected control (MCF-7-NC) and HMGB1 knockdown (MCF-7-shHMGB1) cell lines. The expression of HMGB1 mRNA and the relative telomere length were examined by real-time PCR. Radiosensitivity was detected by clonogenic assay. The protein expressions were determined by western blot analysis. The telomerase activity was detected by PCR-ELISA. Proliferation ability was examined by CCK-8 assay. Cell cycle and apoptosis were examined by flow cytometry. DNA damage foci were detected by immunofluorescence. ShRNA-mediated downregulation of HMGB1 expression increased the radiosensitivity of MCF-7 cells, and reduced the accumulation of hTERT and cyclin D1. Moreover, knockdown of HMGB1 in MCF-7 cells inhibited telomerase activity and cell proliferation, while increasing the extent of apoptosis. Downregulation of HMGB1 modulated telomere homeostasis by changing the level of telomere-binding proteins, such as TPP1 (PTOP), TRF1 and TRF2. This downregulation also inhibited the ATM and ATR signaling pathways. The current data demonstrate that knockdown of HMGB1 breaks telomere homeostasis, enhances radiosensitivity, and suppresses the repair of DNA damage in human breast cancer cells. These results suggested that HMGB1 might be a potential radiotherapy target in human breast cancer. PMID:25501936

  16. A Monte Carlo-based model of gold nanoparticle radiosensitization accounting for increased radiobiological effectiveness.

    Science.gov (United States)

    Lechtman, E; Mashouf, S; Chattopadhyay, N; Keller, B M; Lai, P; Cai, Z; Reilly, R M; Pignol, J-P

    2013-05-21

    Radiosensitization using gold nanoparticles (AuNPs) has been shown to vary widely with cell line, irradiation energy, AuNP size, concentration and intracellular localization. We developed a Monte Carlo-based AuNP radiosensitization predictive model (ARP), which takes into account the detailed energy deposition at the nano-scale. This model was compared to experimental cell survival and macroscopic dose enhancement predictions. PC-3 prostate cancer cell survival was characterized after irradiation using a 300 kVp photon source with and without AuNPs present in the cell culture media. Detailed Monte Carlo simulations were conducted, producing individual tracks of photoelectric products escaping AuNPs and energy deposition was scored in nano-scale voxels in a model cell nucleus. Cell survival in our predictive model was calculated by integrating the radiation induced lethal event density over the nucleus volume. Experimental AuNP radiosensitization was observed with a sensitizer enhancement ratio (SER) of 1.21 ± 0.13. SERs estimated using the ARP model and the macroscopic enhancement model were 1.20 ± 0.12 and 1.07 ± 0.10 respectively. In the hypothetical case of AuNPs localized within the nucleus, the ARP model predicted a SER of 1.29 ± 0.13, demonstrating the influence of AuNP intracellular localization on radiosensitization.

  17. Restoration of IGFBP-rP1 increases radiosensitivity and chemosensitivity in hormone-refractory human prostate cancer

    International Nuclear Information System (INIS)

    We previously reported the tumor-suppressive activity of insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) through induction of apoptosis in human prostate cancer cells. The aim of this study was to investigate the effects of IGFBP-rP1 for radiosensitivity and chemosensitivity in hormone-refractory human prostate PC-3 cancer cells. Five assays were performed using PC-3 cells transfected with IGFBP-rP1 (PC-3rP1) and control cells transfected with an empty vector (PC-3N): PC-3rP1 and PC-3N were compared by clonogenic survival assay, cell cycle analysis and apoptotic assay for radiosensitivity. The number of colonies of PC-3rP1 cells significantly decreased after 4 and 8 Gy of irradiation, compared with those of PC-3N in the clonogenic survival assay. After 16 hr irradiation at 8 Gy, the percentage of apoptotic cells significantly increased in PC-3rP1 compared with PC-3N. Growth of PC-3rP1 was significantly lower than that of PC-3N after docetaxel treatment both in vitro and in vivo. These results indicate that restoration of IGFBP-rP1 to PC-3 cells increases both their radiosensitivity and chemosensitivity. (author)

  18. Radiosensitivity increases with differentiation status of murine hemopoietic progenitor cells selected using enriched marrow subpopulations and recombinant growth factors

    International Nuclear Information System (INIS)

    The radiosensitivity of populations of colony-forming cells (CFC) in murine bone marrow was investigated using different recombinant colony-stimulating factors (CSFs; murine IL-3 and granulocyte-macrophage CSF and human granulocyte CSF), or purified murine macrophage CSF. With unfractionated normal bone marrow the CFC increased in radiosensitivity as they progressed through the granulocyte lineage. The D0 values ranged from 129 +/- 12 cGy for CFC stimulated with GM-CSF down to 42 +/- 2 cGy after stimulation with G-CSF. IL-3 stimulated a CFC population which gave the only survival curve with a shoulder (n = 1.9 +/- 0.3). With semipurified populations of primitive or bipotential CFC, D0 values were generally lower with respect to the equivalent values for unpurified bone marrow (range 62 +/- 7 cGy to 135 +/- 7 cGy). Changes in cluster/colony ratio and colony morphology together possibly with products of accessory cells influence the interpretation of the radiosensitivity parameters

  19. Is Increased Low-dose somatic Radiosensitivity Associated with Increased Transgenerational Germline Mutation

    Energy Technology Data Exchange (ETDEWEB)

    Brenner, David J.

    2008-10-02

    Using single-molecule polymerase chain reaction, the frequency of spontaneous and radiation-induced mutation at an expanded simple tandem repeat (ESTR) locus was studied in DNA samples extracted from sperm and bone marrow of Atm knockout (Atm+/–) heterozygous male mice. The frequency of spontaneous mutation in sperm and bone marrow in Atm+/– males did not significantly differ from that in wild-type BALB/c mice. Acute gamma-ray exposure did not affect ESTR mutation frequency in bone marrow and resulted in similar increases in sperm samples taken from Atm+/– and BALB/c males. Taken together, these results suggest that the Atm haploinsufficiency analyzed in our study does not affect spontaneous and radiation-induced ESTR mutation frequency in mice.

  20. Treatment of HeLa cells with Giloe (Tinospora cordifolia meirs) increases the radiosensitivity by increasing DNA damage

    International Nuclear Information System (INIS)

    Radiotherapy is an important treatment modality and screening of phytoceuticals may enhance the clinical outcome of radiotherapy, therefore radiosensitizing activity of various guduchi (Tinospora cordifolia) extracts was studied in HeLa cells. Chromosomal aberrations were scored in HeLa cells treated with 10 μg/ml of aqueous, methanol, or methylene chloride guduchi extracts or doxorubicin before exposure to 0, 0.5, 1, 2 or 3 Gy of γ-radiation at 12, 24, 36 or 48 h post-irradiation. Irradiation of HeLa cells caused a dose dependent rise in the chromatid breaks, chromosome breaks, dicentric, centric rings, acentric fragments and total aberrations at all post-irradiation times and the dose response was linear quadratic for all types of aberrations scored. Chromatid breaks increased up to 12 h post-irradiation and declined steadily up to 48 h post-irradiation, whereas chromosome breaks, dicentric, acentric fragments and total aberrations elevated up to 24 h post-irradiation and declined thereafter. However, centric rings continued to rise steadily up to 48 h post-irradiation. Treatment of HeLa cells with aqueous, methanol or methylene chloride guduchi extract or doxorubicin before irradiation significantly enhanced various types of chromosomal aberrations and a maximum rise in the chromosome aberrations was observed in the HeLa cells treated with methylene chloride extract before irradiation when compared to other groups. Various guduchi extracts enhanced the effect of radiation in HeLa cells by increasing the molecular damage to cellular genome and their effect was similar to or even greater than doxorubicin (positive control) pretreatment, depending on the type of guduchi extract used. (author)

  1. Increased radiosensitivity of colorectal tumors with intra-tumoral injection of low dose of gold nanoparticles

    Science.gov (United States)

    Shi, Minghan; Paquette, Benoit; Thippayamontri, Thititip; Gendron, Louis; Guérin, Brigitte; Sanche, Léon

    2016-01-01

    The potential of gold nanoparticles (GNPs) as radiosensitizers for the treatment of malignant tumors has been limited by the large quantities of GNPs that must be administered and the requirement for low-energy X-ray irradiation to optimize radiosensitization. In this study, we enhance the radiosensitivity of HCT116 human colorectal cells with tiopronin-coated GNPs (Tio-GNPs) combined with a low-energy X-ray (26 keV effective energy) source, similar to the Papillon 50 clinical irradiator used for topical irradiation of rectal tumors. Sensitizer enhancement ratios of 1.48 and 1.69 were measured in vitro, when the HCT116 cells were incubated with 0.1 mg/mL and 0.25 mg/mL of Tio-GNPs, respectively. In nude mice bearing the HCT116 tumor, intra-tumoral (IT) injection of Tio-GNPs allowed a 94 times higher quantity of Tio-GNPs to accumulate than was possible by intravenous injection and facilitated a significant tumor response. The time following irradiation, for tumors growing to four times their initial tumor volume (4Td) was 54 days for the IT injection of 366.3 μg of Tio-GNPs plus 10 Gy, compared to 37 days with radiation alone (P=0.0018). Conversely, no significant improvement was obtained when GNPs were injected intravenously before tumor irradiation (P=0.6547). In conclusion, IT injection of Tio-GNPs combined with low-energy X-rays can significantly reduce the growth of colorectal tumors.

  2. 3-Methyl pyruvate enhances radiosensitivity through increasing mitochondria-derived reactive oxygen species in tumor cell lines

    International Nuclear Information System (INIS)

    Considerable interest has recently been focused on the special characteristics of cancer metabolism, and several drugs designed to modulate cancer metabolism have been tested as potential anticancer agents. To date, however, very few studies have been conducted to investigate the combined effects of anticancer drugs and radiotherapy. In this study, to evaluate the role of mitochondria-derived reactive oxygen species (ROS) in the radiation-induced cell death of tumor cells, we have examined the effect of 3-methyl pyruvate (MP). MP is a membrane-permeable pyruvate derivative that is capable of activating mitochondrial energy metabolism in human lung carcinoma A549 cells and murine squamous carcinoma SCCVII cells. Pretreatment with MP significantly enhanced radiation-induced cell death in both cell lines, and also led to increases in the mitochondrial membrane potential, intracellular adenosine triphosphate content, and mitochondria-derived ROS production following the exposure of the cells to X-rays. In A549 cells, MP-induced radiosensitization was completely abolished by vitamin C. In contrast, it was partially abolished in SCCVII cells. These results therefore suggest that the treatment of the cells with MP induced radiosensitization via the production of excess mitochondria-derived ROS in tumor cells. (author)

  3. Increased radiosensitivity of a subpopulation ot T-lymphocyte progenitors from patients with Fanconi's anemia

    International Nuclear Information System (INIS)

    In vitro radiation survival of peripheral blood T lymphocytes was studied in 15 clinically normal adults and 4 patients with Fanconi's anemia. Tritiated thymidine incorporation in a whole blood lymphocyte stimulation test (LST) and a newly developed whole blood T-lymphocyte colony assay were used to measure lymphocyte blastogenesis and colony formation in response to phytohemagglutinin (PHA) or concanavalin-A (Con-A) stimulation. Lymphocyte colony formation was found to be consistently more sensitive than the LST for detection of low-level radiation effects using both normal cells and lymphocytes from Fanconi's anemia patients. Lymphocytes from patients with Fanconi's anemia were significantly more sensitive to in vitro x-irradiation than lymphocytes from clinically normal individuals as measured by their ability to divide when stimulated by PHA in the LST (patients, D37 . 198 R; normals, D37 . 309 R, p . 0.057) and colony formation assay (patients, D37 . 53 R; normals, D37 . 109 R, p . 0.016). No significant difference in the radiosensitivity of the Con-A response was observed between the two groups. The PHA-responsive T-lymphocyte subpopulation in Fanconi's anemia patients appears to be intrinsically defective. The nature of this defect, significance in the disease process, and relevancy of these findings to the establishment of radiation protection standards are discussed

  4. AG825对乳腺癌细胞的辐射增敏作用%AG825 increases radiosensitivity of breast cancer cell

    Institute of Scientific and Technical Information of China (English)

    Bo Luo; Shiying Yu; Liang Zhuang; Shu Xia; Zhen Zhao; Lei Rong

    2008-01-01

    Objective: To observe the radiosensitivity effect of AG825 on breast cancer cell line with high expression of ERBB2 in vitro. Methods: MTT and clone formation assay were used to observe the effect of AG825 on proliferation and radiosensitivity of breast cancer line MDA-MB-453. After MDA-MB-453 was exposed to AG825 and radiation, comet assay and Western blotting were applied to detect double strand break and expressions DNA-PKcs protein, respectively. Results: AG825 inhibited proliferation rate and decrease survival fraction of MDA-MB-453. After radiation, compared with control group, expression of DNA-PKcs was lower in group with AG825 presence but double strand break was higher. Conclusion: AG825 could increase radiosensitivity of breast cancer cell line MDA-MB-453, and it may associate with its inhibition of radiation induced expression of DNA-PKcs and double strand break repair.

  5. 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.

  6. The HER2-binding affibody molecule (Z(HER2∶342₂ increases radiosensitivity in SKBR-3 cells.

    Directory of Open Access Journals (Sweden)

    Lina Ekerljung

    Full Text Available We have previously shown that the HER2-specific affibody molecule (Z(HER2∶342₂ inhibits proliferation of SKBR-3 cells. Here, we continue to investigate its biological effects in vitro by studying receptor dimerization and clonogenic survival following irradiation. We found that (Z(HER2∶342₂ sensitizes the HER2-overexpressing cell line SKBR-3 to ionizing radiation. The survival after exposure to (Z(HER2∶342₂ and 8 Gy (S(8Gy 0.006 was decreased by a factor four compared to the untreated (S(8Gy 0.023. The low HER2-expressing cell line MCF-7 was more radiosensitive than SKBR-3 but did not respond to (Z(HER2∶342₂. Treatment by (Z(HER2∶342₂ strongly increased the levels of dimerized and phosphorylated HER2 even after 5 minutes of stimulation. The monomeric Z(HER2∶342 does not seem to be able to induce receptor phosphorylation and dimerization or sensitize cells to irradiation.

  7. The occurrence of recruitment supported from the finding of an increase in radiosensitivity of quiescent cells in solid tumors after fractionated irradiation with X-rays

    International Nuclear Information System (INIS)

    We examined the behavior of quiescent cells in solid tumors irradiated twice at various intervals with X-rays, using our recently developed method for selectively detecting the response of quiescent cells in solid tumors. To determine the labeling indices of tumors at the second irradiation, each mouse group included mice that were continuously administered BrdU until just before the second irradiation using mini-osmotic pumps which had been implanted before the first irradiation. Radiosensitivity of total tumor cells at the second irradiation decreased in proportion to the increase in interval time. However, radiosensitivity of quiescent cells was raised with increase in the interval time. In addition, the labeling index at the second irradiation was higher than that at the first irradiation. These findings supported the occurrence of recruitment from quiescent to proliferating state during fractionated irradiation. (author)

  8. 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.

  9. Knock-down of hypoxia-induced carbonic anhydrases IX and XII radiosensitizes tumor cells by increasing intracellular acidosis

    Directory of Open Access Journals (Sweden)

    Jérôme eDoyen

    2013-01-01

    Full Text Available The relationship between acidosis within the tumor microenvironment and radioresistance of hypoxic tumor cells remains unclear. Previously we reported that hypoxia-induced carbonic anhydrases CAIX and CAXII constitute a robust pHi-regulating system that confers a survival advantage on hypoxic human colon carcinoma LS174Tr cells in acidic microenvironments. Here we investigate the role of acidosis, CAIX and CAXII knock-down in combination with ionizing radiation. Fibroblasts cells (-/+ CAIX and LS174Tr cells (inducible knock-down for ca9/ca12 were analyzed for cell cycle phase distribution and survival after irradiation in extracellular pHo manipulations and hypoxia (1% O2 exposure. Radiotherapy was used to target ca9/ca12-silenced LS174Tr tumors grown in nude mice. We found that diminishing the pHi-regulating capacity of fibroblasts through inhibition of NHE-1 sensitize cells to radiation-induced cell death. Secondly, the pHi-regulating function of CAIX plays a key protective role in irradiated fibroblasts in an acidic environment as accompanied by a reduced number of cells in the radiosensitive phases of the cell cycle. Thirdly, we demonstrate that irradiation of LS174Tr spheroids, silenced for either ca9 or both ca9/ca12, showed a respective 50% and 75% increase in cell death as a result of a decrease in cell number in the radioresistant S phase and a disruption of CA-mediated pHi regulation. Finally, LS174Tr tumor progression was strongly decreased when ca9/ca12 silencing was combined with irradiation in vivo. These findings highlight the combinatory use of radiotherapy with targeting of the pHi-regulating carbonic anhydrases as an anti-cancer strategy.

  10. Histone deacetylase inhibitor, 2-propylpentanoic acid, increases the chemosensitivity and radiosensitivity of human glioma cell lines in vitro

    Institute of Scientific and Technical Information of China (English)

    SHAO Cui-jie; WU Ming-wei; CHEN Fu-rong; LI Cong; XIA Yun-fei; CHEN Zhong-ping

    2012-01-01

    Background Treatment for malignant glioma generally consists of cytoreductive surgery followed by radiotherapy and chemotherapy.In this study,we intended to investigate the effects of 2-propylpentanoic acid (VPA),a histone deacetylase inhibitor,on chemosensitivity and radiosensitivity in human glioma cell lines.Methods Human glioma cell lines,T98-G,and SF295,were treated with temozolomide (TMZ) or irradiation (IR),with or without VPA (1.0 mmol/L).Then,cytotoxicity and clonogenic survival assay was performed.Cell cycle stage,apoptosis,and autophagy were also detected using flow cytometry and dansyl monocadaverin (MDC) incorporation assay.One-way analysis of variance (ANOVA) and t-test were used to analyze the differences among variant groups.Results Mild cytotoxicity of VPA was revealed in both cell lines,T98-G and SF295,with the 50% inhibiting concentration (IC50) value of (3.85±0.58) mmol/L and (2.15±0.38) mmol/L,respectively; while the IC50 value of TMZ was (0.20±0.09) mmol/L for T98-G and (0.08±0.02) mmol/L for SF295.Moreover,if combined with VPA (1.0 mmol/L) for 96hours,the sensitivity of glioma cells to TMZ was significant increased (P <0.05).The surviving fractions at 2 Gy (SF2) of T98-G and SF295 cells exposed to IR alone were 0.52 and 0.58.However,when VPA was combined with IR,the SF2 of T98-G and SF295 dropped to 0.39 (P=0.047) and 0.49 (P=-0.049),respectively.Treatment with VPA plus TMZ or IR also resulted in a significant decrease in the proportion of cells in the G2 phase and increased apoptotic rates as well as autophagy in T98-G and SF295 cell lines (P <0.01).Conclusion VPA may enhance the activities of TMZ and IR on glioma cells possibly through cell cycle block and promote autophagy,and thus could be a potential sensitizer of glioma treatment.

  11. Chromosomes, cancer and radiosensitivity

    International Nuclear Information System (INIS)

    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

  12. Chromosomes, cancer and radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Samouhos, E.

    1983-08-01

    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.

  13. Increased radiosensitivity and radiothermosensitivity of human pancreatic MIA PaCa-2 and U251 glioblastoma cell lines treated with the novel Hsp90 inhibitor NVP-HSP990

    International Nuclear Information System (INIS)

    Heat shock Protein 90 (Hsp90) is a molecular chaperone that folds, stabilizes, and functionally regulates many cellular proteins involved in oncogenic signaling and in the regulation of radiosensitivity. It is upregulated in response to stress such a heat. Hyperthermia is a potent radiosensitizer, but induction of Hsp90 may potentially limit its efficacy. Our aim was to investigate whether the new Hsp90 inhibitor NVP-HSP990 increases radiosensitivity, thermosensitivity and radiothermosensitivity of human tumor cell lines. U251 glioblastoma and MIA PaCa-2 pancreatic carcinoma cells were used. To determine clonogenic survival, colony forming assays were performed. Cell viability and proliferation were assesed by Trypan blue staining. Cell cycle and apoptosis analyses were performed by flow cytometry. DAPI staining was used to detect mitotic catastrophe. NVP-HSP990 increased the thermosensitivity, radiosensitivity and radio-thermosensitivity of both cell lines in clonogenic assays. 72 hours after irradiation with 4 Gy, a significant reduction in cell number associated with considerable G2/M acumulation and mitotic catastrophe as well as cell death by apoptosis/necrosis was observed. Treatment with NVP-HSP990 strongly sensitized U251 and MIA PaCa-2 cells to hyperthermia and ionizing radiation or combination thereof through augmentation of G2/M arrest, mitotic catastrophe and associated apoptosis

  14. Radiosensitizing effects of perfluorochemicals

    Energy Technology Data Exchange (ETDEWEB)

    Hasegawa, Takeo; Harima, Keizo; Tanaka, Yoshimasa

    1988-10-01

    Malignant neoplasms are often refractory to radiotherapy because they contain areas of hypoxic cells that tolerate irradiation, reducing the effect of the treatment. If these areas of hypoxic cells can be oxygenated, the effect of radiotherapy is expected to be enhanced. Hyperbaric oxygen theray was devised in the 1950s, and the radiosensitizing agent Misonidazole was developed in 1970. However, neither produced satisfactory clinical effects in radiotherapy of tumors. In this study, hypoxic cells in a solid tumor were efficiency oxygenated by the use of perfluorochemicals (PFC) developed as artificial blood with carbogen gas (CG), and the anti-tumor effect of irradiation was enhanced. In C3H mice bearing RIF-1 tumor, the mean oxygen pressure increased to 79.8 mmHg in those treated with PFC and CG as compared with 12.9 mmHg in the controls, and the does modification factor in irradiation of these mice was TCD/sub 50/ 1.47. PFC is currently under clinical trials, and we also noted effective oxygenation of tumors. These findings indicate the usefulness of PFC as a radiosensitizing agent.

  15. Activation and increase of radio-sensitive CD11b+ recruited Kupffer cells/macrophages in diet-induced steatohepatitis in FGF5 deficient mice

    Science.gov (United States)

    Nakashima, Hiroyuki; Nakashima, Masahiro; Kinoshita, Manabu; Ikarashi, Masami; Miyazaki, Hiromi; Hanaka, Hiromi; Imaki, Junko; Seki, Shuhji

    2016-01-01

    We have recently reported that Kupffer cells consist of two subsets, radio-resistant resident CD68+ Kupffer cells and radio-sensitive recruited CD11b+ Kupffer cells/macrophages (Mφs). Non-alcoholic steatohepatitis (NASH) is characterized not only by hepatic steatosis but also chronic inflammation and fibrosis. In the present study, we investigated the immunological mechanism of diet-induced steatohepatitis in fibroblast growth factor 5 (FGF5) deficient mice. After consumption of a high fat diet (HFD) for 8 weeks, FGF5 null mice developed severe steatohepatitis and fibrosis resembling human NASH. F4/80+ Mφs which were both CD11b and CD68 positive accumulated in the liver. The production of TNF and FasL indicated that they are the pivotal effectors in this hepatitis. The weak phagocytic activity and lack of CRIg mRNA suggested that they were recruited Mφs. Intermittent exposure to 1 Gy irradiation markedly decreased these Mφs and dramatically inhibited liver inflammation without attenuating steatosis. However, depletion of the resident subset by clodronate liposome (c-lipo) treatment increased the Mφs and tended to exacerbate disease progression. Recruited CD11b+ CD68+ Kupffer cells/Mφs may play an essential role in steatohepatitis and fibrosis in FGF5 null mice fed with a HFD. Recruitment and activation of bone marrow derived Mφs is the key factor to develop steatohepatitis from simple steatosis. PMID:27708340

  16. Extracting the normal lung dose–response curve from clinical DVH data: a possible role for low dose hyper-radiosensitivity, increased radioresistance

    International Nuclear Information System (INIS)

    In conventionally fractionated radiation therapy for lung cancer, radiation pneumonitis’ (RP) dependence on the normal lung dose-volume histogram (DVH) is not well understood. Complication models alternatively make RP a function of a summary statistic, such as mean lung dose (MLD). This work searches over damage profiles, which quantify sub-volume damage as a function of dose. Profiles that achieve best RP predictive accuracy on a clinical dataset are hypothesized to approximate DVH dependence.Step function damage rate profiles R(D) are generated, having discrete steps at several dose points. A range of profiles is sampled by varying the step heights and dose point locations. Normal lung damage is the integral of R(D) with the cumulative DVH. Each profile is used in conjunction with a damage cutoff to predict grade 2 plus (G2+) RP for DVHs from a University of Michigan clinical trial dataset consisting of 89 CFRT patients, of which 17 were diagnosed with G2+ RP.Optimal profiles achieve a modest increase in predictive accuracy—erroneous RP predictions are reduced from 11 (using MLD) to 8. A novel result is that optimal profiles have a similar distinctive shape: enhanced damage contribution from low doses (<20 Gy), a flat contribution from doses in the range ∼20–40 Gy, then a further enhanced contribution from doses above 40 Gy. These features resemble the hyper-radiosensitivity / increased radioresistance (HRS/IRR) observed in some cell survival curves, which can be modeled using Joiner’s induced repair model.A novel search strategy is employed, which has the potential to estimate RP dependence on the normal lung DVH. When applied to a clinical dataset, identified profiles share a characteristic shape, which resembles HRS/IRR. This suggests that normal lung may have enhanced sensitivity to low doses, and that this sensitivity can affect RP risk. (paper)

  17. Neoplasms radiosensitivity: how to increase the efficiency of radiotherapy. Radiosensibilite des tumeurs: comment augmenter l'efficacite de la radiotherapie

    Energy Technology Data Exchange (ETDEWEB)

    Calais, G. (Hopital Bretonneau, 37 - Tours (FR))

    1991-12-01

    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.

  18. Increased radiosensitivity of HPV-positive head and neck cancer cell lines due to cell cycle dysregulation and induction of apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Arenz, Andrea; Ziemann, Frank; Wittig, Andrea; Preising, Stefanie; Engenhart-Cabillic, Rita [Philipps-University, Department of Radiotherapy and Radiooncology, BMFZ - Biomedical Research Center, Marburg (Germany); Mayer, Christina; Wagner, Steffen; Klussmann, Jens-Peter; Wittekindt, Claus [Justus Liebig University, Department of Otorhinolaryngology and Head and Neck Surgery, Giessen (Germany); Dreffke, Kirstin [Philipps-University, Institute for Radiobiology and Molecular Radiooncology, Marburg (Germany)

    2014-09-15

    Human Papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) respond favourably to radiotherapy as compared to HPV-unrelated HNSCC. We investigated DNA damage response in HPV-positive and HPV-negative HNSCC cell lines aiming to identify mechanisms, which illustrate reasons for the increased sensitivity of HPV-positive cancers of the oropharynx. Radiation response including clonogenic survival, apoptosis, DNA double-strand break (DSB) repair, and cell cycle redistribution in four HPV-positive (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) and four HPV-negative (UD-SCC-1, UM-SCC-6, UM-SCC-11b, UT-SCC-33) cell lines was evaluated. HPV-positive cells were more radiosensitive (mean SF2: 0.198 range: 0.22-0.18) than HPV-negative cells (mean SF2: 0.34, range: 0.45-0.27; p = 0.010). Irradiated HPV-positive cell lines progressed faster through S-phase showing a more distinct accumulation in G2/M. The abnormal cell cycle checkpoint activation was accompanied by a more pronounced increase of cell death after x-irradiation and a higher number of residual and unreleased DSBs. The enhanced responsiveness of HPV-related HNSCC to radiotherapy might be caused by a higher cellular radiosensitivity due to cell cycle dysregulation and impaired DNA DSB repair. (orig.) [German] Fuer Patienten mit HPV-assoziierten Kopf-Hals-Tumoren (HNSCC) ist im Vergleich zu Patienten mit nicht-HPV-assoziierten Tumoren ein besseres Ueberleben nach Radiotherapie gesichert. Ziel der Untersuchung war die Identifizierung von Unterschieden in der zellulaeren DNA-Schadensantwort von HPV-positiven und HPV-negativen Zelllinien, wodurch die bereits in Erprobung stehende Deeskalation einer Radiotherapie bei Patienten mit HPV-assoziierten HNSCC durch experimentelle Daten abgesichert werden koennte. Klonogenes Ueberleben, Induktion von Apoptose, DNA-Doppelstrang-Reparatur und Zellzyklusverhalten wurden in vier HPV-positiven (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) und vier HPV

  19. Preliminary report. Concomitant irradiation and paclitaxel as radiosensitizer to increase the operability of unresectable locally advanced breast cancer

    International Nuclear Information System (INIS)

    The objective of this non-randomized, single-arm pilot study was to investigate whether paclitaxel (50 mg/m2 body surface area) concomitantly administered with radiation (2 Gy/fr, total 50 Gy) could increase the operability of unresectable locally advanced breast cancer (LABC). Operability was assessed based on the Haagensen criteria, toxicity based on EORTC criteria, and response to therapy based on WHO criteria. Thus far 13 inoperable LABC patients have participated in the study as subjects in the treatment group, and 12 of the cases have been analyzable. As a result of radiopaclitaxel therapy, 10 of the 12 tumors became operable (>83%), and in 3 of the 10 patients there was no evidence of residual tumor. To date there have been no cases of local relapse in the treatment group. Given these results, the preliminary conclusions of the study are as follows: The results of radiochemotherapy, specifically with radiopaclitaxel, are quite promising as a method of treating inoperable LABC by reducing tumor size until it becomes operable. The efficacy and safety of the 50 mg/m2 body surface area dose of paclitaxel were adequate, allowing use of higher doses with the expectation of better results. The schedule of administration in this study yielded effective results. (K.H.)

  20. Radiosensitivity in ataxia-telangiectasia

    International Nuclear Information System (INIS)

    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

  1. 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

  2. ADPRT inhibitors and hyperthermia as radiosensitizers

    International Nuclear Information System (INIS)

    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)

  3. Simultaneous alteration of de novo and salvage pathway to the deoxynucleoside thriphosphate pool by (E)-2'-deoxy-(fluoromethylene)cytidine (FMDC) and zidovudine (AZT) results in increased radiosensitivity in vitro.

    OpenAIRE

    Coucke, Philippe; Cottin, Eliane; Laurent, A.; Decosterd, A.

    2007-01-01

    Abstract To test whether a thymidine analog zidovudine (=AZT), is able to modify the radiosensitizing effects of (E)-2'-Deoxy-(fluoromethylene)cytidine (FMdC). A human colon cancer cell line Widr was exposed for 48 hours prior to irradiation to FMdC. Zidovudine was added at various concentrations immediately before irradiation. We measured cell survival and the effect of FMdC, AZT and FMdC + AZT on deoxynucleotide triphosphate pool. FMdC results in a significant increase of radiosensitivit...

  4. Early increase of radiation-induced γH2AX foci in a human Ku70/80 knockdown cell line characterized by an enhanced radiosensitivity

    International Nuclear Information System (INIS)

    A better understanding of the underlying mechanisms of DNA repair after exposure to ionizing radiation represents a research priority aimed at improving the outcome of clinical radiotherapy. Because of the close association with DNA double strand break (DSB) repair, phosphorylation of the histone H2AX protein (γH2AX), quantified by immunodetection, has recently been used as a method to study DSB induction and repair at low and clinically relevant radiation doses. However, the lack of consistency in literature points to the need to further validate the role of H2AX phosphorylation in DSB repair and the use of this technique to determine intrinsic radiosensitivity. In the present study we used human mammary epithelial MCF10A cells, characterized by a radiosensitive phenotype due to reduced levels of the Ku70 and Ku80 repair proteins, and investigated whether this repair-deficient cell line displays differences in the phosphorylation pattern of H2AX protein compared to repair-proficient MCF10A cells. This was established by measuring formation and disappearance of γH2AX foci after irradiating synchronized cell populations with 60Co γ-rays. Our results show statistically significant differences in the number of γH2AX foci between the repair-deficient and -proficient cell line, with a higher amount of γH2AX foci present at early times post-irradiation in the Ku-deficient cell line. However, the disappearance of those differences at later post-irradiation times questions the use of this assay to determine intrinsic radiosensitivity, especially in a clinical setting. (author)

  5. On the radiosensitivity of man in space

    Science.gov (United States)

    Esposito, R. D.; Durante, M.; Gialanella, G.; Grossi, G.; Pugliese, M.; Scampoli, P.; Jones, T. D.

    Astronauts' radiation exposure limits are based on experimental and epidemiological data obtained on Earth. It is assumed that radiation sensitivity remains the same in the extraterrestrial space. However, human radiosensitivity is dependent upon the response of the hematopoietic tissue to the radiation insult. It is well known that the immune system is affected by microgravity. We have developed a mathematical model of radiation-induced myelopoiesis which includes the effect of microgravity on bone marrow kinetics. It is assumed that cellular radiosensitivity is not modified by the space environment, but repopulation rates of stem and stromal cells are reduced as a function of time in weightlessness. A realistic model of the space radiation environment, including the HZE component, is used to simulate the radiation damage. A dedicated computer code was written and applied to solar particle events and to the mission to Mars. The results suggest that altered myelopoiesis and lymphopoiesis in microgravity might increase human radiosensitivity in space.

  6. Age-dependent radiosensitivity of mouse oocytes

    Energy Technology Data Exchange (ETDEWEB)

    Koehler, C.

    1976-06-08

    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). (auth)

  7. Age-dependent radiosensitivity of mouse oocytes

    International Nuclear Information System (INIS)

    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)

  8. Radiosensitivity in plants

    International Nuclear Information System (INIS)

    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

  9. 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.

  10. Development of Radiosensitizer using farnesyltransferase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    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.

  11. Radiosensitivity and the clinician

    Energy Technology Data Exchange (ETDEWEB)

    1985-07-06

    The existence of differences in cellular radiosensitivity in individuals with different disorders has implications for the clinician from the points of view of diagnosis and therapy. Comments are made on the abnormal response of lymphocytes from patients with various disorders such as ataxia-telangiectasis, Friedreich's ataxia, familial retinoblastoma, multiple sclerosis, Rothmund-Thomson syndrome, tuberous sclerosis, Huntington's disease, and auto-immune diseases such as rheumatoid arthritis and polymyosotis. The possibility of using the variations in radiation response as a means of identification of A-T heterozygotes and Huntington's disease carriers is raised.

  12. Radiosensitizers action on Iodine 131 therapeutical effect

    International Nuclear Information System (INIS)

    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)

  13. Predictive radiosensitivity tests in human lymphocytes

    International Nuclear Information System (INIS)

    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

  14. Chromosomal radiosensitivity in common variable immune deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Vorechovsky, Igor (Karolinska Institute, Center for BioTechnology, Huddinge (Sweden)); Scott, David (Cancer Research Campaign Department of Cancer Genetics, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester (United Kingdom)); Haeney, Mansel R. (Department of Immunology, Hope Hospital, Salford (United Kingdom)); Webster, David A.B. (Clinical Research Centre, Northwick Park Hospital, Harrow, Middlesex (United Kingdom))

    1993-12-01

    From more than 500 tumours reported in human primary immune deficiencies a majority has been observed in two disorders: ataxia telangiectasia (A-T) and common variable immune deficiency (CVID). Since both diseases have an increased risk of lymphomas/leukaemias and gastrointestinal tumours, suggesting a common risk factor, and the cells derived from A-T patients exhibit an increased chromosomal radiosensitivity we analysed chromosome damage in the G[sub 2] lymphocytes of 24 CVID patients and 21 controls after X-irradiation in vitro. There was a significant difference in mean aberration yields between patients and controls. Three CVID patients had yields higher than the mean+3SD of the controls. Six patients but only one control had yields higher than the mean+2SD of controls. The patient with the highest chromosomal radiosensitivity subsequently developed a lymphoma. Repeat assays on the same blood sample, with a 24-h delay in setting up the second culture, showed as much variability for control donors as the variation between control donors although for CVID patients inter-individual variation was greater than the difference between results of repeat samples. There was a weak positive correlation between radiosensitivity and age of donor. Chromosomal radiosensitivity of five patients with X-linked hypogammaglobulinaemia was not different from healthy donors. The mean mitotic index (MI) for unirradiated samples from CVID patients was significantly lower than for controls and there was an inverse relationship between MI and aberration yields in the patients, but not in controls. We suggest that the defect in CVID patients that reduces response to mitogenic stimuli may have mechanism(s) in common with those involved in cellular repair processes.

  15. Differential radiosensitivity among B cell subpopulations

    Energy Technology Data Exchange (ETDEWEB)

    Riggs, J.E.; Lussier, A.M.; Lee, S.K.; Appel, M.C.; Woodland, R.T.

    1988-09-15

    We have previously shown that low doses of ionizing radiation selectively impair a functionally defined B cell subpopulation. Normal mice, after exposure to 200 rad of ionizing radiation, have normal or near normal splenic plaque-forming cell responses to thymus-independent type 1 Ag, but reduced responses to thymus-independent type 2 Ag. Here, we confirm and extend the original findings by using hapten-specific serum RIA to demonstrate this differential radiosensitivity is systemic. We also examined splenocytes stained with a panel of lymphocyte surface Ag by FACS analysis to determine if these functional changes are accompanied by a physical alteration of the B cell pool of irradiated mice. Single-parameter FACS analyses demonstrate a diminution in both B cell number and the heterogeneity of membrane Ag expression within the surviving B cell pool after irradiation. In contrast, T cells are relatively radioresistant as the relative percentage of T cells in the irradiated splenocyte pool increases, whereas the heterogeneity of membrane Ag expression remains constant. Multiparameter FACS analyses indicate that B cells with the sIgM much greater than sIgD phenotype are more radiosensitive than B cells of the sIgM much less than sIgD phenotype. In addition, immunohistochemical analysis of splenic sections stained with anti-IgM or anti-IgD reveal the enhanced radiosensitivity of marginal zone B cells.

  16. Thiols and radiosensitivity

    International Nuclear Information System (INIS)

    The role played by non-protein (NPSH) and protein sulfhydryls (PSH) in hypoxic and aerated cell radiosensitivity was investigated using human skin fibroblasts derived from patients affected with 5-oxoprolinuria. These cells have lowered levels of the enzyme GSH-synthetase which results in a decreased concentration of glutathione. Six cell lines were studied; GM3877 and GM3878, SR and SUR from a single family and OB and AB from a French family. Only GM3877, with GSH levels of 0.6 nmoles/mg protein and NPSH levels of 4 nmoles/mg protein, was found to exhibit a reduced OER of 1.8. Experiments are now in progress to investigate the effect of depleting thiol levels with the ∫-glutamyl cysteine synthetase inhibitor DL Buthionine-SR-sulfoximine to determine if the OER is further reduced, especially in the cell line which already has a lowered OER. The results are discussed with a view toward developing a model which takes into account the role of thiols and DNA repair processes in the resistance of hypoxic cells to ionizing radiation

  17. Individual radiosensitivity, its mechanisms and manifestations

    International Nuclear Information System (INIS)

    Considerable differences exist in radiosensitivity between individuals of the same species. Radiation damage to the organism may be influenced by the immediate state of its physiological functions. A survey is given of the radiosensitivity of cells, cell systems and their role in radiation damage of the organism. Other factors influencing the radiosensitivity of the organism are metabolic processes, biological rhythms and the age of the individual. Radiosensitivity is polyfactorially conditioned and is controlled either by genetic or by peristatic factors. (E.S.)

  18. A comprehensive analysis of radiosensitization targets; functional inhibition of DNA methyltransferase 3B radiosensitizes by disrupting DNA damage regulation.

    Science.gov (United States)

    Fujimori, Hiroaki; Sato, Akira; Kikuhara, Sota; Wang, Junhui; Hirai, Takahisa; Sasaki, Yuka; Murakami, Yasufumi; Okayasu, Ryuichi; Masutani, Mitsuko

    2015-01-01

    A comprehensive genome-wide screen of radiosensitization targets in HeLa cells was performed using a shRNA-library/functional cluster analysis and DNMT3B was identified as a candidate target. DNMT3B RNAi increased the sensitivity of HeLa, A549 and HCT116 cells to both γ-irradiation and carbon-ion beam irradiation. DNMT3B RNAi reduced the activation of DNA damage responses induced by γ-irradiation, including HP1β-, γH2AX- and Rad51-foci formation. DNMT3B RNAi impaired damage-dependent H2AX accumulation and showed a reduced level of γH2AX induction after γ-irradiation. DNMT3B interacted with HP1β in non-irradiated conditions, whereas irradiation abrogated the DNMT3B/HP1β complex but induced interaction between DNMT3B and H2AX. Consistent with radiosensitization, TP63, BAX, PUMA and NOXA expression was induced after γ-irradiation in DNMT3B knockdown cells. Together with the observation that H2AX overexpression canceled radiosensitization by DNMT3B RNAi, these results suggest that DNMT3B RNAi induced radiosensitization through impairment of damage-dependent HP1β foci formation and efficient γH2AX-induction mechanisms including H2AX accumulation. Enhanced radiosensitivity by DNMT3B RNAi was also observed in a tumor xenograft model. Taken together, the current study implies that comprehensive screening accompanied by a cluster analysis enabled the identification of radiosensitization targets. Downregulation of DNMT3B, one of the targets identified using this method, radiosensitizes cancer cells by disturbing multiple DNA damage responses. PMID:26667181

  19. Radiosensitivity studies in basmati rice

    International Nuclear Information System (INIS)

    Three Basmati rice varieties (Basmati 370, Basmati Pak, and Super Basmati)were used to examine varietals differences in radiosensitivity to gamma radiation. Dry seeds of rice varieties were exposed to 150, 200, 250 and 300 Gy of gamma rays. Sensitivity to dose was determined by various measurements on the M1 generation and on the basis of frequency of various types of chlorophyll mutations obtained in the M2 generation. With the increase in radiation dose a decrease in germination, seedling height, root length and emergence under field conditions was observed in M1 generation. In contrast,the gamma rays doses had some stimulatory effects on total spike lets at the maturity stage. These effects were observed in all the gamma radiation treatments in case of Basmati 370 where total spike lets increased above the non-irradiated control. Plant height and seed fertility decreased with increase in gamma radiation dose in an approximately linear fashion. The LD50 values for seed fertility were 238, 232 and 223 Gy for Basmati 370, Basmati Pak and Super Basmati, respectively. The effectiveness of the dose in inducing genetical changes was estimated by counting the number of chlorophyll mutations in the M2 generation. The frequency of chlorophyll mutations increased with the radiation dosage up to 250 Gy which sharply decreased thereafter. Gamma ray dose of 200 and 250 Gy produced the highest mutation frequency for Basmati 370 followed by Basmati Pak and Super Basmati. The albina type of mutation was most frequent in all the three varieties

  20. 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...

  1. Synthesis and radiosensitization properties of hydrogen peroxide and sodium hyaluronate complex

    Energy Technology Data Exchange (ETDEWEB)

    Rosli, Nur Ratasha Alia Md.; Mohamed, Faizal; Heng, Cheong Kai; Rahman, Irman Abdul; Ahmad, Ainee Fatimah; Mohamad, Hur Munawar Kabir [School of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM, Bangi, Selangor (Malaysia)

    2014-09-03

    Cancer cells which are large in size are resistant towards radiation therapy due to the presence of large amount of anti-oxidative enzymes and hypoxic cancer cells. Thus radiosensitizer agents have been developed to enhance the therapeutic effect of radiotherapy by increasing the sensitivity of these cancer cells towards radiation. This study is conducted to investigate the radiosensitization properties of radiosensitizer complex containing hydrogen peroxide and sodium hyaluronate. Combination with sodium hyaluronate may decrease reactivity of hydrogen peroxide but maintain the oxygen concentration needed for radiosensitizing effect. HepG2 cancer cells are cultured as the mean of test subject. Cancer cell samples which are targeted and not targeted with these radiosensitizers are irradiated with 2Gy single fractionated dose. Results obtained shows that the cancer cells which are not targeted with radiosensitizers has a cell viability of 98.80±0.37% after a time interval of 48 hours and has even repopulated over 100% after a 72 hour time interval. This shows that the cancer cells are resistant towards radiation. However, when the cancer cells are targeted with radiosensitizers prior to irradiation, there is a reduction of cell viability by 25.50±10.81% and 10.30±5.10% at time intervals of 48 and 72 hours respectively. This indicates that through the use of these radiosensitizers, cancer cells are more sensitive towards radiation.

  2. Synthesis and radiosensitization properties of hydrogen peroxide and sodium hyaluronate complex

    Science.gov (United States)

    Rosli, Nur Ratasha Alia Md.; Mohamed, Faizal; Heng, Cheong Kai; Rahman, Irman Abdul; Ahmad, Ainee Fatimah; Mohamad, Hur Munawar Kabir

    2014-09-01

    Cancer cells which are large in size are resistant towards radiation therapy due to the presence of large amount of anti-oxidative enzymes and hypoxic cancer cells. Thus radiosensitizer agents have been developed to enhance the therapeutic effect of radiotherapy by increasing the sensitivity of these cancer cells towards radiation. This study is conducted to investigate the radiosensitization properties of radiosensitizer complex containing hydrogen peroxide and sodium hyaluronate. Combination with sodium hyaluronate may decrease reactivity of hydrogen peroxide but maintain the oxygen concentration needed for radiosensitizing effect. HepG2 cancer cells are cultured as the mean of test subject. Cancer cell samples which are targeted and not targeted with these radiosensitizers are irradiated with 2Gy single fractionated dose. Results obtained shows that the cancer cells which are not targeted with radiosensitizers has a cell viability of 98.80±0.37% after a time interval of 48 hours and has even repopulated over 100% after a 72 hour time interval. This shows that the cancer cells are resistant towards radiation. However, when the cancer cells are targeted with radiosensitizers prior to irradiation, there is a reduction of cell viability by 25.50±10.81% and 10.30±5.10% at time intervals of 48 and 72 hours respectively. This indicates that through the use of these radiosensitizers, cancer cells are more sensitive towards radiation.

  3. Relation of age to lymphocyte radiosensitivity in vitro

    International Nuclear Information System (INIS)

    Lymphocytes from one-year old children were significantly more sensitive to in vitro X-irradiation than those from adults as measured by Con-A-stimulated tritiated thymidine incorporation in a whole blood lymphocyte stimulation test (LST). No significant difference in the radiosensitivity of the PHA response was observed between the two groups in either the LST or colony formation assay. The increased radiosensitivity and poor colony formation of Con-A-responding lymphocytes from the one-year old children may reflect differences in functional maturational differentiation of lymphocyte subpopulations as compared to those of the adult population

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

    International Nuclear Information System (INIS)

    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)

  5. Membrane specific drugs as radiosensitizers

    Energy Technology Data Exchange (ETDEWEB)

    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)

  6. Radiosensitization by cisplatin of RIF1 tumour cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Begg, A.C.; Kolk, P.J. van der; Dewit, L.; Bartelink, H.

    1986-11-01

    The ability of cis-diamminedichloroplatinum (II) (c-DDP) to enhance radiation-induced cell killing was tested on oxic RIF1 tumour cells in monolayer culture. Marked radiosensitization of the survivors of a 1 h drug treatment was found with all c-DDP doses tested, enhancement ratios increasing from 1.2 to 2.2 with increasing drug dose. Isobologram analyses showed that the interactions of c-DDP with X-rays were supra-additive. To test whether part of the enhancement was due to a selection of subpopulations, the diploid and tetraploid RIF1 cells, normally coexisting in culture, were separated by (a) unit gravity velocity sedimentation, and (b) by developing diploid and tetraploid clones. Both methods showed little difference in either drug sensitivity or radiation sensitivity between diploid and tetraploid cells. DNA histograms obtained by flow cytometry showed little or no cycle progression during the 1 h drug treatment. These data indicate that the radiosensitization was not the result of the drug exposure leaving cells in a radiosensitive phase. The observed radiosensitization, therefore, appears to have resulted from a true drug/X-ray interaction.

  7. Proteomics of protein expression profiling in tissues with different radiosensitivity

    International Nuclear Information System (INIS)

    The purpose of this study was to identify Radiosensitivity of proteins in tissues with different radiosensitivity. C3H/HeJ mice were exposed to 10 Gy. The mice were sacrifiud 8 hrs after radiation. Their spleen and liver tissues were collected and analyzed histologically for apoptosis. The expressions of radiosusceptibility protein were analyzed by 2-dimensional electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The peak of apoptosis levels were 35.3 ± 1.7% in spleen and 0.6 ± 0.2% in liver at 8 hrs after radiation. Liver, radioresistant tissues, showed that the levels of ROS metabolism related to proteins such as cytochromm c, glutathione S transferase, NADH dehydrogenase, riken cDNA and peroxiredoxin VI increased after radiation. The expression of cytochrome c increased significantly in spleen and liver tissues after radiation. In spleen, radiosensitivity tissue, the identified proteins showed a significantly quantitative alteration following radiation. It was categorized as signal transduction, apoptosis, cytokine, Ca signal related protein, stress-related protein, cytoskeletal regulation, ROS metabolism, and others. Differences of radiation-induced apoptosis by tissues specifted were coupled with the induction of related radiosensitivity and radioresistant proteins. The result suggests that apoptosis relate protein and redox proteins play important roles in this radiosusceptibility

  8. ATM-mediated Snail Serine 100 phosphorylation regulates cellular radiosensitivity

    International Nuclear Information System (INIS)

    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

  9. Radiosensitivity of lymphocytes among Filipinos: final report

    International Nuclear Information System (INIS)

    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

  10. Radiosensitizing Effect of TRPV1 Channel Inhibitors in Cancer Cells.

    Science.gov (United States)

    Nishino, Keisuke; Tanamachi, Keisuke; Nakanishi, Yuto; Ide, Shunta; Kojima, Shuji; Tanuma, Sei-Ichi; Tsukimoto, Mitsutoshi

    2016-07-01

    Radiosensitizers are used in cancer therapy to increase the γ-irradiation susceptibility of cancer cells, including radioresistant hypoxic cancer cells within solid tumors, so that radiotherapy can be applied at doses sufficiently low to minimize damage to adjacent normal tissues. Radiation-induced DNA damage is repaired by multiple repair systems, and therefore these systems are potential targets for radiosensitizers. We recently reported that the transient receptor potential vanilloid type 1 (TRPV1) channel is involved in early responses to DNA damage after γ-irradiation of human lung adenocarcinoma A549 cells. Therefore, we hypothesized that TRPV1 channel inhibitors would have a radiosensitizing effect by blocking repair of radiation-induced cell damage. Here, we show that pretreatment of A549 cells with the TRPV1 channel inhibitors capsazepine, AMG9810, SB366791 and BCTC suppressed the γ-ray-induced activation of early DNA damage responses, i.e., activation of the protein kinase ataxia-telangiectasia mutated (ATM) and accumulation of p53-binding protein 1 (53BP1). Further, the decrease of survival fraction at one week after γ-irradiation (2.0 Gy) was enhanced by pretreatment of cells with these inhibitors. On the other hand, inhibitor pretreatment did not affect cell viability, the number of apoptotic or necrotic cells, or DNA synthesis at 24 h after irradiation. These results suggest that inhibition of DNA repair by TRPV1 channel inhibitors in irradiated A549 cells caused gradual loss of proliferative ability, rather than acute facilitation of apoptosis or necrosis. TRPV1 channel inhibitors could be novel candidates for radiosensitizers to improve the efficacy of radiation therapy, either alone or in combination with other types of radiosensitizers. PMID:27150432

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

    International Nuclear Information System (INIS)

    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

  12. Radiosensitivity of mesothelioma cell lines

    International Nuclear Information System (INIS)

    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 (DMID) 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.)

  13. Chronic anaemia, hyperbaric oxygen and tumour radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    McCormack, M.; Nias, A.H.W.; Smith, Eileen (Saint Thomas' Hospital, London (UK). Richard Dimbleby Research Lab.)

    1990-10-01

    The present study examined the relationship between anaemia and tumour response to radiation given in air or HPO in C{sub 3}H mice transplanted with a mammary adenocarcinoma using a growth delay assay to assess radiation response. Radiation studies with these anaemic mice demonstrated that the tumour radiosensitivity was decreased when treatment was given in air. HPO was successful in overcoming the increased radioresistance associated with anaemia. This result suggested that tumours grown in anaemic mice have a higher hypoxic fraction than those grown in control mice. Changes in host physiology with chronic anaemia may contribute to the benefit seen with HPO but such alterations per se may be inadequate to maintain tumour oxygenation when treatment is given in air. (author).

  14. Andrographolide radiosensitizes human ovarian cancer SKOV3 xenografts due to an enhanced apoptosis and autophagy.

    Science.gov (United States)

    Zhang, Chao; Qiu, Xingsheng

    2015-11-01

    Andrographolide (AND), a diterpenoid lactone isolated from Andrographis paniculata, has been shown to have radiosensitivity in several types of cancer. Whether AND can radiosensitize ovarian cancer remains unknown. The present study investigated the radiosensitizing effects of AND in human ovarian SKOV3 xenografts and examined the molecular mechanisms of AND-mediated radiosensitization. Nude mice bearing human ovarian SKOV3 were treated with AND to investigate the effects of drug administration on tumor growth, radiosensitivity, apoptosis, and autophagy. Subsequent Western blot analysis and monodansylcadaverine (MDC) staining (autophagy analysis) were used to determine the role of AND. Finally, the pathway of apoptosis was characterized by caspase-3 activity assay as well as TUNEL analysis. AND potently sensitized SKOV3 xenografts to radiation. Moreover, apoptosis and autophagy in radiation combined with drug-treated xenografts increased significantly compared with the simple drug or single radiation treatment. This result was associated with an increase in the Bax/Bcl-2 protein ratio and p-p53 expression after exposure to combination treatment. Meanwhile, the level of Beclin 1 and Atg5 and the conversion from LC3-I to LC3-II, three important proteins involved in autophagy, were increased. AND acts as a strong radiosensitizer in human ovarian SKOV3 xenografts in vivo by increasing the Bax/Bcl-2 protein ratio and promoting the activation of caspase-3, leading to enhanced apoptosis as well as autophagy. PMID:26014516

  15. Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Xiaopeng; Du, Jie; Hua, Song; Zhang, Haowen; Gu, Cheng; Wang, Jie; Yang, Lei; Huang, Jianfeng; Yu, Jiahua, E-mail: yujiahua@suda.edu.cn; Liu, Fenju, E-mail: fangsh@suda.edu.cn

    2015-01-15

    Radiotherapy is an essential component of the standard therapy for newly diagnosed glioblastoma. To increase the radiosensitivity of glioma cells is a feasible solution to improve the therapeutic effects. It has been suggested that inhibition of signal transducer and activator of transcription 3 (STAT3) can radiosensitize glioma cells, probably via the activation of mitochondrial apoptotic pathway. In this study, human malignant glioma cells, U251 and A172, were treated with an STAT3 inhibitor, WP1066, or a short hairpin RNA plasmid targeting STAT3 to suppress the activation of STAT3 signaling. The radiosensitizing effects of STAT3 inhibition were confirmed in glioma cells. Intriguingly, combination of ionizing radiation exposure and STAT3 inhibition triggered a pronounced increase of autophagy flux. To explore the role of autophagy, glioma cells were treated with 3-methyladenine or siRNA for autophagy-related gene 5, and it was demonstrated that inhibition of autophagy further strengthened the radiosensitizing effects of STAT3 inhibition. Accordingly, more apoptotic cells were induced by the dual inhibition of autophagy and STAT3 signaling. In conclusion, our data revealed a protective role of autophagy in the radiosensitizing effects of STAT3 inhibition, and inhibition of both autophagy and STAT3 might be a potential therapeutic strategy to increase the radiosensitivity of glioma cells. - Highlights: • Inactivation of STAT3 signaling radiosensitizes malignant glioma cells. • STAT3 inhibition triggers a significant increase of autophagy flux induced by ionizing radiation in glioma cells. • Suppression of autophagy further strengthens the radiosensitizing effects of STAT3 inhibition in glioma cells. • Dual inhibition of autophagy and STAT3 induce massive apoptotic cells upon exposure to ionizing radiation.

  16. Telomeres: Hallmarks of radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Ayouaz, A.; Raynaud, C.; Heride, C.; Revaud, D.; Sabatier, L. [CEA, DSV, IRCM/SRO, F-92265 Fontenay Aux Roses (France)

    2008-07-01

    Telomeres are the very ends of the chromosomes. They can be seen as natural double-strand breaks (DSB), specialized structures which prevent DSB repair and activation of DNA damage checkpoints. In somatic cells, attrition of telomeres occurs after each cell division until replicative senescence. In the absence of telomerase, telomeres shorten due to incomplete replication of the lagging strand at the very end of chromosome termini. Moreover, oxidative stress and accumulating reactive oxygen species (ROS) lead to an increased telomere shortening due to a less efficient repair of SSB in telomeres. The specialized structures at telomeres include proteins involved in both telomere maintenance and DNA repair. However when a telomere is damaged and has to be repaired, those proteins might fail to perform an accurate repair of the damage.This is the starting point of this article in which we first summarize the well-established relationships between DNA repair processes and maintenance of functional telomeres. We then examine how damaged telomeres would be processed, and show that irradiation alters telomere maintenance leading to possibly dramatic consequences. Our point is to suggest that those consequences are not restricted to the short term effects such as increased radiation-induced cell death. On the contrary, we postulate that the major impact of the loss of telomere integrity might occur in the long term, during multistep carcinogenesis. Its major role would be to act as an amplifying event unmasking in one single step recessive radiation-induced mutations among thousands of genes and providing cellular proliferative advantage. Moreover, the chromosomal instability generated by damaged telomeres will favour each step of the transformation from normal to fully transformed cells. (authors)

  17. Ganetespib radiosensitization for liver cancer therapy

    Science.gov (United States)

    Chettiar, Sivarajan T.; Malek, Reem; Annadanam, Anvesh; Nugent, Katriana M.; Kato, Yoshinori; Wang, Hailun; Cades, Jessica A.; Taparra, Kekoa; Belcaid, Zineb; Ballew, Matthew; Manmiller, Sarah; Proia, David; Lim, Michael; Anders, Robert A.; Herman, Joseph M.; Tran, Phuoc T.

    2016-01-01

    ABSTRACT Therapies for liver cancer particularly those including radiation are still inadequate. Inhibiting the stress response machinery is an appealing anti-cancer and radiosensitizing therapeutic strategy. Heat-shock-protein-90 (HSP90) is a molecular chaperone that is a prominent effector of the stress response machinery and is overexpressed in liver cancer cells. HSP90 client proteins include critical components of pathways implicated in liver cancer cell survival and radioresistance. The effects of a novel non-geldanamycin HSP90 inhibitor, ganetespib, combined with radiation were examined on 3 liver cancer cell lines, Hep3b, HepG2 and HUH7, using in vitro assays for clonogenic survival, apoptosis, cell cycle distribution, γH2AX foci kinetics and client protein expression in pathways important for liver cancer survival and radioresistance. We then evaluated tumor growth delay and effects of the combined ganetespib-radiation treatment on tumor cell proliferation in a HepG2 hind-flank tumor graft model. Nanomolar levels of ganetespib alone exhibited liver cancer cell anti-cancer activity in vitro as shown by decreased clonogenic survival that was associated with increased apoptotic cell death, prominent G2-M arrest and marked changes in PI3K/AKT/mTOR and RAS/MAPK client protein activity. Ganetespib caused a supra-additive radiosensitization in all liver cancer cell lines at low nanomolar doses with enhancement ratios between 1.33–1.78. These results were confirmed in vivo, where the ganetespib-radiation combination therapy produced supra-additive tumor growth delay compared with either therapy by itself in HepG2 tumor grafts. Our data suggest that combined ganetespib-radiation therapy exhibits promising activity against liver cancer cells, which should be investigated in clinical studies. PMID:26980196

  18. The radiosensitivity of nile tilapia (Oreochromis niloticus) fingerlings

    International Nuclear Information System (INIS)

    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 dosage50 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)

  19. [Cisplatin influence on: the radiosensitivity and recovery of yeast cells].

    Science.gov (United States)

    2013-01-01

    The effect of the simultaneous combined action of ionizing radiation and cisplatin on the radiosensitivity and liquid holding recovery (LHR) of diploid yeast cells was studied. It was shown that regardless of the cisplatin concentration (0; 0.002; 0.01; 0.02 g/ml) the radiosensitivity of cells was increased by 1.3 times. The ability of a cell to the LHR was progressively decreased with the increasing cisplatin concentration up to the complete inhibition. It was shown that the LHR of yeast cells after a combined action of ionizing radiation and chemical agents is mainly inhibited due to formation of a greater proportion of irreversible damage. The con- stant of recovery, characterizing the probability of recovery per a unit of time, was independent on cisplatine concentration. PMID:25508873

  20. Non-genetic phenomenons of radiosensitivity

    International Nuclear Information System (INIS)

    Transcription factors are activated by radiation induced DNA damage. This is followed by cell cycle regulation (cell cycle blocks and DNA repair), which influence radiosensitivity. This phenomenon is seen as a genetic effect. Proteins as transcription factors (e.g. NF-κB) are directly activated by ionizing radiation, genes coding for cytokines and growth factors are expressed and influence the radiosensitivity. Damage of the cell membrane also induces signal transduction cascades and activates genes via transcription factors, which influence radiosensitivity. The latter two phenomenons are described as non genetics and will get more and more importance in He radiobiology. (orig.)

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

    OpenAIRE

    Čemažar, Maja; Grošel, Alenka; Kranjc, Simona; Pipan, Živa; Serša, Gregor

    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 ontwo 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-modalitytreatment consisting of cisplatin, ele...

  2. In vitro study of dopaminergic central neurons radiosensitivity

    International Nuclear Information System (INIS)

    An embryonic mesencephalic neuronal culture model was used to analyze the radiosensitivity of a dopaminergic neuronal population. Several criteria have allowed to evaluate the effects of a gamma irradiation. In the order of increasing sensitivity, a reduction of the dopamine uptake, a decrease of the number of differentiated dopaminergic neurons and some modifications of the size and the degree of branching or the neurites were noted. These results are preliminary and have to be confirmed

  3. Predisposition to cancer and radiosensitivity

    Directory of Open Access Journals (Sweden)

    P. Pichierri

    2000-12-01

    Full Text Available 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, micronucleous and G2 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 G2 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 G2 homogeneous cell populations. Cells irradiated are immediately challenged with medium containing bromodeoxyuridine (BrdUrd. Then cells are sampled at different post-irradiation times and BrdUrd 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 G2 chromosomal assay.Muitas doenças que predispõem ao câncer têm se mostrado radiossensíveis. A radiossensibilidade tem sido atribuída a problemas nos mecanismos de reparo de lesões de DNA induzidas ou a uma resposta alterada no "checkpoint" do ciclo celular. Embora existam discrepâncias entre os resultados obtidos por vários autores quanto à radiossensibilidade de indivíduos afetados pela mesma doença, essas discrepâncias podem ser atribuídas à grande variabilidade observada já na resposta de indivíduos normais à radia

  4. Growth and radiosensitivity of irradiated human glioma cell progeny

    Institute of Scientific and Technical Information of China (English)

    Chao Li; Li Li; Changshao Xu; Juying Zhou

    2008-01-01

    BACKGROUND: Progenitors of the immortalized human glioma cell line, SHG-44, are significantly less sensitive to irradiation. Two hypotheses regarding the mechanism of this effect exist: several studies have suggested that there is a subgroup with different radiosensitivities in identical cell group, and the progenitors of irradiate is a adaptive response subgroup, so its radiosensitivity is descend. A second hypothesis suggests that irradiated glioma progeny have a stronger ability to repair DNA damage. This would suggest that when progeny are continuously irradiated, resistance to irradiation-induced DNA increases, and radiosensitivity decreases.OBJECTIVE: To investigate radiosensitivity and growth features after irradiation to progeny of the human glioma cell line SHG-44.DESIGN, TIME AND SETTING: A randomized, controlled experiment, which was performed at the Department of Radiology Laboratory, the First Hospital Affiliated to Soochow University, between September 2004 and January 2006.MATERIALS: The glioma cell line SHG-44 was provided by the Institute of Neuroscience, First Affiliated Hospital of Suzhou University. Propidium iodide reagent was provided by Coulter Corporation. A linear accelerator, KD-2 type, was provided by Siemens, Germany. The flow cytometer EPICS-XL was provided by Coulter Corporation.METHODS: Brain glioma SHG-44 cells were divided into four groups: SHG-44, SHG-44-2, SHG-44-6, and SHG-44-10. The SHG-44-2, SHG-44-6, and SHG-44-10 cells were vertically irradiated with varying doses of 2,6 and 10 Gy by a linear accelerator (6 MVX). The cells were passaged for 15 generations and cultured in RPMI-1640 culture media.MAIN OUTCOME MEASURES: Community re-double time, mean lethal dose (D0), extrapolation number (N), fraction surviving fraction irradiated by 2 Gy dose (SF2), quasi-threshold dose (Dq), and cell cycle.RESULTS: The Population doubling time (PDT) of SHG-44-2, SHG-44-6, and SHG-44-10 cell groups was not significant (P=0.052). Compared to

  5. NASOPHARYNGEAL CARCINOMA RADIOSENSITIVITY PREDICTION BY CYTOKINESIS—BLOCK MICRONUCLEUS ASSAY

    Institute of Scientific and Technical Information of China (English)

    杨星; 史剑慧; 等

    1995-01-01

    Cytokinesis-block micronucleus method is used to evaluate the radiosensityvity of a nasopharyngeal carcinoma cell line(CNE-1) and biopsies obtained from 31 patients with nasopharyngeal carcinoma,The number of micronuclei increases with the radiation dose.A good correlation was found between the radiosensitivity determined by the micro-nucleus assay and that measured by the colony-forming assay in CNE-1 cell line(r=-0.998).Moreover,the results of micronucleus assay for tumor cells from biopsies of patients with primary carcinoma look promising for the prediction of tumor radiosensitivity.These results are encouraging but need to be confirmed with a larger number of patients with a longer follow-up.

  6. Radiosensitivity of hepatocellular carcinoma; Radiosensibilite des cancers du foie

    Energy Technology Data Exchange (ETDEWEB)

    Hennequin, C.; Quero, L.; Rivera, S. [Service de cancerologie-radiotherapie, hopital Saint-Louis, 1, avenue Claude-Vellefeaux, 75475 Paris (France)

    2011-02-15

    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 {alpha}/{beta} 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)

  7. 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.

  8. 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

  9. Radiosensitivity of human colon cancer cell enhanced by immunoliposomal docetaxel

    Institute of Scientific and Technical Information of China (English)

    Qing-Wei Wang; Hui-Lan Lü; Chang-Cheng Song; Hong Liu; Cong-Gao Xu

    2005-01-01

    AIM: To enhance the radiosensitivity of human colon cancer cells by docetaxel.METHODS: Immunoliposomal docetaxel was prepared by coupling monodonal antibody against carcinoembryonic antigen to cyanuric chloride at the PEG terminus of liposome. LoVo adenocarcinoma cell line was treated with immunoliposomal docetaxel or/and irradiation. MTT colorimetric assay was used to estimate cytotoxicity of immunoliposomal docetaxel and radiotoxicity. Cell cycle redistribution and apoptosis were determined with flow cytometry. Survivin expression in LoVo cells was verified by immunohistochemistry. D801 morphologic analysis system was used to semi-quantify immunohistochemical staining of survivin.RESULTS: Cytotoxicity was induced by immunoliposomal docetaxel alone in a dose-dependent manner. Immunoliposomal docetaxel yielded a cytotoxicity effect at a low dose of 2 nmol/L. With a single dose irradiation, the relative surviving fraction of LoVo cells showed a dosedependent response, but there were no significant changes as radiation delivered from 4 to 8 Gy. Compared with liposomal docetaxel or single dose irradiation,strongly radiopotentiating effects of immunoliposomal docetaxel on LoVo cells were observed. A low dose of immunoliposomal docetaxel could yield sufficient radiosensitivity. Immunoliposomal docetaxel were achieved both specificity of the conjugated antibody and drug radiosensitization. Combined with radiation,immunoliposomal docetaxel significantly increased the percentage of G2/M cells and induced apoptosis, but significantly decreased the percentage of cells in G2/G1 and S phase by comparison with liposomal docetaxel.Immunohistochemical analysis showed that the brown stained survivin was mainly in cytoplasm of LoVo cells.Semi-quantitative analysis of the survivin immunostaining showed that the expression of survivin in LoVo cells under irradiation with immunoliposomal docetaxel was significantly decreased.CONCLUSION: Immunoliposomal docetaxel is strongly effective

  10. Repurposing cephalosporin antibiotics as pro-senescent radiosensitizers.

    Science.gov (United States)

    Labay, Edwardine; Mauceri, Helena J; Efimova, Elena V; Flor, Amy C; Sutton, Harold G; Kron, Stephen J; Weichselbaum, Ralph R

    2016-06-01

    Radiation therapy remains a significant therapeutic modality in the treatment of cancer. An attractive strategy would be to enhance the benefits of ionizing radiation (IR)with radiosensitizers. A high-content drug repurposing screen of approved and investigational agents, natural products and other small molecules has identified multiple candidates that blocked repair of IR damage in vitro. Here, we validated a subset of these hits in vitro and then examined effects on tumor growth after IR in a murine tumor model. Based on robust radiosensitization in vivo and other favorable properties of cephalexin, we conducted additional studies with other beta-lactam antibiotics. When combined with IR, each cephalosporin tested increased DNA damage and slowed tumor growth without affecting normal tissue toxicity. Our data implicate reactive oxygen species in the mechanism by which cephalosporins augment the effects of IR. This work provides a rationale for using commonly prescribed beta-lactam antibiotics as non-toxic radiosensitizers to enhance the therapeutic ratio of radiotherapy. PMID:27129153

  11. Radio-sensitivity of the LEC rat

    International Nuclear Information System (INIS)

    Full text: The LEC rat is known to be a mutant strain which spontaneously develops heritable hepatitis due to copper accumulation, caused by mutation of the copper transporting ATPase gene (Atp7b). In addition, immunodeficiency and radio-sensitivity have also been observed. Hayashi et al. extensively examined the radio-sensitivity of the LEC rat and concluded that its hypersensitivity is controlled by a single autosomal gene. Furthermore, they suggested the possibility that it correlates to copper accumulation due to the Atp7b gene mutation, because ionizing radiation-induced hydroxyl radicals might act in concert with copper-induced hydroxyl radicals. Firstly, we analyzed linkage between radio-sensitivity and the mutation responsible for LEC hepatitis in F1 animals of cross with the F344 rat. Our results clearly demonstrated an absence of any significant association. In addition, partial dominance for radio-sensitivity was observed and radio-sensitive (F1 x LEC) backcross rats were twice as numerous as their radio-resistant counterparts, suggesting the possibility of control by two or more recessive genes. In order to select the radio-sensitivity gene in the LEC rat, we wished to develop congenic line of F344 rats using a phenotype-driven breeding protocol: rats of each backcross generation were mated with LEC rats and their progeny were irradiated with 4.5 Gy X rays, which dose cause death in LEC rats but did not in F344 rats, and judged 30 days later. Lately we also combined using genomic-wide genotyping in each backcross generation and their progeny to select heterogeneous rat. Although congenic rat line is not yet established until March of 2003, backcross exceeded 16 generations. This radio-sensitivity gene was demonstrated to locate in the region within 10Mb on the rat chromosome 4

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

    International Nuclear Information System (INIS)

    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.

  13. Hyperthermic radiosensitization : mode of action and clinical relevance

    NARCIS (Netherlands)

    Kampinga, HH; Dikomey, E

    2001-01-01

    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

  14. Curcumin Enhances the Radiosensitivity of U87 Cells by Inducing DUSP-2 Up-Regulation

    Directory of Open Access Journals (Sweden)

    Yu Qian

    2015-03-01

    Full Text Available Objective: Glioblastoma multiforme (GBM, an aggressive primary brain tumor, is radioresistant and recurs despite aggressive surgery, chemotherapy, and radiotherapy. Curcumin as a potential radiosensitizer has received extensive attention in cancer treatment. To explore an effectiveness of this radiosensitizer for GBM treatment, we evaluated the radiosensitizing effect of curcumin and investigated its potential molecular mechanisms in the human glioma cell line U87. Methods: The cytotoxic effects of curcumin on U87 cells were evaluated using the Cell Counting Kit-8 assay, and the radiosensitivity of U87 cells treated with curcumin was accessed by colony information assay. The effects of curcumin on cell proliferation and cell cycle regulation were determined using the 5-ethynyl-2-deoxyuridine incorporation assay and flow cytometry, respectively. Western blotting was applied to determine the effects of curcumin on protein expression of dual-specificity phosphatase-2 (DUSP-2, extracellular signal-regulated kinase (ERK, and c-Jun N-terminal kinase (JNK as well as phosphorylated ERK and JNK. Results: Curcumin significantly inhibited the proliferation of U87 cells in a dose-and time-dependent manner. Curcumin treatment at the concentrations of 5 µM and 10 M could significantly reduce the clonogenic activity and enhance the radiosensitivity of U87 cells with sensitive enhancement ratios (SERs of 1.71 and 4.65, respectively. Curcumin resulted in G2/M cell cycle arrest in U87 cells, which were radiosensitive. Pre-treatment of U87-MG cells with 5 µM curcumin enhanced radiation-induced cell proliferation inhibition and apoptosis. Furthermore, we observed that curcumin increased DUSP-2 protein expression and decreased the phosphorylation of ERK and JNK. Conclusion: Our results suggest that low-dose curcumin may enhance the radiosensitivity of human glioma U87 cells in vitro by inducing G2/M cell cycle arrest through up-regulation of DUSP-2 expression and

  15. Radiosensitization Effect of STI-571 on Pancreatic Cancer Cells In Vitro

    International Nuclear Information System (INIS)

    Purpose: To examine STI-571-induced radiosensitivity in human pancreatic cancer cells in vitro. Methods and Materials: Three human pancreatic cancer cell lines (Bxpc-3, Capan-1, and MiaPaCa-2) exhibiting different expression levels of c-Kit and platelet-derived growth factor receptor β (PDGFRβ) and showing different K-ras mutation types were used. For evaluation of the antitumor activity of STI-571 in combination with radiation, clonogenic survival assays, Western blot analysis, and the annexin V/propidium iodide assay with microscopic evaluation by 4',6-diamidino-2-phenylindole were conducted. Results: Dramatic phosphorylated (p)-c-Kit and p-PDGFRβ attenuation, a modest dose- and time-dependent growth inhibition, and significant radiosensitization were observed after STI-571 treatment in view of apoptosis, although the levels of growth inhibition and increased radiosensitization were different according to cell lines. The grades of radiosensitivity corresponded to the attenuation levels of p-c-Kit and p-PDGFRβ by STI-571, particularly to those of p-c-Kit, and the radiosensitivity was partially affected by K-ras mutation in pancreatic cancer cells. Among downstream pathways associated with c-Kit or PDGFRβ, p-PLCγ was more closely related to radiosensitivity compared with p-Akt1 or p-extracellular signal-regulated kinase 1. Conclusion: STI-571 enhances radiation response in pancreatic cancer cells. This effect is affected by the attenuation levels of p-c-Kit or p-PDGFRβ, and K-ras mutation status. Among them, p-c-Kit plays more important roles in the radiosensitivity in pancreatic cancer compared with p-PDGFRβ or K-ras mutation status.

  16. Huntington's disease: implications of associated cellular radiosensitivity

    International Nuclear Information System (INIS)

    Ionizing radiation sensitivity was studied in a series of Huntington's Disease (HD) patients and controls by measurement of radiation-induced chromosome aberrations in lymphocytes and by clonogenic survival of lymphoblastoid cell lines. As a group, HD patients were found to be significantly more radioisensitive than controls (p<0.001), but there was an overlap between values for the two groups such that an absolute distinction is not possible. These data are consistent with an association between HD and radiosensitivity but not with identity between HD and a radiosensitive phenotype, so that cellular radiosensitivity cannot be used for individual diagnosis. Analysis of three families including 5 HD patients and 11 first-degree relatives confirmed this conclusion and demonstrated that even within a given family presymptomatic diagnosis cannot be based on measurement of radiosensitivity. However, the common association of cellular radiosensitivity with HD probands and their families provides a potential lead to the identification of HD gene(s) and so to an eventual understanding of the aetiopathogenesis of this disease at the molecular level. (author)

  17. Radiosensitivity, radio-curability and DNA repair

    International Nuclear Information System (INIS)

    Improvements in accuracy stand as the heart of the success of today's radiotherapy. The dose may be delivered with a sub millimetric accuracy, may also conform to complex shapes, or track external and internal organ motions. In parallel, we may increase the tumour's radio-curability by modulating the biological effects generated by ionizing radiation into the patient. It was precisely the topic of the 2009 Lucien-Mallet prize organized by the French Society for Radiation Oncology (SFRO) and the Centre Antoine-Beclere under the auspices of the Fondation de France. In this review we will precisely describe the integrated molecular response to ionizing radiations. Starting from early observations, we are going to introduce the concept of cellular radiosensitivity as the global response of the irradiated cell. We will then focus into the cell and especially its nucleus. We will describe here the most complex and deleterious radioinduced damages. In the next chapter, we will dissect the molecular pathway that aims to detect and repair the previous lesions. The last part of the review will finally deal with the diagnostic, prognostic and therapeutic impacts emerging from the alliance between clinical and molecular radiobiology. (author)

  18. Lanthanum fluoride nanoparticles for radiosensitization of tumors

    Science.gov (United States)

    Kudinov, Konstantin; Bekah, Devesh; Cooper, Daniel; Shastry, Sathvik; Hill, Colin; Bradforth, Stephen; Nadeau, Jay

    2016-03-01

    Dense inorganic nanoparticles have recently been identified as promising radiosensitizers. In addition to dose enhancement through increased attenuation of ionizing radiation relative to biological tissue, scintillating nanoparticles can transfer energy to coupled photosensitizers to amplify production of reactive oxygen species, as well as provide UVvisible emission for optical imaging. Lanthanum fluoride is a transparent material that is easily prepared as nanocrystals, and which can provide radioluminescence at a number of wavelengths through simple substitution of lanthanum ions with other luminescent lanthanides. We have prepared lanthanum fluoride nanoparticles doped with cerium, terbium, or both, that have good spectral overlap with chlorine6 or Rose Bengal photosensitizer molecules. We have also developed a strategy for stable conjugation of the photosensitizers to the nanoparticle surface, allowing for high energy transfer efficiencies on a per molecule basis. Additionally, we have succeeded in making our conjugates colloidally stable under physiological conditions. Here we present our latest results, using nanoparticles and nanoparticle-photosensitizer conjugates to demonstrate radiation dose enhancement in B16 melanoma cells. The effects of nanoparticle treatment prior to 250 kVp x-ray irradiation were investigated through clonogenic survival assays and cell cycle analysis. Using a custom apparatus, we have also observed scintillation of the nanoparticles and conjugates under the same conditions that the cell samples are irradiated.

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

    Directory of Open Access Journals (Sweden)

    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.

  20. Radiogenomics: predicting clinical normal tissue radiosensitivity

    DEFF Research Database (Denmark)

    Alsner, Jan

    2006-01-01

    of subcutaneous fibrosis in breast cancer patients will be presented and discussed in relation to possible future studies in radiogenomics. One important and necessary basis for future studies is the collection of carefully designed clinical studies with the accrual of very large numbers of patients (the ESTRO......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...

  1. Radiosensitization by PARP inhibition to proton beam irradiation in cancer cells.

    Science.gov (United States)

    Hirai, Takahisa; Saito, Soichiro; Fujimori, Hiroaki; Matsushita, Keiichiro; Nishio, Teiji; Okayasu, Ryuichi; Masutani, Mitsuko

    2016-09-01

    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. PMID:27425251

  2. A novel NGR-conjugated peptide targets DNA damage responses for radiosensitization.

    Science.gov (United States)

    Ma, Jinlu; Zhang, Dan; Ying, Xia; Zhao, Ying; He, Chenchen; Zhu, Qing; Han, Suxia

    2015-01-01

    Radiotherapy is one of the important treatment strategies for patients with advanced hepatocellular carcinomas. Developing novel sensitizers for radiotherapy is a key issue due to the low intrinsic radiosensitivity of hepatocellular carcinomas. It was reported the wild-type NBS1 inhibitory peptide (wtNIP) can increase radiosensitivity in several cancer cell lines by abrogating ATM-NBS1 interaction and interrupting cellular DNA damage response. Here, we developed a novel NGRconjugated peptide (NGR-sR9-wtNIP) through coupling the CNGRC angiogenic vessel-homing peptide NGR with the wtNIP peptide. Fusion peptide was tested for internalization, cytotoxicity in Hep3B cells and for tumor localization, and for toxicity in nude mice bearing human hepatocellular carcinomas xenografts. The radiosensitizing activity of NGR-sR9-wtNIP was investigated as well. We found that NGR-sR9-wtNIP can inhibit irradiation induced NBS1 phosphorylation and induce radiosensitization in Hep3B cells. When combined with IR, NGR-sR9-wtNIP suppressed tumor growth obviously in xenograft mice. In addition, the fusion peptide localized in tumor tissue specifically and barely led to any side effects on mice. Taken together, our data strongly suggest that NGRsR9- wtNIP has radiosensitizing potential for radiotherapy of hepatocellular carcinomas.

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

    Directory of Open Access Journals (Sweden)

    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

  4. Effect of moisture content of radiosensitivity of avocado (Persea americana Mill)

    International Nuclear Information System (INIS)

    Seven selections and three varieties of avocado were evaluated to measure their sensitivity to gamma radiations of 60 Co and to evaluate the effect of moisture content on radiosensitivity. Selections were treated with 0, 1.5, 3, 4.5 and 6 krad. A differential behavior were found, which implies radiosensitivity differences are inherent in the material. Also we found a negative and significant correlation coefficient (r=-0.73) between moisture content and survival percentage after 150 days grafted. This means that survival of treated scions is influenced at a certain extent by moisture content. Radiosensitivity is greater as moisture increases. The highest dosage resisted by less sensitivity material was 4.5 krad meanwhile 1.5 krad was the highest dosage resisted by the most sensitivity material. (Author)

  5. Radiosensitized treatment of malignant brain tumors

    Science.gov (United States)

    Bloznelyte-Plesniene, Laima

    2003-12-01

    Around 12,000 deaths from glioblastoma occurs within the European Community annually. At present, the best available treatment for malignant brain tumors results in a median survival of patients of 15 months despite surgery, radiotherapy, and chemotherapy. The purpose of this paper is to review our results of radiosensitized treatment of malignant brain tumors.

  6. On the mechanism of salivary gland radiosensitivity

    NARCIS (Netherlands)

    Konings, AWT; Coppes, RP; Vissink, A

    2005-01-01

    Purpose: To contribute to the understanding of the enigmatic radiosensitivity of the salivary glands by analysis of appropriate literature, especially with respect to mechanisms of action of early radiation damage, and to supply information on the possibilities of amelioration of radiation damage to

  7. The High Radiosensitizing Efficiency of a Trace of Gadolinium-Based Nanoparticles in Tumors

    Science.gov (United States)

    Dufort, Sandrine; Le Duc, Géraldine; Salomé, Murielle; Bentivegna, Valerie; Sancey, Lucie; Bräuer-Krisch, Elke; Requardt, Herwig; Lux, François; Coll, Jean-Luc; Perriat, Pascal; Roux, Stéphane; Tillement, Olivier

    2016-07-01

    We recently developed the synthesis of ultrasmall gadolinium-based nanoparticles (GBN), (hydrodynamic diameter contrast agents for magnetic resonance imaging (MRI) and as radiosensitizers. The attempt to determine the most opportune delay between the intravenous injection of GBN and the irradiation showed that a very low content of radiosensitizing nanoparticles in the tumor area is sufficient (0.1 μg/g of particles, i.e. 15 ppb of gadolinium) for an important increase of the therapeutic effect of irradiation. Such a promising and unexpected result is assigned to a suited distribution of GBN within the tumor, as revealed by the X-ray fluorescence (XRF) maps.

  8. Effect of anemia on tumor radiosensitivity under normo and hyperbaric conditions

    Energy Technology Data Exchange (ETDEWEB)

    Rojas, A.; Stewart, F.A.; Smith, K.A.; Soranson, J.A.; Randhawa, V.S.; Stratford, M.R.; Denekamp, J.

    1987-11-01

    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.

  9. Radiosensitization by the novel DNA intercalating agent vosaroxin

    Directory of Open Access Journals (Sweden)

    Gordon Ira K

    2012-02-01

    Full Text Available Abstract Purpose Vosaroxin is a first in class naphthyridine analog structurally related to quinolone antibacterials, that intercalates DNA and inhibits topoisomerase II. Vosaroxin is not a P-glycoprotein receptor substrate and its activity is independent of p53, thus evading common drug resistance mechanisms. To evaluate vosaroxin as a clinically applicable radiation sensitizer, we investigated its effects on tumor cell radiosensitivity in vitro and in vivo. Methods Vosaroxin's effect on post-irradiation sensitivity of U251, DU145, and MiaPaca-2 cells was assessed by clonogenic assay. Subsequent mechanistic and in vivo studies were performed with U251 cells. Cell cycle distribution and G2 checkpoint integrity was analyzed by flow cytometry. DNA damage and repair was evaluated by a high throughput gamma-H2AX assay. Apoptosis was assessed by flow cytometry. Mitotic catastrophe was assessed by microscopic evidence of fragmented nuclei by immunofluorescence. In vivo radiosensitization was measured by subcutaneous tumor growth delay. Results 50-100 nmol/L treatment with vosaroxin resulted in radiosensitization of all 3 cell lines tested with a dose enhancement factor of 1.20 to 1.51 measured at a surviving fraction of 0.1. The maximal dose enhancement was seen in U251 cells treated with 75 nmol/L vosaroxin (DEF 1.51. Vosaroxin exposure did not change cell cycle distribution prior to irradiation nor alter G2 checkpoint integrity after irradiation. No difference was seen in the apoptotic fraction regardless of drug or radiation treatment. The number of cells in mitotic catastrophe was significantly greater in irradiated cells treated with vosaroxin than cells receiving radiation only at 72 hr (p = 0.009. Vosaroxin alone did not significantly increase mitotic catastrophe over control (p = 0.53. Cells treated with vosaroxin and radiation maintained significantly higher gamma-H2AX levels than cells treated with vehicle control (p = 0.014, vosaroxin (p

  10. Docetaxel shows radiosensitization in human hepatocellular carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Chang-Xin Geng; Zhao-Chong Zeng; Ji-Yao Wang; Shi-Ying Xuan; Chong-Mao Lin

    2005-01-01

    AIM: To determine the radiosensitizing potential of docetaxel in human hepatocellular carcinoma SMMC-7721 cells and its mechanisms.METHODS: SMMC-7721 cells were incubated with docetaxel at 0.125, 0.25, and 0.5 nmoL/L for 24 h and at 0.125 and 0.25 nmol/L for 48 h before irradiation. Radiation doses were given from 0 to 10 Gy. Cell survival was measured by a standard clonogenic assay after a 9-d incubation. The reactive oxygen species (ROS) and glutathione (GSH) are detected after being given the same dose of docetaxel for the same time. RESULTS: The sensitization enhancement ratios (SER) for SMMC-7721 cells determined at the 50% survival level were 1.15, 1.21 and 1.49 at 0.125, 0.25, and 0.5 nmol/L for pre-incubation of 24 h, respectively; the SER were 1.42, 1.67 at 0.125 and 0.25 nmol/L, for pre-incubation of 48 h, respectively. The ROS of SMMC-7721 cells increased and GSH decreased after pretreatment with the same doses of docetaxel for 24 or 48 h.CONCLUSION: A radiosensitizing effect of docetaxel could be demonstrated unambiguously in this cell line used. In addition, our data showed that the mechanism of radiopotentiation by docetaxel probably does not involve a G2/M block in SMMC-7721 cells, and ROS generation and GSH deletion may play a key role in the radiosensitizing effect of docetaxel.

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

    International Nuclear Information System (INIS)

    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 60Co 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, P50 at 48 h and 72 h after administration with BVAN08 were 55.3 and 52.7 mol/L, respectively. Obvious G2/M arrest was induced in U-251 cells after 4 h administration with BVAN08, and reached peck at 12 h. The G2/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 G2/M arrest and inhibition of DNA-PKcs expression. BVAN08 seemed to be a promising radiosensitizing anticancer drug. (authors)

  12. Macrophages enhance the radiosensitizing activity of lipid A: A novel role for immune cells in tumor cell radioresponse

    International Nuclear Information System (INIS)

    Purpose: This study examines whether activated macrophages may radiosensitize tumor cells through the release of proinflammatory mediators. Methods and materials: RAW 264.7 macrophages were activated by lipid A, and the conditioned medium (CM) was analyzed for the secretion of cytokines and the production of nitric oxide (NO) through inducible nitric oxide synthase (iNOS). EMT-6 tumor cells were exposed to CM and analyzed for hypoxic cell radiosensitivity. The role of nuclear factor (NF)-κB in the transcriptional activation of iNOS was examined by luciferase reporter gene assay. Results: Clinical immunomodulator lipid A, at a plasma-relevant concentration of 3 μg/mL, stimulated RAW 264.7 macrophages to release NO, tumor necrosis factor (TNF)-α, and other cytokines. This in turn activated iNOS-mediated NO production in EMT-6 tumor cells and drastically enhanced their radiosensitivity. Radiosensitization was abrogated by the iNOS inhibitor aminoguanidine but not by a neutralizing anti-TNF-α antibody. The mechanism of iNOS induction was linked to NF-κB but not to JAK/STAT signaling. Interferon-γ further increased the NO production by macrophages to a level that caused radiosensitization of EMT-6 cells through the bystanding effect of diffused NO. Conclusions: We demonstrate for the first time that activated macrophages may radiosensitize tumor cells through the induction of NO synthesis, which occurs in both tumor and immune cells

  13. ZnFe2O4 nanoparticles for potential application in radiosensitization

    Science.gov (United States)

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

    2016-03-01

    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, ZnFe2O4 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 ZnFe2O4 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 ZnFe2O4 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. ZnFe2O4 nanoparticles showed ability to increase the absorbed dose by 0.5 to 1.0 cGy/g. In addition, the presence of 1 g/L ZnFe2O4 nanoparticles resulted in an increase radiation effect by 6.3% higher than if exposed to radiation only. These results indicated that ZnFe2O4 nanoparticles can be used as the radiosensitizer for increasing radiation effect in radiotherapy.

  14. 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. PMID:25059546

  15. Radiosensitivity of peripheral blood lymphocytes in autoimmune disease

    International Nuclear Information System (INIS)

    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. (author)

  16. 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.

  17. Effect of antisence VEGF on the radiosensitivity of esophageal cancer cells in vitro

    International Nuclear Information System (INIS)

    Objective: To investigate the effect of' antisense VEGF on the cell proliferation, VEGF protein expression and radiosensitivity of esophageal cancer cells in vitro. Methods: Fragments of antisense cDNA, empty vector plasmid DNA and antisense oligodeoxynucleotide of VEGF were transfected into esophageal cancer (TE-1) cells mediated with lipofectamine, respectively. Cell proliferating rate and apoptotic rate of these groups were edetected by MIT and FCM methods, respectively. After irradiation, the expression of VEGF in transfected cells were detected by using RT-PCR and Western blotting. The radiosensitivity of transfected cells were analyzed with colony forming assay. Results: After antisense cDNA plasmid and antisense oligodeoxynucleotide of VEGF were transfected successfully into TE-1 cells, expressions of VEGF protein decreased, however, the changes in cell growth rate and distribution of cell cycle, and the apoptotic rate were not observed in these transfected cells. After irradiation, the radiosensitivity of transfected TE-1 cells were increased, but there was no significant difference in cell growth rate among groups. The apoptotic rates in antisense groups increased slightly compared to TE-1 and TE-1-E groups. Conclusions: Expression of VEGF mRNA and VEGF protein were significantly suppressed in TE-1 cells transfected by antisense cDNA and antisense oligodeoxynucleotide of VEGF. After irradiation, the radiosensitivity of the transfected TE-1 cells was increased. (authors)

  18. 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.

  19. Immunodeficiency, radiosensitivity, and the XCIND syndrome.

    Science.gov (United States)

    Gatti, Richard A; Boder, Elena; Good, Robert A

    2007-01-01

    Through the analysis of a rare disorder called ataxia-telangiectasia (A-T), many important biological lessons have been gleaned. Today, it is clear that the underlying defect of A-T lies in the nucleus, as an inability to repair or process double strand breaks. More important, by the A-T phenotype now allows us to appreciate a much more general distinction between immunodeficiencies that are radiosensitive and those that are not.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  1. In vivo radiosensitization: principles and methods of study

    International Nuclear Information System (INIS)

    The role of animal experiments in helping to develop the clinical applications of hypoxic cell radiosensitizers can be described under four headings. 1) To compare the potential advantages of radiosensitizers with those of other treatments, in the same tumour and normal-tissue systems. 2) To compare the disadvantageous side-effects with the advantageous effects on tumours. 3) To find optimum ways of using the radiosensitizers: the ''best scheduling''. 4) To help in the design and testing of new radiosensitizers. Details of the various methods of measuring the response of experimental tumours in mice or rats are presented, together with results. (Auth.)

  2. Short Hairpin RNA Suppression of Thymidylate Synthase Produces DNA Mismatches and Results in Excellent Radiosensitization

    Energy Technology Data Exchange (ETDEWEB)

    Flanagan, Sheryl A., E-mail: sflan@umich.edu [Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan (United States); Cooper, Kristin S. [Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan (United States); Mannava, Sudha; Nikiforov, Mikhail A. [Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York (United States); Shewach, Donna S. [Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan (United States)

    2012-12-01

    Purpose: To determine the effect of short hairpin ribonucleic acid (shRNA)-mediated suppression of thymidylate synthase (TS) on cytotoxicity and radiosensitization and the mechanism by which these events occur. Methods and Materials: shRNA suppression of TS was compared with 5-fluoro-2 Prime -deoxyuridine (FdUrd) inactivation of TS with or without ionizing radiation in HCT116 and HT29 colon cancer cells. Cytotoxicity and radiosensitization were measured by clonogenic assay. Cell cycle effects were measured by flow cytometry. The effects of FdUrd or shRNA suppression of TS on dNTP deoxynucleotide triphosphate imbalances and consequent nucleotide misincorporations into deoxyribonucleic acid (DNA) were analyzed by high-pressure liquid chromatography and as pSP189 plasmid mutations, respectively. Results: TS shRNA produced profound ({>=}90%) and prolonged ({>=}8 days) suppression of TS in HCT116 and HT29 cells, whereas FdUrd increased TS expression. TS shRNA also produced more specific and prolonged effects on dNTPs deoxynucleotide triphosphates compared with FdUrd. TS shRNA suppression allowed accumulation of cells in S-phase, although its effects were not as long-lasting as those of FdUrd. Both treatments resulted in phosphorylation of Chk1. TS shRNA alone was less cytotoxic than FdUrd but was equally effective as FdUrd in eliciting radiosensitization (radiation enhancement ratio: TS shRNA, 1.5-1.7; FdUrd, 1.4-1.6). TS shRNA and FdUrd produced a similar increase in the number and type of pSP189 mutations. Conclusions: TS shRNA produced less cytotoxicity than FdUrd but was equally effective at radiosensitizing tumor cells. Thus, the inhibitory effect of FdUrd on TS alone is sufficient to elicit radiosensitization with FdUrd, but it only partially explains FdUrd-mediated cytotoxicity and cell cycle inhibition. The increase in DNA mismatches after TS shRNA or FdUrd supports a causal and sufficient role for the depletion of dTTP thymidine triphosphate and consequent DNA

  3. Radiation could induce p53-independent and cell cycle - unrelated apoptosis in 5-fluorouracil radiosensitized head and neck carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Didelot, C.; Mirjolet, J.F.; Barberi-Heyob, M.; Ramacci, C.; Merlin, J.L. [Centre Alexis Vautrin, Lab. de Recherche en Oncologie, Vandoeuvre-les-Nancy CEDEX (France)

    2002-07-01

    The effect of chemoresistance induction in radio sensitivity and cellular behavior after irradiation remains misunderstood. This study was designed to understand the relationship between radiation-induced cell cycle arrest, apoptosis, and radiosensitivity in KB cell line and KB3 subline selected after 5-fluorouracil (5FU) exposure. Exposure of KB cells to 5FU led to an increase in radiosensitivity. G{sub 2}/M cell cycle arrest was observed in the two cell lines after irradiation. The radioresistant KB cell line reached the maximum arrest two hours before KB3. The cellular exit from this arrest was found to be related to the wild type p53 protein expression induction. After irradiation, only KB3 cell line underwent apoptosis. This apoptosis induction seemed to be independent of G{sub 2}/M arrest exit, which was carried out later. The difference in radiosensitivity between KB and KB3 subline may result therefore from both a difference in apoptosis induction and a difference in G{sub 2}/M arrest maximum duration. Moreover, 5FU exposure has led to an increase in constitutive p53 protein expression, which may be associated with an increase in basal apoptosis cell fraction. Given the existing correlation between radiosensitivity and the percentage of basal apoptosis. the constitutive p53 protein expression may be related to intrinsic radiosensitivity in our cellular model. (author)

  4. Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers

    Directory of Open Access Journals (Sweden)

    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.

  5. Celecoxib Enhances the Radiosensitizing Effect of 7-Hydroxystaurosporine (UCN-01) in Human Lung Cancer Cell Lines

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    Kim, Young-Mee; Jeong, In-Hye [Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Pyo, Hongryull, E-mail: Quasar93@yahoo.co.kr [Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-07-01

    Purpose: 7-Hydroxystaurosporine (UCN-01), a Chk1-specific inhibitor, showed promising in vitro and in vivo chemo- or radiosensitizing activity. However, there have been concerns about its limited therapeutic efficacy and risk of side effects. A method of enhancing the treatment efficacy of UCN-01 while not increasing its side effects on normal tissue may therefore be required to apply this drug in clinical settings. Celecoxib is a cyclooxygenase-2 (COX-2)-specific inhibitor that downregulates ataxia telangiectasia and rad3-related (ATR) protein, an upstream kinase of Chk1. In this study, we investigated whether the addition of celecoxib can potentiate the radiosensitizing effect of UCN-01. Methods and Materials: The cooperative radiosensitizing effects and the underlying molecular mechanisms of UCN-01 plus celecoxib were determined by clonogenic assay, tumor growth delay assay, flow cytometry, and Western blotting. Synergism of the three agents combined (UCN-01 plus celecoxib plus radiation) were evaluated using median drug effect analysis and drug-independent action model analysis. Results: The combination of UCN-01 and celecoxib could induce synergistic cytotoxicity and radiosensitizing effects in in vitro and in vivo systems. The combination of both drugs also cooperatively inhibited IR-induced G{sub 2}/M arrest, and increased the G{sub 2} to mitotic transition. Conclusions: Combined treatment with UCN-01 and celecoxib can exert synergistically enhanced radiosensitizing effects via cooperative inhibition of the ionizing radiation-activated G{sub 2} checkpoint. We propose that this combination strategy may be useful in clinical applications of UCN-01 for radiotherapy of cancer patients.

  6. Radiosensitizing effects of 9401 on mice bearing H22 hepatoma

    International Nuclear Information System (INIS)

    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

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

    International Nuclear Information System (INIS)

    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

  8. 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

  9. Chromosomal radiosensitivity in patients with multiple sclerosis

    International Nuclear Information System (INIS)

    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

  10. 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.

  11. DNA-PK. The major target for wortmannin-mediated radiosensitization by the inhibition of DSB repair via NHEJ pathway

    International Nuclear Information System (INIS)

    The effect of wortmannin posttreatment was studied in cells derived from different species (hamster, mouse, chicken, and human) with normal and defective DNA-dependent protein kinase (DNA-PK) activity, cells with and without the ataxia telangiectasia mutated (ATM) gene, and cells lacking other regulatory proteins involved in the DNA double-strand break (DSB) repair pathways. Clonogenic assays were used to obtain all results. Wortmannin radiosensitization was observed in Chinese hamster cells (V79-B310H, CHO-K1), mouse mammary carcinoma cells (SR-1), transformed human fibroblast (N2KYSV), chicken B lymphocyte wild-type cells (DT40), and chicken Rad54 knockout cells (Rad54-/-). However, mouse mammary carcinoma cells (SX9) with defects in the DNA-PK and chicken DNA-PK catalytic subunit (DNA-PKcs) knockout cells (DNA-PKcs-/-/-) failed to exhibit wortmannin radiosensitization. On the other hand, severe combined immunodeficiency (SCID) mouse cells (SC3VA2) exposed to wortmannin exhibited significant increases in radiosensitivity, possibly because of some residual function of DNA-PKcs. Moreover, the transformed human cells derived from AT patients (AT2KYSV) and chicken ATM knockout cells (ATM-/-) showed pronounced wortmannin radiosensitization. These studies demonstrate confirm that the mechanism underlying wortmannin radiosensitization is the inhibition of DNA-PK, but not of ATM, thereby resulting in the inhibition of DSB repair via nonhomologous endjoining (NHEJ). (author)

  12. Radiosensitization mechanism of riboflavin in vitro

    Institute of Scientific and Technical Information of China (English)

    刘官树; 陆长元; 姚思德; 赵芳; 李雨; 孟祥顺; 高建国; 蔡建明; 张黎明; 陈志龙

    2002-01-01

    Riboflavin, suggested to be a radiosensitizer, was studied in murine thymocytes and human hepatoma L02 cell line in vitro with MTT method and fluorescence microscopy. When the murine thymocytes treated with 5-400 μmol/L riboflavin were irradiated by 5 Gy 60Co γ ionizing radiation, the low concentration groups, i.e. treated with 5-50 μmol/L riboflavin, showed a different surviving fractions-time relating correlation compared with the high concentration groups, i.e. treated with 100-400 μmol/L riboflavin. The former had a high survival level at the end of irradiation, but which, after 4-h incubation, decreased rapidly to a low level. On the contrary, the high concentration groups showed a low survival level at the end of irradiation, and a poor correlation was found between the surviving fraction and the incubation time, after 4 h a little difference was observed. The results of fluorescence microscopy indicated that under low concentration conditions, the riboflavin localized mainly in nucleus (both perinuclear area and inside of nuclear membrane), while under high concentration conditions, intensive riboflavin also localized around cytoplasmic membranes. Thus we can conclude: the riboflavin had radiosensitivity effect on DNA under low concentration conditions, and enhanced the damage to cytoplasmic membrane under high concentration conditions. Also the most effective concentration of riboflavin can be evaluated to be approximate 100 μmol/L.

  13. NU7441 Enhances the Radiosensitivity of Liver Cancer Cells

    Directory of Open Access Journals (Sweden)

    Chuanjie Yang

    2016-05-01

    Full Text Available Objective: Radiation therapy, one of the major treatments for liver cancer, causes DNA damage and cell death. Since the liver cancer cells have a strong capacity to repair irradiative injury, new medicines to enhance this treatment are urgently required. In this study, we investigated the effect of NU7441, a synthetic small-molecule compound, as a specific inhibitor of DNA-dependent protein kinase (DNA-PK in radiosensitization of hepatocellular carcinoma HepG2 cells. Methods: Cell Counting Kit-8 (CCK-8 was first used to evaluate the proliferation of HepG2 cells under NU7441 treatment. SDS-PAGE and Western blot were then performed to study the protein expression leading to the DNA damage repair. Further, neutral single cell gel electrophoresis and immunofluorescence assay were carried out to assess DNA repair. Finally, flow cytometry was implemented to examine the changes in cell cycle. Results: NU7441 reduced the CCK-8 counts in the HepG2 culture, further enhanced 60Coγ radiation injury to HepG2 cells, which was manifested by decreasing the DNA-PKcs (S2056 protein expression, increasing γH2AX foci number, prolonging the tail moment of the comet cells, and inducing cell cycle arrest at G2/M phase. Conclusion: NU7441 inhibited the growth of liver cancer cells, enhanced the radiosensitization of these cancer cells by interfering with the DNA repair and cell cycle checkpoint. These data implicate NU7441 as a potential radiotherapy sensitizer for the treatment of liver cancer.

  14. Potential of radiosensitizing agents in cancer chemo-radiotherapy

    Directory of Open Access Journals (Sweden)

    Girdhani S

    2005-01-01

    Full Text Available Potential of herbs and other plant-based formulations have been increasingly recognized in prevention and treatment of human diseases including cancer. There exist enormous prospect for screening and evaluation of herbal/plant products for developing effective radiosensitization and radioprotection relevant to nuclear research program. Investigations in our laboratory have focused on the mechanism of activity of variety of anticancer and antioxidant agents, namely, Eugenol, (EU, Ellagic acid (EA, Triphala (TPL, Tocopherol Succinate (TOS and Arachidonic acid on normal and cancer cells with view to design effective protocols in practical radioprotection and cancer radiotherapy. This paper is mainly focused on studies on cytotoxic effects on cancer cell lines. Results have shown that these agents produced radiosensitizing action involving oxidative damage, membrane alteration and damage to nucleic acid in various human cell lines. Studies were performed employing fluorescence probes and electron spin resonance methods and gel electrophoresis protocols. It has been found that cytotoxic effect was induced by initiating membrane oxidative damage and by triggering intracellular generation of reactive oxygen species (ROS by gamma radiation in combination with phytochemicals like TPL, EA and TOS in tumor cell line Ehrlich Ascites (EAC, Human cervical (HeLa and breast (MCF-7 cells. Membrane damage and ROS generation was measured by DPH and DCF-FDA fluorescent probes respectively after exposure to low to moderate doses of gamma radiation. This talk will present the cytotoxic effects of phytochemicals in combination with ionizing radiation. It is emphasized that modulation of membrane peroxidative damage and intra cellular ROS may help achieve efficient killing of cancer cells which may provide a new approach to developing effective treatment of cancer.

  15. Radiosensitizing effect of epothilone B on human epithelial cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Baumgart, T.; Kriesen, S.; Hildebrandt, G.; Manda, K. [Univ. of Rostock (Germany). Dept. of Radiotherapy and Radiation Oncology; Klautke, G.; Fietkau, R. [Friedrich-Alexander-Univ. Erlangen-Nuernberg, Erlangen (Germany). Dept. of Radiation Oncology; Kuznetsov, S.A.; Weiss, D.G. [Univ. of Rostock (Germany). Inst. of Biological Sciences, Cell Biology, and Biosystems Technology

    2012-02-15

    A combined modality treatment employing radiation and chemotherapy plays a central role in the management of solid tumors. In our study, we examined the cytotoxic and radiosensitive effect of the microtubule stabilizer epothilone B on two human epithelial tumor cell lines in vitro and its influence on the microtubule assembly. Cancer cells were treated with epothilone B in proliferation assays and in combination with radiation in colony-forming assays. For the analysis of ionizing radiation-induced DNA damage and the influence of the drug on its repair a {gamma}H2AX foci assay was used. To determine the effect of epothilone B on the microtubule assembly in cells and on purified tubulin, immunofluorescence staining and tubulin polymerization assay, respectively, were conducted. Epothilone B induced a concentration- and application-dependent antiproliferative effect on the cells, with IC{sub 50} values in the low nanomolar range. Colony forming assays showed a synergistic radiosensitive effect on both cell lines which was dependent on incubation time and applied concentration of epothilone B. The {gamma}H2AX assays demonstrated that ionizing radiation combined with the drug resulted in a concentration-dependent increase in the number of double-strand breaks and suggested a reduction in DNA repair capacity. Epothilone B produced enhanced microtubule bundling and abnormal spindle formation as revealed by immunofluorescence microscopy and caused microtubule formation from purified tubulin. The results of this study showed that epothilone B displays cytotoxic antitumor activity at low nanomolar concentrations and also enhances the radiation response in the tumor cells tested; this may be induced by a reduced DNA repair capacity triggered by epothilone B. It was also demonstrated that epothilone B in fact targets microtubules in a more effective manner than paclitaxel. (orig.)

  16. Optimal energy for cell radiosensitivity enhancement by gold nanoparticles using synchrotron-based monoenergetic photon beams

    Directory of Open Access Journals (Sweden)

    Rahman WN

    2014-05-01

    Full Text Available Wan Nordiana Rahman,1,2 Stéphanie Corde,3,4 Naoto Yagi,5 Siti Aishah Abdul Aziz,1 Nathan Annabell,2 Moshi Geso21School of Health Sciences, Universiti Sains Malaysia, Kelantan, Malaysia; 2Division of Medical Radiation, School of Medical Sciences, Royal Melbourne Institute of Technology, Bundoora, VIC, 3Radiation Oncology, Prince of Wales Hospital, High Street, Randwick, 4Centre for Medical Radiation Physics, University of Wollongong, Wollongong, NSW, Australia; 5Japanese Synchrotron Radiation Research Institute, Sayo-gun, Hyogo, JapanAbstract: 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

  17. Effects of taurolidine on radiosensitivity of murine melanoma cells and its mechanism

    International Nuclear Information System (INIS)

    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 (P0 and SER Dq) 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)

  18. Study on differences of radiosensitivity of human tooth enamel

    International Nuclear Information System (INIS)

    To study differences of radiosensitivity of human tooth enamel, 84 tooth enamel samples from 5 subjects were separated, and irradiated with radiation dose of 5 Gy from 60Co γ rays. After irradiation each sample was measured by ESR technique. Experimental results indicate that some difference in radiosensitivity exists for teeth from each subject (coefficients of variation of each subject range from 9.3% to 14.0%). Nevertheless, the mean values for all teeth of each subject among 5 subjects agree within the range of 325.77 to 386.80. It shows that the radiosensitivity of tooth enamel is basically uniform

  19. Thioredoxin reductase-1 (TxnRd1) mediates curcumin-induced radiosensitization of squamous carcinoma cells

    OpenAIRE

    Javvadi, Prashanthi; Hertan, Lauren; Kosoff, Rachelle; Datta, Tatini; Kolev, Johann; Mick, Rosemarie; Tuttle, Stephen W; Koumenis, Constantinos

    2010-01-01

    Curcumin, a plant polyphenol, is a widely studied chemopreventive agent with demonstrated antitumor activities in preclinical studies and low toxicity profiles in multiple clinical trials against human malignancies. We previously demonstrated that curcumin radiosensitizes cervical tumor cells without increasing the cytotoxic effects of radiation on normal human fibroblasts. Here we report that an inhibitory activity of curcumin on the anti-oxidant enzyme Thioredoxin Reductase-1 (TxnRd1) is re...

  20. Radiosensitivity of California Wonder pepper variety to Co-60 gamma rays

    International Nuclear Information System (INIS)

    Seeds of California wonder pepper variety were irradiated with dosages among 100-800 Gy, to intervals of 100 Gy, in a source of Co 60 gamma rays, with the objective of determining its radiosensitivity and to establish the adequate interval of dosage for the mutation breeding. A decrease of the growing indicators, productivity and plant fertility was observed with the increasing of irradiation dosages and the interval among 130-460 Gy was established as the most adequate

  1. Assessment of individual radiosensitivity in human lymphocytes using micronucleus and microgel electrophoresis Comet assays

    International Nuclear Information System (INIS)

    Background and purpose: Individual radiosensitivity is an inherent characteristic, associated with an increased reaction to ionizing radiation on the human body. Individuals show marked differences in radiation sensitivity, which has consequences in the fields of both radiation protection and radiation therapy. 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 suitable approaches to evaluate individual radiosensitivity in vitro. The amins of this study were: 1) to assess the in vitro radisensitivity of peripheral blood lymphocytes from two with the observed clinical response and 2) to test the predictive potential of both techniques. Materials and methods: 38 cancer patients receiving radiation therapy were enrolled in this study. The tumor sites were: head and neck (n=25) and cervic (n=13). 19 pateints were evaluated prior, mid-way and on completion of treatment (prospective group) and 19 patients were evaluated about 2-480 month after radiotherapy (retrospective group). Cytogenetic data from the prospective group were analyzed 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 cytogentic 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 analyzed comparing expected MN frequencies (calibration curve from health donors) with values observed after in vitro irradiation. One over-reactor ad patients that did not develop late effects were also evaluated through comet assay. DNA damage and repair capacity were quantified by the Olive tail moment. Lymphocytes of health individuals were used as reference sample. In the prospective evaluation, factor K correlated

  2. Assessment of individual radiosensitivity in human lymphocytes using micronucleus and microgel electrophoresis Comet assays

    Energy Technology Data Exchange (ETDEWEB)

    Giorgio, M. di; Sardi, M.; Busto, M.; Vallerga, M.; Taja, M.; Mairal, I.

    2004-07-01

    Background and purpose: Individual radiosensitivity is an inherent characteristic, associated with an increased reaction to ionizing radiation on the human body. Individuals show marked differences in radiation sensitivity, which has consequences in the fields of both radiation protection and radiation therapy. 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 suitable approaches to evaluate individual radiosensitivity in vitro. The amins of this study were: 1) to assess the in vitro radisensitivity of peripheral blood lymphocytes from two with the observed clinical response and 2) to test the predictive potential of both techniques. Materials and methods: 38 cancer patients receiving radiation therapy were enrolled in this study. The tumor sites were: head and neck (n=25) and cervic (n=13). 19 pateints were evaluated prior, mid-way and on completion of treatment (prospective group) and 19 patients were evaluated about 2-480 month after radiotherapy (retrospective group). Cytogenetic data from the prospective group were analyzed 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 cytogentic 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 analyzed comparing expected MN frequencies (calibration curve from health donors) with values observed after in vitro irradiation. One over-reactor ad patients that did not develop late effects were also evaluated through comet assay. DNA damage and repair capacity were quantified by the Olive tail moment. Lymphocytes of health individuals were used as reference sample. In the prospective evaluation, factor K correlated

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

    International Nuclear Information System (INIS)

    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

  4. HAP1 gene expression is associated with radiosensitivity in breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Jing [The Fourth Clinical School of Nanjing Medical University, Nanjing, Jiangsu (China); Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu (China); Zhang, Jun-ying [Research Center of Clinical Oncology, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu (China); Yin, Li [Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu (China); Research Center of Clinical Oncology, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu (China); Wu, Jian-zhong [Research Center of Clinical Oncology, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu (China); Guo, Wen-jie; Wu, Jian-feng [Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu (China); Chen, Meng; Xia, You-you [The Fourth Clinical School of Nanjing Medical University, Nanjing, Jiangsu (China); Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu (China); Tang, Jin-hai [Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu (China); Ma, Yong-chao [Department of Hematology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu (China); He, Xia, E-mail: hexiadoctor@163.com [Department of Radiation Oncology, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, Jiangsu (China)

    2015-01-02

    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.

  5. Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization.

    Science.gov (United States)

    Maier, Patrick; Hartmann, Linda; Wenz, Frederik; Herskind, Carsten

    2016-01-14

    During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization.

  6. Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

    Directory of Open Access Journals (Sweden)

    Patrick Maier

    2016-01-01

    Full Text Available During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization.

  7. Modulation of radiosensitivity by growth factors

    International Nuclear Information System (INIS)

    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)

  8. HLA‐G modulates the radiosensitivity of human neoplastic cells

    International Nuclear Information System (INIS)

    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)

  9. The degree of pigmentation modulates the radiosensitivity of human melanoma cells.

    Science.gov (United States)

    Kinnaert, E; Morandini, R; Simon, S; Hill, H Z; Ghanem, G; Van Houtte, P

    2000-11-01

    The relationship between cell pigmentation and radiosensitivity was investigated in two selected human melanoma cell lines with different melanin content (mixed type: eumelanin and pheomelanin, and pheomelanotic phenotypes). The same study was also done after stimulation of melanogenesis (1) by addition of the melanin precursor l-tyrosine to each of the cell lines separately and (2) by irradiation alone with doses ranging from 0 to 10 Gy. We found that a decrease in cell radiosensitivity was correlated with the type of melanin, with a clear involvement of eumelanin rather than pheomelanin. Increasing the intracellular content of both melanins promoted the growth of irradiated cells. Moreover, at a dose of 10 Gy, both tyrosinase activity and melanin cell content were significantly increased in the absence of any other melanogenesis promoter. Our data suggest that the amount of intracellular melanin is inversely related to the radiosensitivity of melanoma cells and may explain at least in part the controversial responses to ionizing radiations reported for melanoma. PMID:11025646

  10. Metabolic potentiation of the radiosensitization of hypoxic bacterial cells afforded by nitroaromatic compounds

    International Nuclear Information System (INIS)

    Prolonged preirradiation incubation of nitroaromatic radiosensitizers with Escherichia coli cells has been found to increase the degree of radiosensitization of the cells in anoxia. Studies with E. coli strains which differ in their nitroreductase activity indicate that the increase in sensitization arises from the action of metabolites produced by the nitroreductase system of the cell. The metabolites alone appear to decrease the extrapolation number of irradiated hypoxic cells and when combined with the parent compound give a biphasic survival curve. The combination of misonidazole (1 mmole dm-3) and its metabolites (1 mmole dm-3) gave initial and final enhancement ratios of 2.4 and 1.4, respectively. The final enhancement ratio is that expected for 1 mmole dm-3 misonidazole alone, whereas the initial enhancement ratio indicates that the metabolites potentiate the action of misonidaxole. The preirradiation incubation effect is removed by dithiothreitol at concentrations which do not affect the radiosensitization level of the nitroaromatic sensitizer. This result indicates that the active metabolite probably depletes a certain amount of the free-thiol compounds inside the cell which assist in the repair of radiation-induced damage

  11. Radiosensitization and hypoxic cell toxicity of NLA-1 and NLA-2, two new bioreductive compounds

    Energy Technology Data Exchange (ETDEWEB)

    Papadopoulou, M.V.; Epperly, M.W.; Shields, D.S. (Pittsburgh Cancer Institute PA (USA)); Bloomer, W.D.

    1992-04-01

    Two new bioreductive compounds, 9-(3-(2-nitro-1-imidazolyl)propylamino)acridine hydrochloride (NLA-1) and 9-(2-(2-nitro-1-imidazolyl)ethylamino)acridine hydrochloride (NLA-2), have been prepared. They feature an acridine ring to intercalate with DNA, a 2-nitroimidazole ring as the radiosensitizing moiety and an amino functionality for increased DNA-binding and hydrophilicity. Time concentration dependent cytotoxicity as well as radiosensitization efficacy of the two compounds under hypoxic or aerobic conditions were determined in vitro using V-79 cells and an MTT colorimetric or clonogenic assay. The isosensitization point (ISP), defined as that drug concentration which results in the same survival decrement upon exposure of hypoxic of oxygenated cells to a given radiation dose, has been determined for both compounds at 7.5 Gy and the values are significantly lower than the ISPs of 5-(3-(2-nitro-1-imidazolyl)propyl)phenanthridinium bromide, 2-(2-nitro-1-imidazolyl)ethylamine or misonidazole (MISO). NLA-1 and NLA-2 are potent hypoxic cytotoxins and on a concentration basis, more potent than MISO as radiosensitizers in vitro. The sensitization enhancement ratios were significantly increased when 1 h drug preincubation under hypoxia at 37degC was applied, before irradiation at room temperature. (author).

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Effect of elemene on radiosensitivity of A549 cells and its possible molecular mechanism

    International Nuclear Information System (INIS)

    Objective: To investigate the effect of elemene on the radiosensitivity of A549 cells and its possible molecular mechanism. Methods: The effect of radiosensitivity was detected by colony forming assay. The protein expressions of DNA-PKcs, Bcl-2 and P53 were detected with Western blot. The correlation between the protein expression of DNA-PKcs and Bcl-2, DNA-PKcs and P53 was analyzed. Results: Elemene had radiosensitizing effect on A549 cells, with the SERD0 and SERDq 1.54 ± 0.20 and 1.43±0.15, respectively for 10 μg/ml elemene, and 1.63 ±0.32 and 1.75 ±0.19, respectively for 20 μg/ml elemene. Compared with irradiation group, the expression of DNA-PKcs was reduced significantly in 10, 20 μg/ml elemene combined with radiation group (t=7.52, 8.33, P<0.05), so was for Bcl-2 (t=10.74, 11.33, P<0.05). The expression of P53 protein increased significantly (t=-9.25, 7.66, P<0.05). There was a remarkable negative correlation between the expression of DNA-PKcs and P53 (r=-0.569, P<0.05), and a remarkable positive correlation between DNA-PKcs and Bcl-2 (r=0.755, P<0.05 ). Conclusions: Elemene has radiosensitizing effect on A549 cells, which might be related to down-regulation of DNA-PKcs gene expression, up-regulation of P53 and down-regulation of Bcl-2. (authors)

  14. EGFR-dependent Impact of Indol-3-Carbinol on Radiosensitivity 
of Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Xiao XIAO

    2012-07-01

    Full Text Available Background and objective Indole-3-carbinol (I3C is a naturally occurring phytochemical found in cruciferous vegetables. The aim of the present study is to investigate the influence of I3C on radiosensitivity in epidermal growth factor receptor (EGFR-positive and EGFR-negative lung cancer cell lines. Methods Human lung adenocarcinoma NIH-H1975 cells and human lung squamous carcinoma NIH-H226 and NIH-H520 cells were routinely cultured in RPMI-1640. MTT assay and clonogenic assay were used to detect cell growth and survival, respectively. Western blot and RT-PRC assay was employed to detect EGFR protein and mRNA expression. Results 5 μmol/L of I3C significantly reduced radiosensitivity of EGFR-positive NIH-H1975 and NIH-H226 cells, but failed to affect radiosensitivity of EGFR-negative NIH-H520 cells. Furthermore, I3C caused an increased expression of total EGFR and pEGFR (Y845 protein in NIH-H1975 and NIH-H226 cell lines, but not in NIH-H520 cell line. A reduction of EGFR expression by EGFR-siRNA significantly inhibited I3C-caused radioresistance in NIH-H1975 cells. Conclusion Our data presented here for the first time demonstrate that I3C reduces radiosensitivity of lung cancer cells by mediating EGFR expression, indicating that EGFR may be an important target for I3C-mediated radioresistance in lung cancer.

  15. Impact of various parameters in detecting chromosomal aberrations by FISH to describe radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Keller, U.; Mueller, E.; Grabenbauer, G.; Sauer, R.; Distel, L. [Div. of Radiobiology, Dept. of Radiotherapy, Erlangen (Germany); Kuechler, A. [Div. of Radiotherapy, Dept. of Radiology, Jena (Germany); Inst. for Human Genetics and Anthropology, Jena (Germany); Liehr, T. [Inst. for Human Genetics and Anthropology, Jena (Germany)

    2004-05-01

    Background and purpose: analysis of radiation-induced chromosomal aberrations is regarded as the ''gold standard'' for classifying individual radiosensitivity. A variety of different parameters can be used. The crucial question, however, is to explore which parameter is suited best to describe the differences between patients with increased radiosensitivity and healthy individuals. Patients and methods: in this study, five patients with severe radiation-induced late effects of at least grade 3, classified according to the Radiation Therapy Oncology Group (RTOG), and eleven healthy individuals were examined retrospectively. Peripheral blood lymphocytes were irradiated in vitro with 0.7 Gy and 2.0 Gy prior to cultivation and stained by means of three-color fluorescence in situ hybridization (FISH). The detailed analysis was focused on the number of breaks per metaphase, on breaks from complex chromosomal rearrangements per metaphase, as well as on the percentage of translocations, dicentric chromosomes, breaks, and excess acentric fragments - each in comparison with the total number of mitoses analyzed. Results: using the number of breaks from complex chromosomal rearrangements after 2.0 Gy, radiosensitive patients as endpoint were clearly to be distinguished (p = 0.001) from healthy individuals. Translocations (p = 0.001) as well as breaks per metaphase (p = 0.002) were also suitable indicators for detecting differences between patients and healthy individuals. The parameters ''percentage of dicentric chromosomes'', ''breaks'', and ''excess acentric fragments'' in comparison to the total number of mitoses analyzed could neither serve as meaningful nor as significant criteria, since they showed a strong interindividual variability. Conclusion: to detect a difference in chromosomal aberrations between healthy and radiosensitive individuals, the parameters ''frequency of breaks

  16. MicroRNA-449a enhances radiosensitivity in CL1-0 lung adenocarcinoma cells.

    Directory of Open Access Journals (Sweden)

    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.

  17. Telomere loss, not average telomere length, confers radiosensitivity to TK6-irradiated cells

    Energy Technology Data Exchange (ETDEWEB)

    Berardinelli, F.; Nieri, D.; Sgura, A.; Tanzarella, C. [Dip. Di Biologia, Università “Roma Tre”, Rome (Italy); INFN – “Roma Tre”, Rome (Italy); Antoccia, A., E-mail: antoccia@uniroma3.it [Dip. Di Biologia, Università “Roma Tre”, Rome (Italy); INFN – “Roma Tre”, Rome (Italy)

    2012-12-15

    Highlights: ► Ionizing radiation induced telomere lengthening in TK6 clones from a single cell. ► Telomerase is not involved in the telomere lengthening observed. ► TK6 cells display very heterogeneous values in telomere length and telomere loss. ► A selective process account for telomere lengthening in irradiated cells. ► Telomere loss, not mean telomere length, is predictive of radiosensitivity. - Abstract: Many and varied are the proposed mechanisms that lead to resistance to ionizing radiation treatment. Among them, an inverse relationship between telomere length and radioresistance has been recently advanced. Investigating such a relationship in TK6 lymphoblasts, we found that clones originating from cells survived to 4 Gy of X-rays showed a significantly higher telomere length when compared with clones grown from untreated cells. The lengthening observed was not attributable to a radiation-induced increase in telomerase activity, as demonstrated by TRAP assay performed in the dose range of 1–10 Gy. Given the evidence that TK6 whole population was characterized by heterogeneity in cellular mean telomere length and telomere loss, we tested the hypothesis that a process of selection may favour cells with longer telomeres (more radioresistant cells) following exposure to irradiation. In order to do this 15 independent TK6 clones were selected and characterized for telomere length and loss on the basis of q-FISH and flow-FISH analysis. Among the screened clones four characterized by long telomeres and four characterized by short telomeres were tested for their radiosensitivity by means of clonogenic assay. The results obtained showed that, in our experimental conditions (cellular model, radiation doses) no significant correlation was observed between radiosensitivity and mean telomere lengths, whereas a positive correlation was observed with respect to telomere loss. Overall, these results indicate that telomere loss and not mean telomere length plays

  18. Fulvestrant radiosensitizes human estrogen receptor-positive breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jing, E-mail: wangstella5@163.com [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China); Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China); Yang, Qifeng, E-mail: qifengy@gmail.com [Department of Breast Surgery, Qilu Hospital, Shandong Univeristy, Wenhua Xi Road 107, Shandong Province (China); Haffty, Bruce G., E-mail: hafftybg@umdnj.edu [Department of Radiation Oncology, UMDNJ-Robert Wood Johnson School of Medicine, Cancer Institute of New Jersey, NB (United States); Li, Xiaoyan, E-mail: xiaoyanli1219@gmail.com [Department of Oncology, Affiliated Hospital of Qingdao University Medical College, Shandong Province (China); Moran, Meena S., E-mail: meena.moran@yale.edu [Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT (United States)

    2013-02-08

    Highlights: ► Fulvestrant radiosensitizes MCF-7 cells. ► Fulvestrant increases G1 arrest and decreases S phase in MCF-7 cells. ► Fulvestrant down-regulates DNA-PKcs and RAD51 in MCF-7 cells. -- Abstract: The optimal sequencing for hormonal therapy and radiation are yet to be determined. We utilized fulvestrant, which is showing promise as an alternative to other agents in the clinical setting of hormonal therapy, to assess the cellular effects of concomitant anti-estrogen therapy (fulvestrant) with radiation (F + RT). This study was conducted to assess the effects of fulvestrant alone vs. F + RT on hormone-receptor positive breast cancer to determine if any positive or negative combined effects exist. The effects of F + RT on human breast cancer cells were assessed using MCF-7 clonogenic and tetrazolium salt colorimetric (MTT) assays. The assays were irradiated with a dose of 0, 2, 4, 6 Gy ± fulvestrant. The effects of F + RT vs. single adjuvant treatment alone on cell-cycle distribution were assessed using flow cytometry; relative expression of repair proteins (Ku70, Ku80, DNA-PKcs, Rad51) was assessed using Western Blot analysis. Cell growth for radiation alone vs. F + RT was 0.885 ± 0.013 vs. 0.622 ± 0.029 @2 Gy, 0.599 ± 0.045 vs. 0.475 ± 0.054 @4 Gy, and 0.472 ± 0.021 vs. 0.380 ± 0.018 @6 Gy RT (p = 0.003). While irradiation alone induced G2/M cell cycle arrest, the combination of F + RT induced cell redistribution in the G1 phase and produced a significant decrease in the proportion of cells in G2 phase arrest and in the S phase in breast cancer cells (p < 0.01). Furthermore, levels of repair proteins DNA-PKcs and Rad51 were significantly decreased in the cells treated with F + RT compared with irradiation alone. F + RT leads to a decrease in the surviving fraction, increased cell cycle arrest, down regulating of nonhomologous repair protein DNA-PKcs and homologous recombination repair protein RAD51. Thus, our findings suggest that F + RT

  19. Radiosensitization of non-small cell lung carcinoma by EGFR inhibition

    Directory of Open Access Journals (Sweden)

    Keta Otilija D.

    2014-01-01

    Full Text Available Molecular targeted cancer therapy is a promising treatment strategy. Considering the central role of the epidermal growth factor receptor in cell proliferation and survival, there are indications that targeted agents like tyrosine kinase inhibitors, i. e., erlotinib, may enhance the antitumor treatment by radiation. The aim of this study is to analyze the inactivation effects of g-rays and to test the radiosensitizing potential of erlotinib on human lung adenocarcinoma cells in vitro. Irradiations were performed with doses ranging from 1 Gy to 8 Gy. In order to increase the radiosensitivity of CRL-5876 lung adenocarcinoma cells, the cells were treated with a clinically relevant concentration of 2 µM erlotinib. The effects of single and combined treatments were monitored using clonogenic survival, cell viability and proliferation assays at different time points. For the detection and visualization of the phosphorylated histone H2AX (γ-H2AX, an important biological marker of DNA double-strand break formation, fluorescence immunocytochemistry, was performed. The response to the treatment was monitored at four time points: 30 min, 2, 6, and 24 h. Irradiations with g-rays resulted in significant cell inactivation regarding all analyzed biological endpoints. Combined treatments revealed consistent cell inactivation. Moreover, compared to g-rays alone, elevated levels of g-H2AX foci were observed after pretreatment with erlotinib, indicating radiosensitization through impaired DNA repair. [Projekat Ministarstva nauke Republike Srbije, br. 173046 i br. 171019

  20. Radiosensitivity of two propagules of citrus; Radiossensibilidade de dois tipos de propagulos de citros

    Energy Technology Data Exchange (ETDEWEB)

    Gonzaga, Daniela Loschtschagina; Latado, Rodrigo Rocha; Pio, Rose Mary, E-mail: rodrigo@centrodecitricultura.b [Instituto Agronomico de Campinas, Cordeiropolis, SP (Brazil). Centro Avancado de Pesquisa Tecnologica do Agronegocio de Citros Sylvio Moreira; Tulmann Neto, Augusto [Centro de Energia Nuclear na Agricultura (CENA/USP), Piracicaba, SP (Brazil)

    2011-07-01

    Studies have shown that the radiosensitivity in plants varies depending on the varieties and the propagules used in mutagenic treatment. The purpose of this study was to evaluate the radiosensitivity of two types of propagules (buds and in vitro segments of epicotyl) in 'Murcott' tangor, 'Thomas' and 'Fremont' mandarins and 'Rangpur' lime (only in vitro segments of epicotyl) and to compare the gamma-rays sensitivity among propagules and among varieties. The following doses were used: 0, 10, 20, 30, 40 and 50 Gy of gamma-rays. The parameters shoot mortality and shoot height, for experiment of bud irradiation, and number of regenerated shoots per explant and percentage of responsive explants, for experiment of epicotyl segments irradiation were evaluated after 60 days. The mutagenic doses tested in buds caused significant reduction in shoot height of all varieties. In the experiment of irradiation of in vitro segments of epicotyl, only 'Murcott' tangor and 'Rangpur' lime showed significant reduction in the number of regenerated shoots per explant, due to the increase of mutagen doses. Results indicate that radiosensitivity of in vitro (segments of epicotyl) and in vivo (buds) propagules is variable depending on the variety. Also, in some cases the in vitro propagules are more sensitive, to irradiation and in other cases, there is no differential sensibility (author)

  1. Radiosensitizing effect of medroxyprogesterone acetate on endometrial cancer cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Huber, H.; Husslein, P.; Michalica, W.; Wagenbichler, P.

    1984-09-15

    From clinical experience it is known that medroxyprogesterone acetate (MPA) can increase the radiosensitivity of adenocarcinomas of the corpus uteri. This study investigates this phenomenon in vitro. Primary explants of highly differentiated adenocarcinomas were irradiated with or without pretreatment with MPA and compared with an untreated control group and to a group treated with MPA only. Cell culture itself was performed on an agarose medium in order to prevent overgrowth by fibroblasts. Untreated samples formed 43 +/- 5 clones, explants treated with MPA only produced 39 +/- 5 clones, a difference which was not statistically different; samples irradiated without pretreatment produced 16 +/- 8 and samples after combined treatment 9 +/- 3 clones (all values means +/- SD). This numeric reduction of cell growth through preirradiation treatment with MPA was statistically significant. The effect of MPA as a radiosensitizer may be due to its potential to prolong the radiosensitive G2 phase of the cell cycle. This effect of MPA may be useful also in other hormone-dependent tumors.

  2. Micronucleus assay as radiosensitivity indicator in head and neck tumor patients. Retrospective and prospective study

    International Nuclear Information System (INIS)

    differences between observed and expected MN frequencies and thus, individual radiosensitivity or adioresistance. Prospective evaluation: 15 patients with H and N and cervix tumors, undergoing radiation therapy as part of their oncological protocol, were prospectively analyzed; the blood for MN assay was obtained from the patients during fractionated therapy. Blood samples were taken just before treatment, mid-way during treatment and /or on completion of treatment.The cytogenetic data were analyzed 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) and its correlation with the individual radiosensitivity. Results: In the retrospective evaluation, lymphocytes from 3 of the 4 patients that developed late reactions were significantly more radiosensitive than lymphocytes from the rest of the patients and normal donors. The individual cytogenetic response suggests a correlation with the maximum grade of late reaction (osteonecrosis, fibrosis and trismus). In the prospective evaluation, a significant difference between patient's data and the calibration curve was found above 2 Gy of equivalent whole body dose. Factor (k) correlated with the individual radiosensitivity. Patients with low recovery from the cytogenetic effect (k tending to zero) developed late toxicity (fibrosis, trismus and actinic rectitis). Conclusions: In the retrospective evaluations, both, spontaneous and radiation induced micronucleus frequencies were significantly increased, compared with the expected values from the calibration curve, in those patients who had developed late tissue reactions. This hypersensitivity to radiation may be due to a lack of repair capacity of DNA damage.In the prospective evaluations, in vitro irradiation of the patient blood samples before radiation therapy was not predictive of the individual cytogenetic response. In the same group of

  3. Effect of E1A gene on radiosensitivity of human laryngeal carcinoma cells and its correlated mechanisms

    International Nuclear Information System (INIS)

    Objective: To investigate the effect of E1A gene on the radiosensitivity of human laryngeal carcinoma cells and its correlated mechanisms. Methods: The Ad-E1A and Ad-β-gal were amplificated in Hek293 cells, extracted by freezing(-80 degree C) and thawing (37 degree C) repeatedly (3 times), purificated by the method of density gradient of CsCl and titrated by plaque assay method. Then they were transfected into human laryngeal carcinoma cells (Hep-2) and authenticated by RT-PCR. The radiosensitivity of Hep-2 cells transfected with or without E1A were studied by cell survival curve. Finally we investigated the correlated mechanisms including cell apoptosis studied by flow cytometry and VEGF content studied by RT-PCR. Results: The radiosensitivity of Hep-2 cells transfected with E1A was intensified, D0 and Dq were lowered and α was increased. Flow cytometry showed that the apoptosis rate of cells with E1A or with E1A and radiotherapy was increased. The VEGF content of the cells transfected with E1A or treated by radiotherapy was decreased, which reached the lowest level when the cells were treated with the both methods. Conclusions: E1A gene can intensify the radiosensitivity and contribute to the apoptosis of human laryngeal carcinoma cells. E1A gene and radiotherapy can markedly decrease the VEGF content. (authors)

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

    Science.gov (United States)

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

    2016-09-01

    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. PMID:27381867

  5. Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  6. Chemosensitization and radiosensitization of a lung cancer cell line A549 induced by a composite polymer micelle.

    Science.gov (United States)

    Xu, Jing; Zhang, Bi-Cheng; Li, Xiang-Long; Xu, Wen-Hong; Zhou, Juan; Shen, Li; Wei, Qi-Chun

    2016-08-01

    Multidrug resistance (MDR) to Doxorubicin (DOX) remains a major obstacle to successful cancer treatment. The present study sought to overcome the MDR of lung cancer cells and achieve radiosensitization by developing a composite DOX-loaded micelle (M-DOX). M-DOX containing PEG-PCL/Pluronic P105 was prepared by the solvent evaporation method. Lung cancer cell line A549 was adopted in this study. In vitro cytotoxicity, cellular uptake behavior, subcellular distribution, and radiosensitivity were evaluated by the treatment with M-DOX, and free DOX was used as a control. A549 cells treated with M-DOX as opposed to free DOX showed greater cellular uptake as well as greater cytotoxicity. Furthermore, M-DOX reached the mitochondria and lysosome effectively after cellular uptake, and fluorescence used to track M-DOX was found to be surrounding the nucleus. Finally, colony-forming assays demonstrated that M-DOX treatment improved radiosensitization when compared to free DOX. Based on the increased cytotoxicity and radiosensitization, M-DOX could be considered as a promising drug delivery system to overcome MDR in lung cancer therapy. PMID:27585226

  7. Silver nanoparticles outperform gold nanoparticles in radiosensitizing U251 cells in vitro and in an intracranial mouse model of glioma

    Science.gov (United States)

    Liu, Peidang; Jin, Haizhen; Guo, Zhirui; Ma, Jun; Zhao, Jing; Li, Dongdong; Wu, Hao; Gu, Ning

    2016-01-01

    Radiotherapy performs an important function in the treatment of cancer, but resistance of tumor cells to radiation still remains a serious concern. More research on more effective radiosensitizers is urgently needed to overcome such resistance and thereby improve the treatment outcome. The goal of this study was to evaluate and compare the radiosensitizing efficacies of gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) on glioma at clinically relevant megavoltage energies. Both AuNPs and AgNPs potentiated the in vitro and in vivo antiglioma effects of radiation. AgNPs showed more powerful radiosensitizing ability than AuNPs at the same mass and molar concentrations, leading to a higher rate of apoptotic cell death. Furthermore, the combination of AgNPs with radiation significantly increased the levels of autophagy as compared with AuNPs plus radiation. These findings suggest the potential application of AgNPs as a highly effective nano-radiosensitizer for the treatment of glioma. PMID:27757033

  8. Cellular Redox Status Regulates Emodin-Induced Radiosensitization of Nasopharyngeal Carcinoma Cells In Vitro and In Vivo

    Directory of Open Access Journals (Sweden)

    Huaxin Hou

    2013-01-01

    Full Text Available Here, we report that regulation of cellular redox status is required for radiosensitization of nasopharyngeal carcinoma (NPC cells by emodin. We evaluated emodin’s radiosensitivity-enhancing ability by using NPC cells in vitro and xenografts in vivo. A clonogenic assay was performed to evaluate NPC cell survival and to determine dose modification factors. Flow cytometry, western blot analysis, and in vivo radiation-induced tumor regrowth delay assays were performed to characterize emodin’s effects. Exposure of CNE-1 NPC cells to emodin enhanced their radiosensitivity. HIF-1α expression significantly increased under hypoxic conditions but did not change after treatment with emodin alone. Emodin downregulated mRNA and protein expression of HIF-1α. Cells exposed to radiation and emodin underwent significant cell cycle arrest at the G2/M phase. The percentage of apoptotic cells and reactive oxygen species (ROS levels were significantly higher in the group exposed to emodin and radiation hypoxic group than in the other groups. Compared to the CNE-1 xenografts exposed to radiation alone, CNE-1 xenografts exposed to radiation with emodin showed significantly enhanced radiation effects. Our data suggest that emodin effectively enhanced the radiosensitivity of CNE-1 cells in vitro and in vivo. The mechanism appears to involve ROS generation and ROS-mediated inhibition of HIF-1α expression.

  9. Paraquat-induced radiosensitization of mammalian cells

    International Nuclear Information System (INIS)

    The herbicide, paraquat (methyl viologen, 1-1' dimethy1-4, 4'-bipyridinium dichloride), stimulates the production of superoxide anion (O2sup(-.)) in aerobic cells and therefore mimics some effects of ionizing radiation. In addition, concentrations of cellular glutathione are reduced by reaction with O2sup(-.). It is reported here that paraquat, toxic in its own right to aerobic cells, acts as a radiosensitizer when cells are exposed to nontoxic concentrations of the drug prior to and during irradiation. The radiomimetic effect of paraquat, alone and in combination with X-rays, was examined. Paraquat affects aerated cells (hamster lung V79 cells) in a dose-dependent manner. Doses in excess of 1 mM for two hours cause significant cell killing. In combination with radiation, sublethal doses of paraquat, given for two hours prior to irradiation, enhance the lethal effects of radiation. However, if cells are exposed to the same concentration of paraquat following irradiation, no additional lethal effect is observed. Paraquat is a useful tool to study the effects of O2sup(-.) and may lead to better understanding of the mechanisms of radiation-induced energy deposition in cells. (author)

  10. Radiosensitivity of cultured insect cells: I. Lepidoptera

    Energy Technology Data Exchange (ETDEWEB)

    Koval, T.M.

    1983-10-01

    The radiosensitivity of five lepidopteran insect cell lines representing five different genera has been investigated. These lines are: (1) TN-368, Trichoplusia ni; (2) IPLB-SF-1254, Spodoptera frugiperda; (3) IPLB-1075, Heliothis zea; (4) MRRL-CHl, clone GVl, Manduca sexta; and (5) IAL-PID2, Plodia interpunctella. The cell lines grew at different rates and had population doubling times that ranged from 19 to 52 hr. All of the lines are highly heteroploid and have approximate chromosome numbers near or above 100. The chromosomes are very small. All of the lines are extremely radioresistant; cell populations are able to recover from 260 kVp X-ray exposures up to and including 400 Gy, the highest dose examined. Cell survival curves were obtainable for only the TN-368 and IPLB-SF-1254 lines. The TN-368 cells displayed a biphasic survival response with D/sub 0/, d/sub q/, and n values of 65.7 and 130.2 Gy, 9.0 and -36.1 Gy, and 1.2 and 0.8, respectively, for the steep and shallow portions of the curve. The IPLB-SF-1254 cells had a D/sub 0/ of 63.9 Gy. D/sub q/ of 19.0 Gy, and n value of 1.4. These studies provide definitive evidence of the radioresistance of lepidopteran cells, and suggest that this radioresistance is a characteristic of lepidopteran insects.

  11. Clonal cell populations unresponsive to radiosensitization induced by telomerase inhibition

    International Nuclear Information System (INIS)

    Research highlights: → In our present manuscript, we have clearly showed an interesting but problematic obstacle of a radiosensitization strategy based on telomerase inhibition by showing that: Clonal population unresponsive to this radiosensitization occasionally arise. → The telomere length of unsensitized clones was reduced, as was that of most sensitized clones. → The unsensitized clones did not show chromosome end fusion which was noted in all sensitized clones. → P53 status is not associated with the occurrence of unsensitized clone. → Telomere end capping in unsensitized clone is operative even under telomerase deficiency. -- Abstract: A combination of a radiotherapeutic regimen with telomerase inhibition is valuable when tumor cells are to be sensitized to radiation. Here, we describe cell clones unresponsive to radiosensitization after telomere shortening. After extensive division of individual transformed clones of mTERC-/- cells, about 22% of clones were unresponsive to radiosensitization even though telomerase action was inhibited. The telomere lengths of unsensitized mTERC-/- clones were reduced, as were those of most sensitized clones. However, the unsensitized clones did not exhibit chromosomal end-to-end fusion to the extent noted in all sensitized clones. Thus, a defense mechanism preventing telomere erosion is operative even when telomeres become shorter under conditions of telomerase deficiency, and results in unresponsiveness to the radiosensitization generally mediated by telomere shortening.

  12. Clonal cell populations unresponsive to radiosensitization induced by telomerase inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Ju, Yeun-Jin; Shin, Hyun-Jin; Park, Jeong-Eun; Juhn, Kyoung-Mi; Woo, Seon Rang; Kim, Hee-Young; Han, Young-Hoon; Hwang, Sang-Gu; Hong, Sung-Hee; Kang, Chang-Mo [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Yoo, Young-Do [Laboratory of Molecular Cell Biology, Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Park, Won-Bong [Division of Natural Science, Seoul Women' s University, Seoul 139-774 (Korea, Republic of); Cho, Myung-Haing [Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul (Korea, Republic of); Park, Gil Hong, E-mail: ghpark@korea.ac.kr [Department of Biochemistry, College of Medicine, Korea University, Seoul (Korea, Republic of); Lee, Kee-Ho, E-mail: khlee@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)

    2010-11-12

    Research highlights: {yields} In our present manuscript, we have clearly showed an interesting but problematic obstacle of a radiosensitization strategy based on telomerase inhibition by showing that: Clonal population unresponsive to this radiosensitization occasionally arise. {yields} The telomere length of unsensitized clones was reduced, as was that of most sensitized clones. {yields} The unsensitized clones did not show chromosome end fusion which was noted in all sensitized clones. {yields} P53 status is not associated with the occurrence of unsensitized clone. {yields} Telomere end capping in unsensitized clone is operative even under telomerase deficiency. -- Abstract: A combination of a radiotherapeutic regimen with telomerase inhibition is valuable when tumor cells are to be sensitized to radiation. Here, we describe cell clones unresponsive to radiosensitization after telomere shortening. After extensive division of individual transformed clones of mTERC{sup -/-} cells, about 22% of clones were unresponsive to radiosensitization even though telomerase action was inhibited. The telomere lengths of unsensitized mTERC{sup -/-} clones were reduced, as were those of most sensitized clones. However, the unsensitized clones did not exhibit chromosomal end-to-end fusion to the extent noted in all sensitized clones. Thus, a defense mechanism preventing telomere erosion is operative even when telomeres become shorter under conditions of telomerase deficiency, and results in unresponsiveness to the radiosensitization generally mediated by telomere shortening.

  13. Phenotypic Heterogeneity in Cell Proliferation and Radiosensitivity in Human Laryngocarcinoma Hep-2 Cells

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    1 IntroductionRadiotherapy is one of the major clinical treatments for malignant tumors. However, tumor cells are heterogenic in response to radiation (radiosensitivity) which limits the achievement ratio of radiotherapy in many non-sensitive tumors. At the same time, radiosensitivity plays an important role in radiobiology and it is regarded as the fifth “R”- Radiosensitivity in fractionation radiotherapy. Understanding the mechanism of heterogeneity of tumor cell radiosensitivity is critical in radiation ...

  14. Optical control of DNA-base radio-sensitivity

    CERN Document Server

    Abolfath, Ramin M

    2009-01-01

    {\\bf Purpose}: Manipulation of the radio-sensitivity of the nucleotide-base driven by the spin blockade mechanism of diffusive free radicals against ionizing radiation. {\\bf Materials and methods}: We theoretically propose a mechanism which uses the simultaneous application of circularly polarized light and an external magnetic field to control the polarization of the free radicals and create S=1 electron-hole spin excitations (excitons) on nucleotide-base. We deploy an ab-initio molecular dynamics model to calculate the characteristic parameters of the light needed for optical transitions. {\\bf Results}: As a specific example, we present the numerical results calculated for a Guanine, in the presence of an OH free radical. To increase the radio-resistivity of this system, a blue light source for the optical pumping and induction of excitons on guanine can be used. {\\bf Conclusions}: The effect of spin-injection on the formation of a free energy barrier in diffusion controlled chemical reaction pathways leads...

  15. Effect of anesthetics on the radiosensitivity of a murine tumor

    Energy Technology Data Exchange (ETDEWEB)

    Sheldon, P.W.; Chu, A.M.

    1979-09-01

    The effect of four anesthetics on the single dose of x rays required to locally control 50% of implanted MT tumors was investigated. Compared with unanesthetized animals, no change in radiosensitivity was observed if mice were irradiated under either tribromoethanol or fentanyl-fluanisone-diazepam anesthesia. However, a small but significant degree of radioprotection was observed under chloral hydrate or pentobarbital anesthesia. Hypothermia or increased hypoxia are considered unlikely mechanisms for the protection, a direct chemical action being most probable. The preferred method for immobilizing the mice in order to locally irradiate the tumors was by simple physical restraint (with care taken to minimize physiological stress). However, if anesthesia was a necessity, the present work suggests that for the MT tumor at least the nonprotecting tribromoethanol and fentanyl-fluanisone-diazepam are preferable to the protecting chloral hydrate and pentobarbital. Tribromoethanol is preferable to fetanyl-fluanisone-diazepam in that it produces a smaller drop in temperature. However, it is only a short-acting anesthetic, and prolongation of the state of anesthesia by repeated doses simply prolongs the temperature decline so that there may be no real benefit over fentanyl-fluanisone-diazepam.

  16. Targeted Radiosensitization by the Chk1 Inhibitor SAR-020106

    Energy Technology Data Exchange (ETDEWEB)

    Borst, Gerben R., E-mail: g.borst@nki.nl [The Institute of Cancer Research, London (United Kingdom); Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); McLaughlin, Martin; Kyula, Joan N.; Neijenhuis, Sari; Khan, Aadil; Good, James; Zaidi, Shane [The Institute of Cancer Research, London (United Kingdom); Powell, Ned G. [HPV Research Group, School of Medicine, Cardiff University, Cardiff (United Kingdom); Meier, Pascal; Collins, Ian; Garrett, Michelle D. [The Institute of Cancer Research, London (United Kingdom); Verheij, Marcel [Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands); Harrington, Kevin J. [The Institute of Cancer Research, London (United Kingdom)

    2013-03-15

    Purpose: To explore the activity of a potent Chk1 inhibitor (SAR-020106) in combination with radiation. Methods and Materials: Colony and mechanistic in vitro assays and a xenograft in vivo model. Results: SAR-020106 suppressed-radiation-induced G{sub 2}/M arrest and reduced clonogenic survival only in p53-deficient tumor cells. SAR-020106 promoted mitotic entry following irradiation in all cell lines, but p53-deficient cells were likely to undergo apoptosis or become aneuploid, while p53 wild-type cells underwent a postmitotic G{sub 1} arrest followed by subsequent normal cell cycle re-entry. Following combined treatment with SAR-020106 and radiation, homologous-recombination-mediated DNA damage repair was inhibited in all cell lines. A significant increase in the number of pan-γH2AX-staining apoptotic cells was observed only in p53-deficient cell lines. Efficacy was confirmed in vivo in a clinically relevant human head-and-neck cell carcinoma xenograft model. Conclusion: The Chk1 inhibitor SAR-020106 is a potent radiosensitizer in tumor cell lines defective in p53 signaling.

  17. 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...

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

    DEFF Research Database (Denmark)

    Feketeova, Linda; Bassler, Niels

    Purpose(s): Radiosensitizers are commonly used in radiotherapy in Denmark (following the DAHANCA 5 clinical trail) to enhance tumour control of radioresistant hypoxic tumours. Radiosensitizers implemented particularly in the treatment of hypoxic cells are called ‘electron-affinic’ radiosensitizer...

  19. HPV-positive HNSCC cell lines but not primary human fibroblasts are radiosensitized by the inhibition of Chk1

    International Nuclear Information System (INIS)

    Purpose: Despite the comparably high cure rates observed for HPV-positive HNSCC, there is still a great need for specific tumor radiosensitization due to the often severe side effects resulting from intense radiochemotherapy. We recently demonstrated that HPV-positive HNSCC cell lines are characterized by a defect in DNA double-strand break repair associated with a pronounced G2-arrest. Here we tested whether abrogation of this radiation-induced G2-arrest by the inhibition of Chk1 results in specific radiosensitization of HPV-positive HNSCC cells. Materials and methods: Experiments were performed with five HPV and p16-positive (93-VU-147T, UM-SCC-47, UT-SCC-45, UD-SCC-2, UPCI-SCC-154) and two HPV and p16-negative HNSCC cell lines, as well as two normal human fibroblast strains. Chk1 was inhibited by the selective inhibitor PF-00477736. Cell cycle distribution was determined by flow cytometry, Chk1-activity via Western blot and cell survival by colony formation assay. Results: With the exception of UPCI-SCC-154, the inhibition of Chk1 was found to abolish the pronounced radiation-induced G2-arrest in all HPV-positive cells utilized. All tumor cell lines that demonstrated the abrogation of G2-arrest also demonstrated radiosensitization. Notably, in G1-arrest-proficient normal human fibroblasts no radiosensitization was induced. Conclusion: Abrogation of the G2 checkpoint through the inhibition of Chk1 may be used to selectively increase the cellular radiosensitivity of HPV-positive HNSCC without affecting the surrounding normal tissue

  20. Correlation of RAD51 and radiosensitization of methotrexate

    International Nuclear Information System (INIS)

    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)

  1. Recent data on biological and clinical properties of radiosensitizers

    International Nuclear Information System (INIS)

    In order to reduce the radioresistance due, among others, to hypoxia in solid tumors, research on radiosensitizers (especially the electron-affinic sensitizers) has been active for many years. The radiosensitization efficiency and the cytotoxic and transforming effects of a great number of substances was first studied in vitro. Then two drugs, metronidazole and misonidazole, were tested especially in vivo in animals; this research concerned their effect both on tumors and on normal tissues. After presenting an overwiew of the experimental results, we summarize the preliminary results of the first clinical trials with misonidazole. The general tolerance to this drug is now well known: its local influence on tumors and also normal tissues radiosensitivity is the object of most of the present clinical trials

  2. Cellular radiosensitivity of small-cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Krarup, M; Poulsen, H S; Spang-Thomsen, M

    1997-01-01

    . The multitarget single hit model was applied to calculate the cellular radiosensitivity (D0), the capacity for sublethal damage repair (Dq), and the extrapolation number (n). Values for alpha and beta were determined from best-fit curves according to the linear-quadratic model and these values were applied...... to calculate the surviving fraction after 2-Gy irradiation (SF2). RESULTS: In our investigation, the extrapolation method proved to be inappropriate for the study of in vitro cellular radiosensitivity due to lack of reproducibility. The results obtained by the clonogenic assay showed that the cell lines...

  3. The heritability of G2 chromosomal radiosensitivity and its association with cancer in Danish cancer survivors and their offspring

    DEFF Research Database (Denmark)

    Curwen, Gillian B; Cadwell, Kevin K; Winther, Jeanette Falck;

    2010-01-01

    To investigate the relationship between chromosomal radiosensitivity and early-onset cancer under the age of 35 years and to examine the heritability of chromosomal radiosensitivity.......To investigate the relationship between chromosomal radiosensitivity and early-onset cancer under the age of 35 years and to examine the heritability of chromosomal radiosensitivity....

  4. The long non-coding RNA HOTAIR affects the radiosensitivity of pancreatic ductal adenocarcinoma by regulating the expression of Wnt inhibitory factor 1.

    Science.gov (United States)

    Jiang, Yanhui; Li, Zhihua; Zheng, Shangyou; Chen, Huimou; Zhao, Xiaohui; Gao, Wenchao; Bi, Zhuofei; You, Kaiyun; Wang, Yingxue; Li, Wenzhu; Li, Liting; Liu, Yimin; Chen, Rufu

    2016-03-01

    Pancreatic ductal adenocarcinoma (PDAC) is seriously resistant to radiotherapy and the mechanism is largely unknown. HOX transcript antisense intergenic RNA (HOTAIR) is overexpressed in PDAC. However, the function of HOTAIR has never been related to the radiosensitivity of PDAC. In this present study, the expression of HOTAIR in the PDAC cell lines and tissues was measured by quantitative real-time PCR (qRT-PCR), and the association between HOTAIR expression levels and X-ray treatment in PDAC cell lines was investigated. Additionally, the influence of HOTAIR knockdown on radiosensitivity, proliferation, and apoptosis of PDAC cells after radiation was evaluated by colony formation assays, Cell Counting Kit-8 (CCK-8) assays, and flow cytometry, respectively. Furthermore, the correlation between HOTAIR and Wnt inhibitory factor 1 (WIF-1) expression in PDAC cell lines and tissues was studied to assess the role of HOTAIR and WIF-1 in the radiosensitivity of PDAC. The results confirmed that HOTAIR expression was significantly increased in the PDAC cell lines and tissues (n = 90) compared with human normal pancreatic ductal epithelial cell line (HPDE) and matched adjacent normal tissues (n = 90). Functionally, HOTAIR knockdown enhanced the radiosensitivity of PDAC cells, reduced the proliferation, and increased the apoptosis of cells after radiation. And HOTAIR silencing increased the expression of WIF-1. Furthermore, the overexpression of WIF-1 revealed that HOTAIR modulated the radiosensitivity of PDAC cells by regulating the expression of WIF-1. These data reveals that HOTAIR can affect the radiosensitivity of PDAC cells partly via regulating the expression of WIF-1, and HOTAIR-WIF-1 axis is a potential target for PDAC radiotherapy. PMID:26482614

  5. Can Drugs Enhance Hypofractionated Radiotherapy? A Novel Method of Modeling Radiosensitization Using In Vitro Data

    International Nuclear Information System (INIS)

    Purpose: Hypofractionated radiotherapy (hRT) is being explored for a number of malignancies. The potential benefit of giving concurrent chemotherapy with hRT is not known. We sought to predict the effects of combined modality treatments by using mathematical models derived from laboratory data. Methods and Materials: Data from 26 published clonogenic survival assays for cancer cell lines with and without the use of radiosensitizing chemotherapy were collected. The first three data points of the RT arm of each assay were used to derive parameters for the linear quadratic (LQ) model, the multitarget (MT) model, and the generalized linear quadratic (gLQ) model. For each assay and model, the difference between the predicted and observed surviving fractions at the highest tested RT dose was calculated. The gLQ model was fitted to all the data from each RT cell survival assay, and the biologically equivalent doses in 2-Gy fractions (EQD2s) of clinically relevant hRT regimens were calculated. The increase in cell kill conferred by the addition of chemotherapy was used to estimate the EQD2 of hRT along with a radiosensitizing agent. For comparison, this was repeated using conventionally fractionated RT regimens. Results: At a mean RT dose of 8.0 Gy, the average errors for the LQ, MT, and gLQ models were 1.63, 0.83, and 0.56 log units, respectively, favoring the gLQ model (p < 0.05). Radiosensitizing chemotherapy increased the EQD2 of hRT schedules by an average of 28% to 82%, depending on disease site. This increase was similar to the gains predicted for the addition of chemotherapy to conventionally fractionated RT. Conclusions: Based on published in vitro assays, the gLQ equation is superior to the LQ and MT models in predicting cell kill at high doses of RT. Modeling exercises demonstrate that significant increases in biologically equivalent dose may be achieved with the addition of radiosensitizing agents to hRT. Clinical study of this approach is warranted.

  6. Can Drugs Enhance Hypofractionated Radiotherapy? A Novel Method of Modeling Radiosensitization Using In Vitro Data

    Energy Technology Data Exchange (ETDEWEB)

    Ohri, Nitin; Dicker, Adam P. [Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Lawrence, Yaacov Richard, E-mail: yaacovla@gmail.com [Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Center for Translational Research in Radiation Oncology, Sheba Medical Center, Tel Hashomer (Israel)

    2012-05-01

    Purpose: Hypofractionated radiotherapy (hRT) is being explored for a number of malignancies. The potential benefit of giving concurrent chemotherapy with hRT is not known. We sought to predict the effects of combined modality treatments by using mathematical models derived from laboratory data. Methods and Materials: Data from 26 published clonogenic survival assays for cancer cell lines with and without the use of radiosensitizing chemotherapy were collected. The first three data points of the RT arm of each assay were used to derive parameters for the linear quadratic (LQ) model, the multitarget (MT) model, and the generalized linear quadratic (gLQ) model. For each assay and model, the difference between the predicted and observed surviving fractions at the highest tested RT dose was calculated. The gLQ model was fitted to all the data from each RT cell survival assay, and the biologically equivalent doses in 2-Gy fractions (EQD2s) of clinically relevant hRT regimens were calculated. The increase in cell kill conferred by the addition of chemotherapy was used to estimate the EQD2 of hRT along with a radiosensitizing agent. For comparison, this was repeated using conventionally fractionated RT regimens. Results: At a mean RT dose of 8.0 Gy, the average errors for the LQ, MT, and gLQ models were 1.63, 0.83, and 0.56 log units, respectively, favoring the gLQ model (p < 0.05). Radiosensitizing chemotherapy increased the EQD2 of hRT schedules by an average of 28% to 82%, depending on disease site. This increase was similar to the gains predicted for the addition of chemotherapy to conventionally fractionated RT. Conclusions: Based on published in vitro assays, the gLQ equation is superior to the LQ and MT models in predicting cell kill at high doses of RT. Modeling exercises demonstrate that significant increases in biologically equivalent dose may be achieved with the addition of radiosensitizing agents to hRT. Clinical study of this approach is warranted.

  7. Use of a temperature-sensitive p53 mutant to evaluate mechanisms of 5-fluorodeoxyuridine-mediated radiosensitization

    International Nuclear Information System (INIS)

    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 G1/S boundary in the presence of the drug. It has been demonstrated that wild type p53 levels increase following fluoropyrimidine treatment and that G1 arrest is associated with increased p53 levels. We hypothesized that the restoration of wild type p53 function might restore G1/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 G1 arrest, S phase depletion, and G2 arrest. In addition, FdUrd-mediated radiosensitization was abrogated

  8. Hereditary syndromes with enhanced radiosensitivity; Erbliche syndromale Erkrankungen mit erhoehter Strahlenempfindlichkeit

    Energy Technology Data Exchange (ETDEWEB)

    Lohmann, D. [Essen Universitaetsklinikum (Germany). Inst. fuer Humangenetik

    2000-07-01

    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.) [German] Die Reaktion auf Strahlenexposition wird durch erbliche genetische Faktoren mit bestimmt. Dieser genetische Einfluss ist besonders deutlich bei Erkrankungen erkennbar, die durch eine erhebliche Disposition zu Entwicklung von Tumoren charakterisiert sind. Zellen von Patienten mit Ataxia Telangiektatika, Nijmegen Breakage Syndrom und Ataxia Telangiektatika-like disorder zeigen eine deutlich veraenderte Reaktion auf ionisierende Strahlen und dieser zellulaeren Reaktion entspricht - zumindest bei Patienten mit Ataxia Telangiektatika - auch eine klinisch nachweisbar erhoehte Strahlenempfindlichkeit. Neben diesen rezessiv erblichen ist auch bei einigen autosomal dominant erblichen Tumordispositionserkrankungen eine erhoehte Strahlenempfindlichkeit nachgewiesen worden. Da Zellen von Patienten autosomal dominant

  9. Hedgehog Pathway Inhibition Radiosensitizes Non-Small Cell Lung Cancers

    Energy Technology Data Exchange (ETDEWEB)

    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.

  10. Radiosensitivity and parameters for its measurement in some cucurbits

    Energy Technology Data Exchange (ETDEWEB)

    Vishnoi, A.K.; Joshi, M.C. (Defence Research and Development Organization, Almora (India). Agricultural Research Unit)

    1981-12-01

    Treatment with gamma-rays resulted in a significant reduction in the germination percentage and root and shoot lengths in Luffa cylindrica (inn). M. Roem, Momordica charantia Linn. Lagenaria siceraria (Mol.) Standl. and Cylanthera pedata Schrad., but radiation had no significant effect on nuclear volume. Species having higher value of nuclear volume had more radiosensitivity.

  11. Role of DNA-PK subunits in radiosensitization by hyperthermia

    NARCIS (Netherlands)

    Woudstra, EC; Konings, AWT; Jeggo, PA; Kampinga, HH

    1999-01-01

    Thermal radiosensitization is thought to result from inhibition of repair of radiation-induced DNA damage, DNA double-strand breaks in particular. Since the DNA-dependent protein kinase (DNA-PK) complex plays a major role in the nonhomologous end-joining of DSBs, it has been suggested that inactivat

  12. Proteomics of protein expression profiling in tissues with different radiosensitivity

    International Nuclear Information System (INIS)

    Ionizing radiation activates multiple signaling pathways, resulting in diverse stress responses including apoptosis, cell cycle arrest, and gene induction. Liver tissue is known to be rather resistant to radiation while a spleen tissue is highly radiosentitive. Our purpose was to compare radioresponse in liver and spleen following exposure to radiation to further investigate the differentially protein expression profile in radiosensitive and radioresistant tissues

  13. Neoadjuvant immunotherapy enhances radiosensitivity through natural killer cell activation.

    Science.gov (United States)

    Chi, Chau-Hwa; Wang, Yu-Shan; Yang, Chieh-Han; Chi, Kwan-Hwa

    2010-02-01

    We investigated whether natural killer (NK) cells in the tumor microenvironment have a radiosensitization effect. The radiosensitization effect of combined CpG and Herceptin((R)) (Genentech, Inc., South San Francisco, CA) (CpG/Herceptin), given before or after radiation, was evaluated by using a murine colon cancer cell line overexpressing human HER2/neu, CT26HER2/neu. In vitro radiosensitization effects were investigated by coculture of CT26HER2/neu with splenocytes, CpG, and Herceptin before applying radiation. Tumor cells, cocultured with CpG-pretreated splenocytes and Herceptin, were more vulnerable to radiation damage. In BALB/c mice injected with CT26HER2/neu, CpG/Herceptin administered before radiotherapy was associated with a better retardation of tumor growth than when administered after radiotherapy. The radiosensitization effect was significantly abrogated by NK-cell depletion, indicating that NK cells play an essential role in it. Further, surviving mice treated with CpG or CpG/Herceptin and reverse transcriptase were resistant to renewed tumor challenge, suggesting the presence of an induced immune response to the tumor. Neoadjuvant immunotherapy with CpG/Herceptin may improve response to radiotherapy of HER2/neu-expressing tumors. PMID:20187795

  14. Artemisinin derivative artesunate induces radiosensitivity in cervical cancer cells in vitro and in vivo

    International Nuclear Information System (INIS)

    Cervical cancer is the third most common type of cancer in women worldwide and radiotherapy remains its predominant therapeutic treatment. Artesunate (ART), a derivative of artemisinin, has shown radiosensitization effect in previous studies. However, such effects of ART have not yet been revealed for cervical cancer cells. The effect of ART on radiosensitivity of human cervical cancer cell lines HeLa and SiHa was assessed using the clonogenic assay. Cell cycle progression and apoptosis alterations were analyzed by flow cytometry. For in vivo study, HeLa or SiHa cells were inoculated into nude mice to establish tumors. Tissues from xenografts were obtained to detect the changes of microvessel density, apoptosis and cell cycle distribution. Microarray was used to analyze differentially expressed genes. ART increased the radiosensitivity of HeLa cells (SER = 1.43, P < 0.001) but not of SiHa cells. Apoptosis and the G2-M phase transition induced by X-ray irradiation (IR) were enhanced by ART via increased Cyclin B1 expression in HeLa cells. Tumor growth of xenografts from HeLa but not SiHa cells was significantly inhibited by irradiation combined with ART (tumor volume reduction of 72.34% in IR + ART group vs. 41.22% in IR group in HeLa cells and 48.79% in IR + ART group vs. 44.03% in IR alone group in SiHa cells). Compared with the irradiated group, cell apoptosis was increased and the G2/M cell cycle arrest was enhanced in the group receiving irradiation combined with ART. Furthermore, compared with radiation alone, X-ray irradiation plus ART affected the expression of 203 genes that function in multiple pathways including RNA transport, the spliceosome, RNA degradation and p53 signaling. ART potently abrogates the G2 checkpoint control in HeLa cells. ART can induce radiosensitivity of HeLa cells in vitro and in vivo

  15. A potential pitfall in the use of electroporation: cellular radiosensitization by pulsed high-voltage electric fields

    International Nuclear Information System (INIS)

    CHO cells have been exposed to high-voltage electric fields causing electroporation (EP) and the interaction between EP and radiation-induced cell lethality investigated. There was a voltage-dependent decrease in plating efficiency, assessed immediately following EP, and cell viability, assessed at 24 h. A linear decrease was seen for both, accompanied by a voltage-dependent increase in cell volume, assessed immediately following EP. A good correlation between increases in cell volume and decreases in plating efficiency was seen (τ = -0.91). The application of electric fields immediately prior to, or following, irradiation led to radiosensitization of the cells, which still occurred when a 6 h interval was left between radiation and EP but was lost when cells were irradiated 24 h prior to EP. When cells were irradiated following EP, radiosensitization was lost with a 1 h interval between the two treatments. (author)

  16. Potential clinical impact of normal-tissue intrinsic radiosensitivity testing

    International Nuclear Information System (INIS)

    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 SF2. 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 SF2. 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 assays

  17. The combination of olaparib and camptothecin for effective radiosensitization

    Directory of Open Access Journals (Sweden)

    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

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

    International Nuclear Information System (INIS)

    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

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

    Directory of Open Access Journals (Sweden)

    Brooks Colin

    2012-09-01

    Full Text Available Abstract Background 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. Methods 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. Results 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. Conclusions 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

  20. Investigation of radiosensitivity gene signatures in cancer cell lines.

    Directory of Open Access Journals (Sweden)

    John S Hall

    Full Text Available Intrinsic radiosensitivity is an important factor underlying radiotherapy response, but there is no method for its routine assessment in human tumours. Gene signatures are currently being derived and some were previously generated by expression profiling the NCI-60 cell line panel. It was hypothesised that focusing on more homogeneous tumour types would be a better approach. Two cell line cohorts were used derived from cervix [n = 16] and head and neck [n = 11] cancers. Radiosensitivity was measured as surviving fraction following irradiation with 2 Gy (SF2 by clonogenic assay. Differential gene expression between radiosensitive and radioresistant cell lines (SF2 median was investigated using Affymetrix GeneChip Exon 1.0ST (cervix or U133A Plus2 (head and neck arrays. There were differences within cell line cohorts relating to tissue of origin reflected by expression of the stratified epithelial marker p63. Of 138 genes identified as being associated with SF2, only 2 (1.4% were congruent between the cervix and head and neck carcinoma cell lines (MGST1 and TFPI, and these did not partition the published NCI-60 cell lines based on SF2. There was variable success in applying three published radiosensitivity signatures to our cohorts. One gene signature, originally trained on the NCI-60 cell lines, did partially separate sensitive and resistant cell lines in all three cell line datasets. The findings do not confirm our hypothesis but suggest that a common transcriptional signature can reflect the radiosensitivity of tumours of heterogeneous origins.

  1. WE-G-BRE-08: Radiosensitization by Olaparib Eluting Nanospheres

    Energy Technology Data Exchange (ETDEWEB)

    Tangutoori, S; Kumar, R; Sridhar, S [Northeastern University, Boston, MA (United States); Korideck, H; Makrigiorgos, G [Dana-Farber Cancer Institute, Boston, MA (United States); Cormack, R [Harvard Medical School, Boston, MA (United States)

    2014-06-15

    Purpose: Permanent prostate brachytherapy often uses inert bio-absorbable spacers to achieve the desired geometric distribution of sources within the prostate. Transforming these spacers into implantable nanoplatforms for chemo-radiation therapy (INCeRT) provides a means of providing sustained in-situ release of radiosensitizers in the prostate to enhance the therapeutic ratio of the procedure. Olaparib, a PARP inhibitor, suppresses DNA repair processes present during low dose rate continuous irradiation. This work investigates the radiosensitizing/DNA damage repair inhibition by NanoOlaparib eluting nanospheres. Methods: Human cell line PC3 (from ATCC), was maintained in F12-k medium supplemented with fetal bovine serum. Clonogenic assay kit (from Fischer Scientific) was used to fix and stain the cells to determine the long term effects of irradiation. Nanoparticle size and zeta potential of nanospheres were determined using a Zeta particle size analyzer. The incorporation of Olaparib in nanospheres was evaluated by HPLC. Irradiation was performed in a small animal irradiator operating at 220 KeV.The long term effects of radio-sensitization with olaparib and nanoolaparib was determined using the clonogenic assay at 2 Gy and 4 Gy doses. The cells were allowed to grow for around 10 doubling cycles, The colonies were fixed and stained using clonogenic assay kit. The excess stain was washed off using DI water and the images were taken using a digital camera. Results: Radiosensitization studies were carried out in prostate cancer cell line, PC3 radiation at 0, 2 and 4Gy doses. Strongest dose response was observed with nanoolaparib treated cells compared to untreated cells. Conclusion: A two stage drug release of drug eluting nanospheres from a biodegradable spacer has been suggested for sustained in-situ release of Olaparib to suppress DNA repair processes during prostate brachytherapy. The Olaparib eluting nanospheres had the same in-vitro radiosensitizing effect as

  2. Biomarkers of Radiosensitivity in A-Bomb Survivors Pregnant at the Time of Bombings in Hiroshima and Nagasaki

    OpenAIRE

    Masazumi Akahoshi; Saeko Fujiwara; Kei Nakachi; Yoichiro Kusonoki; Thomas Seed; Yoshiaki Kodama; Eiji Nakashima; Naoko Kamada; Sachiyo Funamoto; Yoshimi Tatsukawa; Miles, Edward F.; Kazuo Neriishi

    2011-01-01

    Purpose. There is evidence in the literature of increased maternal radiosensitivity during pregnancy. Materials and Methods. We tested this hypothesis using information from the atomic-bomb survivor cohort, that is, the Adult Health Study database at the Radiation Effects Research Foundation, which contains data from a cohort of women who were pregnant at the time of the bombings of Hiroshima and Nagasaki. Previous evaluation has demonstrated long-term radiation dose-response effects. Results...

  3. HPV16 E6/E7 Negatively Affect Radiosensitivity of Lung Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    Lu Lu; Qinghui Meng; Ming Cui; Xiaofei Chu; Shuyi Zhao; Huiwen Xiao; Jiali Dong

    2016-01-01

    Objective Lung cancer cells associated with radioresistance are likely to give rise to local recurrence and distant metastatic relapse,but little is known about its underlying mechanisms.In the present paper,the effects of the HPV16 E6 and HPV16 E7 oncoprotein on the radiosensitivity of lung cancer cell lines were investigated.Methods The HPV16 E6 or HPV16 E7 oncoprotein was expressed by a transient transfection with pcDNA3-HPV16 E6 or pcDNA3-HPV16 E7 expression vector.Human lung cancer H2179 cells and mouse lung cancer Lewis cells were exposed to a γ-ray radiation source,cellular survival was evaluated by using a colony formation assay.The expression of HPV16 oncoproteins E6/E7,extracellular signal-regulated kinases 1/2(ERK1/2) and AKT signaling was determined by Western blot assay.VEGF secretion was determined by ELISA.Results Both HPV16 oncoproteins E6 and E7 significantly decreased radiosensitivity of H2179 cells,associated with a promotion of the ERK1/2 and AKT phosphorylation.A decrease of reactive oxygen species(ROS) and an increase of VEGF levels were observed in the cells expressing the HPV16 oncoproteins E6 and E7.Furthermore,a similar reduction of radiosensitivity mediated by the HPV16 oncoproteins E6 and E7 was also observed in a mouse lung cancer Lewis cells.Conclusion The findings indicate that the HPV16 oncoproteins E6 and E7 negatively affects susceptibility of lung cancer cells to radiotherapy via regulation of the ERK1/2 and Akt signaling pathway and VEGF expression.

  4. Comparison of clonogenic assay with premature chromosome condensation assay in prediction of human cell radiosensitivity

    Institute of Scientific and Technical Information of China (English)

    Zhuan-Zi Wang; Wen-Jian Li; Hong Zhang; Jian-She Yang; Rong Qiu; Xiao Wang

    2006-01-01

    AIM: To determine whether the number of non-rejoining G2-chromatid breaks can predict the radiosensitivity of human cell lines.METHODS: Cell lines of human ovary carcinoma cells (HO8910), human hepatoma cells (HepG2) and liver cells (L02) were irradiated with a range of doses and assessed both of cell survival and non-rejoining G2-chromatid breaks at 24 h after irradiation. Cell survival was documented by a colony assay. Non-rejoining G2-chromatid breaks were measured by counting the number of non-rejoining G2 chromatid breaks at 24 h after irradiation, detected by the prematurely chromosome condensed (PCC) technique.RESULTS: A linear-quadratic survival curve was observed in three cell lines, and HepG2 was the most sensitive to y-radiation. A dose-dependent linear increase was observed in radiation-induced non-rejoining G2-PCC breaks measured at 24 h after irradiation in all cell lines, and HepG2 was the most susceptible to induction of non-rejoining G2-PCC breaks. A close correlation was found between the clonogenic radiosensitivity and the radiation-induced non-rejoining G2-PCC breaks (r= 0.923). Furthermore, survival-aberration correlations for two or more than two doses lever were also significant.CONCLUSION: The number of non-rejoining G2 PCC breaks holds considerable promise for predicting the radiosensitivity of normal and tumor cells when two or more than two doses lever is tested.

  5. Adenoviral transduction of human acid sphingomyelinase into neo-angiogenic endothelium radiosensitizes tumor cure.

    Directory of Open Access Journals (Sweden)

    Branka Stancevic

    Full Text Available These studies define a new mechanism-based approach to radiosensitize tumor cure by single dose radiotherapy (SDRT. Published evidence indicates that SDRT induces acute microvascular endothelial apoptosis initiated via acid sphingomyelinase (ASMase translocation to the external plasma membrane. Ensuing microvascular damage regulates radiation lethality of tumor stem cell clonogens to effect tumor cure. Based on this biology, we engineered an ASMase-producing vector consisting of a modified pre-proendothelin-1 promoter, PPE1(3x, and a hypoxia-inducible dual-binding HIF-2α-Ets-1 enhancer element upstream of the asmase gene, inserted into a replication-deficient adenovirus yielding the vector Ad5H2E-PPE1(3x-ASMase. This vector confers ASMase over-expression in cycling angiogenic endothelium in vitro and within tumors in vivo, with no detectable enhancement in endothelium of normal tissues that exhibit a minute fraction of cycling cells or in non-endothelial tumor or normal tissue cells. Intravenous pretreatment with Ad5H2E-PPE1(3x-ASMase markedly increases SDRT cure of inherently radiosensitive MCA/129 fibrosarcomas, and converts radiation-incurable B16 melanomas into biopsy-proven tumor cures. In contrast, Ad5H2E-PPE1(3x-ASMase treatment did not impact radiation damage to small intestinal crypts as non-dividing small intestinal microvessels did not overexpress ASMase and were not radiosensitized. We posit that combination of genetic up-regulation of tumor microvascular ASMase and SDRT provides therapeutic options for currently radiation-incurable human tumors.

  6. The c-Met receptor tyrosine kinase inhibitor MP470 radiosensitizes glioblastoma cells

    International Nuclear Information System (INIS)

    Glioblastoma multiforme (GBM) is resistant to current cytotoxic therapies, in part because of enhanced DNA repair. Activation of the receptor tyrosine kinase c-Met has been shown to protect cancer cells from DNA damage. We hypothesized that inhibiting c-Met would decrease this protection and thus sensitize resistant tumor cells to the effects of radiation therapy. Eight human GBM cell lines were screened for radiosensitivity to the small-molecule c-Met inhibitor MP470 with colony-count assays. Double-strand (ds) DNA breaks was quantified by using antibodies to gamma H2AX. Western blotting demonstrate expression of RAD51, glycogen synthase kinase (GSK)-3β, and other proteins. A murine xenograft tumor flank model was used for in vivo radiosensitization studies. MP470 reduced c-Met phosphorylation and enhanced radiation-induced cell kill by 0.4 logs in SF767 cells. Cells pretreated with MP470 had more ds DNA damage than cells treated with radiation alone. Mechanistically, MP470 was shown to inhibit dsDNA break repair and increase apoptosis. MP470 influences various survival and DNA repair related proteins such as pAKT, RAD51 and GSK3β. In vivo, the addition of MP470 to radiation resulted in a tumor-growth-delay enhancement ratio of 2.9 over radiation alone and extended survival time. GBM is a disease site where radiation is often used to address both macroscopic and microscopic disease. Despite attempts at dose escalation outcomes remain poor. MP470, a potent small-molecule tyrosine kinase inhibitor of c-Met, radiosensitized several GBM cell lines both in vitro and in vivo, and may help to improve outcomes for patients with GBM

  7. Investigation of gold nanoparticle radiosensitization mechanisms using a free radical scavenger and protons of different energies

    International Nuclear Information System (INIS)

    Gold nanoparticles (GNPs) have been shown to sensitize cancer cells to x-ray radiation, particularly at kV energies where photoelectric interactions dominate and the high atomic number of gold makes a large difference to x-ray absorption. Protons have a high cross-section for gold at a large range of relevant clinical energies, and so potentially could be used with GNPs for increased therapeutic effect. Here, we investigate the contribution of secondary electron emission to cancer cell radiosensitization and investigate how this parameter is affected by proton energy and a free radical scavenger. We simulate the emission from a realistic cell phantom containing GNPs after traversal by protons and x-rays with different energies. We find that with a range of proton energies (1–250 MeV) there is a small increase in secondaries compared to a much larger increase with x-rays. Secondary electrons are known to produce toxic free radicals. Using a cancer cell line in vitro we find that a free radical scavenger has no protective effect on cells containing GNPs irradiated with 3 MeV protons, while it does protect against cells irradiated with x-rays. We conclude that GNP generated free radicals are a major cause of radiosensitization and that there is likely to be much less dose enhancement effect with clinical proton beams compared to x-rays. (paper)

  8. Doxorubicin-mediated radiosensitivity in multicellular spheroids from a lung cancer cell line is enhanced by composite micelle encapsulation

    Directory of Open Access Journals (Sweden)

    Xu WH

    2012-05-01

    growth ability verified higher radiosensitivity for the composite micelles loaded with doxorubicin than for free doxorubicin.Conclusion: Our composite doxorubicin-loaded micelle was demonstrated to have radiosensitization. Doxorubicin loading in the composite micelles significantly increased its cellular uptake, improved drug retention, and enhanced its antitumor effect relative to free doxorubicin, thereby providing a novel approach for treatment of cancer.Keywords: doxorubicin, lung cancer, micelles, radiosensitivity, spheroids

  9. 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

  10. Assessment of individual radiosensitivity in human lymphocytes of cancer patients and its correlation with adverse side effects to radiation therapy

    CERN Document Server

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

    2003-01-01

    Background and purpose: Individual radiosensitivity is an inherent characteristic, associated with an increased reaction to ionizing radiation on the human body. Biological endpoints such as clonogenic survival, chromosome aberration formation and repair capacity of radiation-induced damage have been applied to evaluate individual radiosensitivity in vitro. 5%-7% of cancer patients develop adverse side effects to radiation therapy in normal tissues within the treatment field, which are referred as 'clinical radiation reactions' and include acute effects, late effects and cancer induction. It has been hypothesized that the occurrence and severity of these reactions are mainly influenced by genetic susceptibility to radiation. Additionally, the nature of the genetic disorders associated with hypersensitivity to radiotherapy suggests that DNA repair mechanisms are involved. Consequently, the characterization of DNA repair in lymphocytes through cytokinesis blocked micronucleus (MN) and alkaline single-cell micro...

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

    International Nuclear Information System (INIS)

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

  12. MG132 enhances the radiosensitivity of lung cancer cells in vitro and in vivo.

    Science.gov (United States)

    Zhu, Wei; Liu, Jing; Nie, Jihua; Sheng, Wenjiong; Cao, Han; Shen, Wenhao; Dong, Aijing; Zhou, Jundong; Jiao, Yang; Zhang, Shuyu; Cao, Jianping

    2015-10-01

    Radiotherapy is a common treatment modality for lung cancer, however, radioresistance remains a fundamental barrier to attaining the maximal efficacy. Cancer cells take advantage of the ubiquitin-proteasome system (UPS) for increased proliferation and decreased apoptotic cell death. MG132 (carbobenzoxyl-leucinyl-leucinyl-leucinal‑H), a specific and selective reversible inhibitor of the 26S proteasome, has shown anticancer effect in multiple types of cancers. Previously, we have reported that MG132 enhances the anti‑growth and anti-metastatic effects of irradiation in lung cancer cells. However, whether MG132 can enhance the radiosensitivity in lung cancer cells in vitro and in vivo is still unknown. In this study, we found that MG132 increased apoptosis and dicentric chromosome ratio of A549 and H1299 cells treated by irradiation. Radiation-induced NF-κB expression and IκBα phosphorylation was attenuated in MG132 plus irradiation-treated cells. The in vivo model of H1299 xenografts of nude mice showed that the tumor size of MG132 plus irradiation treated xenografts was smaller than that of irradiation, MG132 or the control group. Moreover, MG132 plus irradiation group showed significant reduced Ki67 expression. Taken together, these results demonstrate that MG132 enhances the radiosensitivity through multiple mechanisms in vitro and in vivo. PMID:26238156

  13. Dexamethasone acts as a radiosensitizer in three astrocytoma cell lines via oxidative stress.

    Science.gov (United States)

    Ortega-Martínez, Sylvia

    2015-08-01

    Glucocorticoids (GCs), which act on stress pathways, are well-established in the co-treatment of different kinds of tumors; however, the underlying mechanisms by which GCs act are not yet well elucidated. As such, this work investigates the role of glucocorticoids, specifically dexamethasone (DEXA), in the processes referred to as DNA damage and DNA damage response (DDR), establishing a new approach in three astrocytomas cell lines (CT2A, APP.PS1 L.1 and APP.PS1 L.3). The results show that DEXA administration increased the basal levels of gamma-H2AX foci, keeping them higher 4h after irradiation (IR) of the cells, compared to untreated cells. This means that DEXA might cause increased radiosensitivity in these cell lines. On the other hand, DEXA did not have an apparent effect on the formation and disappearance of the 53BP1 foci. Furthermore, it was found that DEXA administered 2h before IR led to a radical change in DNA repair kinetics, even DEXA does not affect cell cycle. It is important to highlight that DEXA produced cell death in these cell lines compared to untreated cells. Finally and most important, the high levels of gamma-H2AX could be reversed by administration of ascorbic acid, a potent blocker of reactive oxygen species, suggesting that DEXA acts by causing DNA damage via oxidative stress. These exiting findings suggest that DEXA might promote radiosensitivity in brain tumors, specifically in astrocytoma-like tumors.

  14. Radiosensitization of cetuximab on human tongue cancer cell line Tca8113

    International Nuclear Information System (INIS)

    Objective: To investigate the mechanism of radiosensitization by cetuximab (C225) on human tongue cancer Tca8113 cell line in vitro. Methods: Tca8113 cell line with and without C225 treatment received 6 MV X-ray irradiation of different doses (0, 2, 4, 6, 8 and 10 Gy). Cell proliferation, cell-cycle distribution and clonogenic survival were analyzed through cell counting, MTT, colony formation assay, and flow cytometry, respectively. Results: After irradiation of different doses, the growth inhibition rates in C225 group were higher than control (t =-15.6 - -3.0, P<0.05), the radiobiological parameters (D0, Dq, N, and SF2) in C225 group were lower than control so that SER of C225 group was 1.353, and the proportions of G0/G1 cells in C225 group were higher than control (t=-7.64, -7.89, -4.78, P<0.05) at 4, 6, 8 Gy. When the irradiation doses increased, the early phase apoptosis in both groups increased at first and then decreased with the maximum difference at 4 Gy [(7.96±0.36)% in C225 group and (4.13 ±0.29)% in control group, t=-12.75, P<0.01]. Conclusions: C225 has radiosensitization effect on Tca8113 cell line, possible through G0/G1 arrest and induction of apoptosis. (authors)

  15. Radiosensitization effects of nicotinamide on malignant and normal mouse tissue

    International Nuclear Information System (INIS)

    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

  16. Radiosensitivity in lung cancer with focus on p53

    CERN Document Server

    Bergqvist, M

    2002-01-01

    In Sweden approximately 2800 new lung cancer patients are diagnosed every year. Radiotherapy is used with curative intention in certain groups of patients. The aim of this thesis is to study the basis of differences in radioresistance and the possibility to predict response to radiotherapy. In the first study we investigated, using the comet assay, four lung cancer cell lines with different sensitivity towards radiation. A clear dose-response relationship for radiation-induced DNA single strand and double strand breaks were found. All cell lines showed a remarkably efficient repair of both the DNA single strand and double strand breaks one hour after irradiation. However, further studies in one radioresistant and one radiosensitive cell line demonstrated that repair during the first 15 min had the best accordance with radiosensitivity measured as surviving fraction. In the second and third study, sequencing studies of the p53 gene were performed on cell lines as well as on tumour material. Cell lines that wer...

  17. Pharmacological targeting of Mdm2: Rationale and perspectives for radiosensitization

    International Nuclear Information System (INIS)

    The central role of p53 after exposure to ionizing radiation has been widely demonstrated. Mdm2, the main cellular regulator of p53, is a promising target for radiosensitizing purposes. In this article, we review the most recent data on the pharmacological targeting of Mdm2, with focus on strategies of radiosensitization. Antitumor activity of Mdm2 inhibitors has been related with activation of p53-dependant apoptosis, action on DNA repair systems, and anti-angiogenic activity. Preliminary data suggested a synergic interaction between Mdm2 inhibitors and ionizing radiations. However, no clinical data has been published yet on the pharmacological targeting of Mdm2. Given their new mechanisms of action, these new molecules should be subject to careful clinical assessment. Although promising, these strategies expose to unexpected toxicities. (authors)

  18. Radiosensitivity of the moss Drepanocladus aduncus (Hedw. Mnkm.

    Directory of Open Access Journals (Sweden)

    Jan Sarosik

    2014-02-01

    Full Text Available Radiosensitivity was determined in isolated fragments of Drepanocladus aduncus gametophytes cultured in vitro, on the basis of the growth reaction to acute gamma Co-60 radiation and postirradiation survival of the plants. A high resistivity of D. aduncus to this radiation was noted. At 12°C a 100 per cent LD was 120 kR and at 22°C it was 160 kR. The nuclear index of radiosensitivity (ICV - interphase chromosome volume for various gametophyte cells has a value from 1.54 to 9.00 μm3. Drepanocladus aduncus plants exhibit postradiation developmental anomalies. In natural conditions they are characterised by an enhanced beta and gamma radiation activity. The plants contain Sr-90, Cs-137, much calcium, beryllium and lithium.

  19. 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.

  20. Comparison of the Radiosensitizing Effect of ATR, ATM and DNA-PK Kinase Inhibitors on Cervical Carcinoma Cells.

    Science.gov (United States)

    Vávrová, J; Zárybnická, L; Jošt, P; Tichý, A; Řezáčová, M; Šinkorová, Z; Pejchal, J

    2016-01-01

    Here, we compared the effects of inhibitors of three phosphatidylinositol-3-kinase-related kinases, ATM, ATR a DNA-PK, on radiosensitization of cervical carcinoma cells. We demonstrated that DNA-PK inhibitor NU7441 enhanced phosphorylation of Chk1 and Chk2 kinases 2 h after irradiation of HeLa cells at a dose of 8 Gy in contrast to ATM kinase inhibitor KU55933, which completely blocked the Chk2 kinase phosphorylation on threonine 68, and ATR kinase inhibitor VE-821, which blocked the Chk1 kinase phosphorylation on serine 345. Most HeLa cells were accumulated in G2 phase of the cell cycle 24 h after irradiation at a high dose of 15 Gy, which was even potentiated after adding the inhibitors NU7441 and KU55933. Compared to all other irradiated groups, inhibitor VE-821 increased the number of cells in S phase and reduced the number of cells in G2 phase 24 h after irradiation at the high dose of 15 Gy. HeLa cells entered the mitotic cycle with unrepaired DNA, which resulted in cell death and the radiosensitizing effect of VE-821. Short-term application of the inhibitors (2 h before and 30 min after the irradiation by the dose of 8 Gy) significantly decreased the colony-forming ability of HeLa cells. Using real-time monitoring of cell proliferation by the xCELLigence system we demonstrated that while the radiosensitizing effect of VE-821 (ATR inhibitor) is manifested early after the irradiation, the radiosensitizing effect of KU55933 (ATM inhibitor) and NU7441 (DNA-PK inhibitor) is only observed as late as 72 h after the irradiation. PMID:27643582

  1. Targeting FAK Radiosensitizes 3-Dimensional Grown Human HNSCC Cells Through Reduced Akt1 and MEK1/2 Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Hehlgans, Stephanie [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany); Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt am Main (Germany); Institute of Radiopharmacy, Helmholtz Center Dresden-Rossendorf, Dresden (Germany); Eke, Iris [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany); Cordes, Nils, E-mail: Nils.Cordes@OncoRay.de [OncoRay-National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany); Institute of Radiopharmacy, Helmholtz Center Dresden-Rossendorf, Dresden (Germany); Department of Radiation Oncology, University Hospital and Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden (Germany)

    2012-08-01

    Purpose: Focal adhesion kinase (FAK), a main regulator of integrin signaling and cell migration, is frequently overexpressed and hyperphosphorylated in human head-and-neck squamous cell carcinoma (HNSCC). We have previously shown that pharmacologic FAK inhibition leads to radiosensitization of 3-dimensionally grown HNSCC cell lines. To further evaluate the role of FAK in radioresistance and as a potential cancer target, we examined FAK and FAK downstream signaling in HNSCC cell lines grown in more physiologic extracellular matrix-based 3-dimensional cell cultures. Methods and Materials: Seven HNSCC cell lines were grown in 3-dimensional extracellular matrix and the clonogenic radiation survival, expression, and phosphorylation of FAK, paxillin, Akt1, extracellular signal-regulated kinase (ERK)1/2, and MEK1/2 were analyzed after siRNA-mediated knockdown of FAK, Akt1, MEK1, FAK+Akt1, or FAK+MEK1 compared with controls or stable overexpression of FAK. The role of MEK1/2 for clonogenic survival and signaling was investigated using the MEK inhibitor U0126 with or without irradiation. Results: FAK knockdown moderately or significantly enhanced the cellular radiosensitivity of 3-dimensionally grown HNSCC cells. The FAK downstream targets paxillin, Akt1, and ERK1/2 were substantially dephosphorylated under FAK depletion. FAK overexpression, in contrast, increased radiation survival and paxillin, Akt1, and ERK1/2 phosphorylation. The degree of radiosensitization upon Akt1, ERK1/2, or MEK1 depletion or U0126 was superimposable to FAK knockdown. Combination knockdown conditions (ie, Akt1/FAK, MEK1/FAK, or U0126/FAK) failed to provide additional radiosensitization. Conclusions: Our data provide further evidence for FAK as important determinant of radiation survival, which acts in the same signaling axis as Akt1 and ERK1/2. These data strongly support our hypothesis that FAK is a relevant molecular target for HNSCC radiotherapy.

  2. Radiosensitivity study and radiation effects on morphology characterization of grey oyster mushroom Pleurotus sajor-caju

    Science.gov (United States)

    Rashid, Rosnani Abdul; Daud, Fauzi; Senafi, Sahidan; Awang, Mat Rasol; Mohamad, Azhar; Mutaat, Hassan Hamdani; Maskom, Mohd Meswan

    2014-09-01

    Radiosensitive dosage and morphology characterization of irradiated grey oyster mushroom Pleurotus sajor-caju by gamma rays was investigated due to effects of irradiation. In order to establish the effect, mycelium of P. sajor-caju was irradiated by gamma rays at dose 0.1 to 8.0 kGy with dose rate 0.227 Gy sec-1. The irradiation of mycelia was carried out at the radiation facility in Malaysian Nuclear Agency. The radiosensitivity study was performed by evaluating the percentage of survival irradiated mycelia. The lethal dose of the mycelium P. sajor-caju was determined at 4.0 kGy and LD50 to be equal at 2.2 kGy. The radiation effects on morphology were evaluated based on growth rate of irradiated mycelia, mycelia types, colonization period on substrate, morphology of fruit bodies and yields. The results shown growth rate of irradiated mycelium was slightly lower than the control and decreased as the dose increased. Irradiation was found can induced the primordia formation on PDA and the BE of irradiated seed is higher than to control. The irradiation is proven to be useful for generating new varieties of mushroom with commercial value to the industry.

  3. Radiosensitivity study and radiation effects on morphology characterization of grey oyster mushroom Pleurotus sajor-caju

    Energy Technology Data Exchange (ETDEWEB)

    Rashid, Rosnani Abdul; Awang, Mat Rasol; Mohamad, Azhar; Mutaat, Hassan Hamdani; Maskom, Mohd Meswan [Bioprocess Group, Agrotechnology and Biosciences Division, Malaysian Nuclear Agency, Bangi 43600, Selangor (Malaysia); Daud, Fauzi; Senafi, Sahidan [School of Bioscience and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor (Malaysia)

    2014-09-03

    Radiosensitive dosage and morphology characterization of irradiated grey oyster mushroom Pleurotus sajor-caju by gamma rays was investigated due to effects of irradiation. In order to establish the effect, mycelium of P. sajor-caju was irradiated by gamma rays at dose 0.1 to 8.0 kGy with dose rate 0.227 Gy sec{sup −1}. The irradiation of mycelia was carried out at the radiation facility in Malaysian Nuclear Agency. The radiosensitivity study was performed by evaluating the percentage of survival irradiated mycelia. The lethal dose of the mycelium P. sajor-caju was determined at 4.0 kGy and LD{sub 50} to be equal at 2.2 kGy. The radiation effects on morphology were evaluated based on growth rate of irradiated mycelia, mycelia types, colonization period on substrate, morphology of fruit bodies and yields. The results shown growth rate of irradiated mycelium was slightly lower than the control and decreased as the dose increased. Irradiation was found can induced the primordia formation on PDA and the BE of irradiated seed is higher than to control. The irradiation is proven to be useful for generating new varieties of mushroom with commercial value to the industry.

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

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Yan Nan; Shin, Hyun-Jin; Joo, Hyun-Yoo; Park, Eun-Ran; Kim, Su-Hyeon; Hwang, Sang-Gu [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Park, Sang Jun; Kim, Chun-Ho [Laboratory of Tissue Engineering, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Lee, Kee-Ho, E-mail: khlee@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)

    2014-01-17

    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.

  5. Gamma radiosensitivity in common bean plant and cowpea; Gama radiossensitividade em feijoeiro comum e caupi

    Energy Technology Data Exchange (ETDEWEB)

    Guimaraes, Sandra da Silva; Colaco, Waldeciro [Pernambuco Univ., Recife, PE (Brazil). Dept. de Energia Nuclear

    2002-07-01

    An indispensable step in mutation induction experiments is the determination of the sensitivity to mutagens to be used. Taking this into consideration the radiosensitivity of bean cultivars Carioca, Princesa (P. vulgaris L.), and IPA-206 [V. unguiculata (L.) Walp] to gamma rays from a {sup 60} Co source was evaluated. Sets of seeds (40 seeds/sample) were irradiated with 100, 150, 200, 250 Gy, and compared to a control without irradiation (0 Gy), under greenhouse conditions. Bean and cowpea seeds were respectively inoculated with a suspension of Rhizobium (SEMIA-4077) and Bradyrhizobium (SEMIA-6145) strains. The radiosensitivity was evaluated through seedling height reduction determined at 15 days after emergence (15-DAE), and also through dry matter yield of above-ground part and root nodules at 40-DAE. Seedling height was significantly reduced with increased dose of radiation in relation to the control. The dose causing reduction of 50% seedling height for P. vulgaris cultivar Princesa was set up between 150-250 Gy. Cowpea (IPA-206) was less sensitive to radiation than common bean cultivars, considering the dose range of radiation studied, and a 75% seedling height reduction was reached in the range of 150-250 Gy. Dry mater yield of the above-ground part, root and nodule, were inversely related to the doses. It is recommended a dose range of 300-350 Gy for mutation breeding purposes using the cowpea cultivar (IPA-206). (author)

  6. PLK1-inhibition can cause radiosensitization or radioresistance dependent on the treatment schedule

    International Nuclear Information System (INIS)

    Background and purpose: PLK1-inhibitors are emerging as new potential anticancer agents. It is therefore important to explore the combined effects of PLK1-inhibitors with conventional therapies. Based on the functional roles of PLK1 in both mitosis and the G2 checkpoint, we hypothesized that the treatment schedule might influence the combined effects of PLK1-inhibiton and radiation. Materials and methods: Human osteosarcoma U2OS and colorectal cancer HT29 and SW620 cells were treated with the PLK1-inhibitor BI2536 before or after X-ray irradiation (0–6 Gy). Clonogenic assays, flow cytometry, immunofluorescence and mCherry-53BP1 time-lapse imaging were used to assay cell survival, cell cycle progression and DNA damage repair. Results: Treatment with the PLK1-inhibitor for 24 h before radiation caused cells to accumulate in G2/M and resulted in increased radiosensitivity. In contrast, the cytotoxic effects of the two treatments were less-than-additive when cells were treated with the PLK1-inhibitor for 24 h after radiation. This resistance was associated with a prolonged G2 checkpoint causing enhanced repair of the radiation-induced damage and decreased BI2536-mediated mitotic damage. Conclusions: PLK1-inhibitors need to be administrated several hours before radiation to achieve radiosensitization. If PLK1-inhibitors are given after radiation, cell killing is reduced due to the prolonged G2 checkpoint

  7. Optimizing the radiosensitive liquid-core microcapsules for the targeting of chemotherapeutic agents

    Energy Technology Data Exchange (ETDEWEB)

    Harada, S. [Department of Radiology, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505 (Japan)]. E-mail: sharada@iwate-med.ac.jp; Ehara, S. [Department of Radiology, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505 (Japan); Ishii, K. [Department of Quantum Science and Energy Engineering, Tohoku University, Sendai, Miyagi (Japan); Yamazaki, H. [Department of Quantum Science and Energy Engineering, Tohoku University, Sendai, Miyagi (Japan); Matsuyama, S. [Department of Quantum Science and Energy Engineering, Tohoku University, Sendai, Miyagi (Japan); Kamiya, T. [Takasaki Institute of the Radiation Chemistry Research Establishment, Japan Atomic Energy Research Institute, Takasaki, Gunma (Japan); Sakai, T. [Takasaki Institute of the Radiation Chemistry Research Establishment, Japan Atomic Energy Research Institute, Takasaki, Gunma (Japan); Arakawa, K. [Takasaki Institute of the Radiation Chemistry Research Establishment, Japan Atomic Energy Research Institute, Takasaki, Gunma (Japan); Sato, T. [Takasaki Institute of the Radiation Chemistry Research Establishment, Japan Atomic Energy Research Institute, Takasaki, Gunma (Japan); Oikawa, S. [Takasaki Institute of the Radiation Chemistry Research Establishment, Japan Atomic Energy Research Institute, Takasaki, Gunma (Japan)

    2007-07-15

    Microcapsules consisting of alginate and hyaluronic acid that can be decomposed by radiation are currently under development. In this study, the composition of the microcapsule material was optimized by changing the amounts of alginate and hyaluronic acid. Solutions of 0.025%, 0.05%, 0.1%, 0.2%, or 0.4% (wt./vol.) hyaluronic acid were mixed into a 0.2% alginate solution. To these mixtures, carboplatin (0.2 mmol) was added and the resulting material was used for the capsule preparation. The capsules were prepared by spraying the material into a CaCl{sub 2} solution (0.34 mol/l) using a microatomizer. These capsules were irradiated by a single dose of 2, 5, or 10 Gy {sup 60}Co {gamma}-ray radiation. Immediately after irradiation, the releasing of core content of microcapsule was determined, using a micro particle induced X-ray emission (PIXE) camera. The average diameter of the microcapsules was 22.3 {+-} 3.3 {mu}m, and that of the liquid core was 10.2 {+-} 4.3 {mu}m. The maximum radiation-induced content release was observed with liquid-core microcapsules containing 0.1% hyaluronic acid and 0.2% alginate. Our liquid-core microcapsules suggest a new potential use for radiation: the targeted delivery of the chemotherapeutic agents or radiosensitizers. This offers the prospect of increased combined effectiveness of radiation with chemotherapy or radiosensitization and decreased adverse side effects.

  8. Lentivirus-Mediated Nox4 shRNA Invasion and Angiogenesis and Enhances Radiosensitivity in Human Glioblastoma

    Directory of Open Access Journals (Sweden)

    Yongsheng Li

    2014-01-01

    Full Text Available Radioresistance remains a significant therapeutic obstacle in glioblastoma. Reactive oxygen species (ROS are associated with multiple cellular functions such as cell proliferation and apoptosis. Nox4 NADPH oxidase is abundantly expressed and has proven to be a major source of ROS production in glioblastoma. Here we investigated the effects of Nox4 on GBM tumor cell invasion, angiogenesis, and radiosensitivity. A lentiviral shRNA vector was utilized to stably knockdown Nox4 in U87MG and U251 glioblastoma cells. ROS production was measured by flow cytometry using the fluorescent probe DCFH-DA. Radiosensitivity was evaluated by clonogenic assay and survival curve was generated. Cell proliferation activity was assessed by a cell counting proliferation assay and invasion/migration potential by Matrigel invasion assay. Tube-like structure formation assay was used to evaluate angiogenesis ability in vitro and VEGF expression was assessed by MTT assay. Nox4 knockdown reduced ROS production significantly and suppressed glioblastoma cells proliferation and invasion and tumor associated angiogenesis and increased their radiosensitivity in vitro. Our results indicate that Nox4 may play a crucial role in tumor invasion, angiogenesis, and radioresistance in glioblastoma. Inhibition of Nox4 by lentivirus-mediated shRNA could be a strategy to overcome radioresistance and then improve its therapeutic efficacy for glioblastoma.

  9. Radiosensitization of metformin in pancreatic cancer cells via abrogating the G2 checkpoint and inhibiting DNA damage repair.

    Science.gov (United States)

    Wang, Zheng; Lai, Song-Tao; Ma, Ning-Yi; Deng, Yun; Liu, Yong; Wei, Dong-Ping; Zhao, Jian-Dong; Jiang, Guo-Liang

    2015-12-01

    Recent evidences have demonstrated the potential of metformin as a novel agent for cancer prevention and treatment. Here, we investigated its ability of radiosensitization and the underlying mechanisms in human pancreatic cancer cells. In this study, we found that metformin at 5 mM concentration enhanced the radiosensitivity of MIA PaCa-2 and PANC-1 cells, with sensitization enhancement ratios of 1.39 and 1.27, respectively. Mechanistically, metformin caused abrogation of the G2 checkpoint and increase of mitotic catastrophe, associated with suppression of Wee1 kinase and in turn CDK1 Tyr15 phosphorylation. Furthermore, metformin inhibited both expression and irradiation-induced foci formation of Rad51, a key player in homologous recombination repair, ultimately leading to persistent DNA damage, as reflected by γ-H2AX and 53BP1 signaling. Finally, metformin-mediated AMPK/mTOR/p70S6K was identified as a possible upstream pathway controlling translational regulation of Wee1 and Rad51. Our data suggest that metformin radiosensitizes pancreatic cancer cells in vitro via abrogation of the G2 checkpoint and inhibition of DNA damage repair. However, the in vivo study is needed to further confirm the findings from the in vitro study. PMID:26304716

  10. Radiosensitization of metformin in pancreatic cancer cells via abrogating the G2 checkpoint and inhibiting DNA damage repair.

    Science.gov (United States)

    Wang, Zheng; Lai, Song-Tao; Ma, Ning-Yi; Deng, Yun; Liu, Yong; Wei, Dong-Ping; Zhao, Jian-Dong; Jiang, Guo-Liang

    2015-12-01

    Recent evidences have demonstrated the potential of metformin as a novel agent for cancer prevention and treatment. Here, we investigated its ability of radiosensitization and the underlying mechanisms in human pancreatic cancer cells. In this study, we found that metformin at 5 mM concentration enhanced the radiosensitivity of MIA PaCa-2 and PANC-1 cells, with sensitization enhancement ratios of 1.39 and 1.27, respectively. Mechanistically, metformin caused abrogation of the G2 checkpoint and increase of mitotic catastrophe, associated with suppression of Wee1 kinase and in turn CDK1 Tyr15 phosphorylation. Furthermore, metformin inhibited both expression and irradiation-induced foci formation of Rad51, a key player in homologous recombination repair, ultimately leading to persistent DNA damage, as reflected by γ-H2AX and 53BP1 signaling. Finally, metformin-mediated AMPK/mTOR/p70S6K was identified as a possible upstream pathway controlling translational regulation of Wee1 and Rad51. Our data suggest that metformin radiosensitizes pancreatic cancer cells in vitro via abrogation of the G2 checkpoint and inhibition of DNA damage repair. However, the in vivo study is needed to further confirm the findings from the in vitro study.

  11. Enhancement of radiosensitization by metal-based nanoparticles in cancer radiation therapy

    Institute of Scientific and Technical Information of China (English)

    Xiang-Yu Su; Pei-Dang Liu; Hao Wu; Ning Gu

    2014-01-01

    Radiation therapy performs an important function in cancer treatment. However, resistance of tumor cells to radiation therapy still remains a serious concern, so the study of radiosensitizers has emerged as a persistent hotspot in radiation oncology. Along with the rapid advancement of nanotechnology in recent years, the potential value of nanoparticles as novel radiosensitizers has been discovered. hTis review summarizes the latest experimental ifndings bothin vitro andin vivo and attempts to highlight the underlying mechanisms of response in nanoparticle radiosensitization.

  12. Intrinsic Radiosensitivity and Cellular Characterization of 27 Canine Cancer Cell Lines.

    Science.gov (United States)

    Maeda, Junko; Froning, Coral E; Brents, Colleen A; Rose, Barbara J; Thamm, Douglas H; Kato, Takamitsu A

    2016-01-01

    Canine cancer cell lines have progressively been developed, but are still underused resources for radiation biology research. Measurement of the cellular intrinsic radiosensitivity is important because understanding the difference may provide a framework for further elucidating profiles for prediction of radiation therapy response. Our studies have focused on characterizing diverse canine cancer cell lines in vitro and understanding parameters that might contribute to intrinsic radiosensitivity. First, intrinsic radiosensitivity of 27 canine cancer cell lines derived from ten tumor types was determined using a clonogenic assay. The 27 cell lines had varying radiosensitivities regardless tumor type (survival fraction at 2 Gy, SF2 = 0.19-0.93). In order to understand parameters that might contribute to intrinsic radiosensitivity, we evaluated the relationships of cellular radiosensitivity with basic cellular characteristics of the cell lines. There was no significant correlation of SF2 with S-phase fraction, doubling time, chromosome number, ploidy, or number of metacentric chromosomes, while there was a statistically significant correlation between SF2 and plating efficiency. Next, we selected the five most radiosensitive cell lines as the radiosensitive group and the five most radioresistant cell lines as the radioresistant group. Then, we evaluated known parameters for cell killing by ionizing radiation, including radiation-induced DNA double strand break (DSB) repair and apoptosis, in the radiosensitive group as compared to the radioresistant group. High levels of residual γ-H2AX foci at the sites of DSBs were present in the four out of the five radiosensitive canine cancer cell lines. Our studies suggested that substantial differences in intrinsic radiosensitivity exist in canine cancer cell lines, and radiation-induced DSB repair was related to radiosensitivity, which is consistent with previous human studies. These data may assist further investigations

  13. Radiosensitization by small interfering RNAs (siRNA) targeting ATM

    International Nuclear Information System (INIS)

    Previous work by us (Guha, C., et al, Gene Therapy 7, 2000 and Fan, Z., et al, Human Gene Therapy 7, 2000), using antisense ATM approaches demonstrated radiosensitization of prostate and glioblastoma cell lines. In an attempt to further develop radiosensitizing gene therapy strategies for attenuation of ATM protein expression, we screened a series of siRNAs against ATM in human transformed kidney and cervical carcinoma cells. siRNAs were constructed as double-stranded ATM siRNA or the siRNA Hairpin cloned into pSilencer 1.0 -U6 expression vectors and transfected into HeLa and 293 cells. All transfected cell-lines were clonally expanded and isolated for Western blot analysis. Clonogenic survival assay (0 - 10Gy single dose or 2Gy x 2q 4hr separation) for selected transfectant lines was perfomed. Cell cycle progression and S-phase fraction were determined by FACScan analysis. Significant down-regulation of ATM expression occurred as early as 48hrs in both oligonucleotide and plasmid-transfected cells. Protein down-regulation was dependent on target sequences selected and independent of format, whether in oligonucleotide only or as hairpin-plasmid. These siRNAs also demonstrated cytotoxicity as assessed by reduction of plating efficiencies in clonogenic assay. ATM siRNA-transfected cells exhibited enhanced radiosensitivity, compared to cells transfected with control vectors. These data suggest that attenuation of ATM by transfection of siRNAs against ATM could be useful tools for studying the role of ATM in radiosensitivty of tumors. Adenoviral vectors expressing these siRNAs are being developed for potential use in radiosensitizing gene therapy

  14. Some regularities in intraspecific variability of wheat radiosensitivity

    International Nuclear Information System (INIS)

    The data are presented on radiosensitivity of some soft wheat varieties grown in Yakutia. The reproducing of seeds of Yakutyanka 224 and Skorospelka varieties, improved in some regions of the Urals and Yakutiya, permitted us to estimate the influence of climatic conditions on the formation in plants of the resistance level against stresses. Each variety was shown to have immanently not only only the definite level of resistance, but also the definite amplitude of radiation response variability

  15. Radiosensitization of EMT6 cells by four platinum complexes

    Energy Technology Data Exchange (ETDEWEB)

    Teicher, B.A.; Rockwell, S.; Lee, J.B.

    1985-05-01

    The compounds described here are dichloro complexes of bivalent platinum with one or two potentially radiosensitizing ligands. The radiosensitization of oxygenated and hypoxic exponentially growing EMT6 cells in vitro was measured. The dose modifying factors obtained with 200 ..mu..M and 400 ..mu..M trans-bis(2-nitroimidazole)dichloroplatinum II (NIPt) in hypoxic cells were 1.5 and 2.1, respectively. For trans-bis(2-amino-5-nitrothiazole)dichloroplatinum II (Plant) under the same conditions, the dose modifying factor was 1.5 at 200 ..mu..M and 1.8 at 400 ..mu..M. Neither compound sensitized oxygenated cells when tested similar protocols. Unlike the trans complexes (1,2-diamino-4-nitrobenzene)dichloroplatinum II (Plato) was cytotoxic toward the hypoxic cells in the absence of X rays. The time course of cytotoxicity for 100 ..mu..M Plato in exponentially growing cells showed rapid killing of hypoxic cells, and much less toxicity toward oxygenated cells. In radiosensitization studies, dose modifying factors of 1.6 and 2.0 were found with 200 ..mu..M and 400 ..mu..M Plato in hypoxic cells. The compound did not sensitize aerobic cells. The well-known platinum complex cis-dipyridinedichloroplatinum II (PyPt) represents a cis-platinum heterocyclic aromatic complex that does not have a nitro-functionality. The dose modifying factor obtained with 400 ..mu..M PyPt in hypoxic cells was 1.7. On a molar basis, the nitro-functional platinum complexes appear to be more effective as hypoxic cell radiosensitizers than the corresponding free ligands.

  16. Gadolinium-based nanoparticles for theranostic MRI-radiosensitization

    OpenAIRE

    Lux, François; Sancey, Lucie; Bianchi, Andrea; Crémillieux, Yannick; Roux, Stéphane; Tillement, Olivier

    2015-01-01

    A rapid development of gadolinium-based nanoparticles is observed due to their attractive properties as MRI-positive contrast agents. Indeed, they display high relaxivity, adapted biodistribution and passive uptake in the tumor thanks to enhanced permeability and retention effect. In addition to these imaging properties, it has been recently shown that they can act as effective radiosensitizers under different types of irradiation (radiotherapy, neutron therapy or hadron therapy). These new t...

  17. The LEC rat as a radiosensitive model animal

    International Nuclear Information System (INIS)

    The author described the review on the LEC rat which had been firstly established as a model animal of spontaneous hepatitis and hepatoma and had been then found to be highly sensitive to ionizing radiation by the author and his coworkers and to be similar to human AT (ataxia-telangiectasia) as for induced DNA damages. The hepatic failure was primarily caused by Cu accumulation and mutation was detected in the same gene as the causative gene of human Wilson disease. LEC rats exerted 2-times higher radiosensitivity in mortality than the control WKAH rats and this was also true in lung fibroblast and other tissue cells isolated from LEC rat fetus. Breeding experiments of LEC x WKAH and of their offspring F1 x LEC (back cross) revealed that the high radiosensitivity of LEC rats was due to the recessive autosomal gene xhs. Similar to AT cells, LEC rat cells exerted a high incidence of X ray-induced chromosome aberration. In LEC rat cells, the sensitivity spectrum to DNA damaging agents was more broad than that in WKAH cells and the rate to repair DNA damage, particularly double strand break, was slower. The extent of the decrease in DNA synthesis post irradiation was small in AT cells (radioresistant DNA synthesis), which was also seen in LEC rat cells. After the whole body X-ray irradiation, cell apoptosis was seen in spleen and thymus more frequently in LEC rats than in WKAH rats. Abnormal signal transduction system involving p53 protein induced by DNA damage post irradiation caused apoptosis and thereby induced abnormal cell cycle regulation, which was considered to be related with the radiosensitivity of AT cells. Thus the LEC rat can be a good model animal of radiosensitivity. (K.H.)

  18. Days on radiosensitivity: individual variability and predictive tests

    International Nuclear Information System (INIS)

    The radiosensitivity is a part of usual clinical observations. It is already included in the therapy protocols. however, some questions stay on its individual variability and on the difficulty to evaluate it. The point will be stocked on its origin and its usefulness in predictive medicine. Through examples on the use of predictive tests and ethical and legal questions that they raise, concrete cases will be presented by specialists such radio biologists, geneticists, immunologists, jurists and occupational physicians. (N.C.)

  19. Assessment of individual radiosensitivity in human lymphocytes of cancer patients and its correlation with adverse side effects to radiation therapy

    International Nuclear Information System (INIS)

    Background and purpose: Individual radiosensitivity is an inherent characteristic, associated with an increased reaction to ionizing radiation on the human body. Biological endpoints such as clonogenic survival, chromosome aberration formation and repair capacity of radiation-induced damage have been applied to evaluate individual radiosensitivity in vitro. 5%-7% of cancer patients develop adverse side effects to radiation therapy in normal tissues within the treatment field, which are referred as 'clinical radiation reactions' and include acute effects, late effects and cancer induction. It has been hypothesized that the occurrence and severity of these reactions are mainly influenced by genetic susceptibility to radiation. Additionally, the nature of the genetic disorders associated with hypersensitivity to radiotherapy suggests that DNA repair mechanisms are involved. Consequently, the characterization of DNA repair in lymphocytes through cytokinesis blocked micronucleus (MN) and alkaline single-cell micro gel electrophoresis (comet) assays could be suitable approaches to evaluate individual radiosensitivity in vitro. The MN assay is an established cytogenetic technique to evaluate intrinsic cell radiosensitivity in tumor cells and lymphocytes; comet assay is a sensitive and rapid method for measuring DNA damage and repair in individual cells. The aims of this study were: 1) To assess the in vitro radiosensitivity of peripheral blood lymphocytes from two groups of cancer patients (retrospectively and prospectively studied), using MN and comet assays, in comparison with the observed clinical response; and 2) To test the predictive potential of both techniques. Materials and methods: 38 cancer patients receiving radiation therapy were enrolled in this study. The tumor sites were: head and neck (n 25) and cervix (n = 13). Nineteen patients were evaluated about 6-18 month after radiotherapy (retrospective group) and 19 patients were evaluated prior, mid-way and on

  20. The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells

    Energy Technology Data Exchange (ETDEWEB)

    Gomez-Casal, Roberto; Bhattacharya, Chitralekha [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Medicine, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Epperly, Michael W. [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Radiation Oncology, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Basse, Per H. [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Immunology, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Wang, Hong [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Biostatistics, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Wang, Xinhui [Harvard Medical School, Harvard University, 25 Shattuck Street, Boston, MA 02115 (United States); Proia, David A. [Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421 (United States); Greenberger, Joel S. [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Radiation Oncology, The University of Pittsburgh, Pittsburgh, PA 15213 (United States); Socinski, Mark A.; Levina, Vera, E-mail: levinav@upmc.edu [The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Medicine, The University of Pittsburgh, Pittsburgh, PA 15213 (United States)

    2015-05-22

    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.

  1. Radiosensitizing Effect of Schinifoline from Zanthoxylum schinifolium Sieb et Zucc on Human Non-Small Cell Lung Cancer A549 Cells: A Preliminary in Vitro Investigation

    Directory of Open Access Journals (Sweden)

    Cheng-Fang Wang

    2014-12-01

    Full Text Available Schinifoline (SF, a 4-quinolinone derivative, was found in Zanthoxylum schinifolium for the first time. 4-Quinolinone moieties are thought to have cytotoxic activity and are often used as a tubulin polymerization inhibitors, heterogeneous enzyme inhibitors and antiplatelet agents. However, very little information respect to radiosensitization has focused on SF. This work aimed to investigate the radiosensitizing effect of SF on A549 cells. The cell viability results indicated cytotoxicity of SF on A549 cells, with IC50 values of 33.7 ± 2.4, 21.9 ± 1.9 and 16.8 ± 2.2 μg/mL, respectively, after 6, 12, 24 h treatment with different concentrations, and the 10% or 20% IC50 concentration during 12 h was applied in later experiments. The results of cell proliferative inhibition and clonogenic assay showed that SF enhanced the radiosensitivity of A549 cells when applied before 60Co γ-irradiation and this effect was mainly time and concentration dependent. The flow cytometric data indicated that SF treatment before the irradiation increased the G2/M phase, thus improving the radiosensitivity of A549, leading to cell apoptosis. This paper is the first study that describes the in vitro radiosensitising, cell cycle and apoptotic-inducing effects of schinifoline.

  2. Effects of autophagy regulation of tumor-associated macrophages on radiosensitivity of colorectal cancer cells.

    Science.gov (United States)

    Shao, Le-Ning; Zhu, Bao-Song; Xing, Chun-Gen; Yang, Xiao-Dong; Young, Wu; Cao, Jian-Ping

    2016-03-01

    Tumor‑associated macrophages (TAMs), a major component of the tumor microenvironment, are crucial to the processes of tumor growth, infiltration and metastasis, and contribute to drug resistance. The importance of TAMs in radiation resistance of colorectal cancer remains unclear. To investigate the effects of autophagy regulation of TAMs on the radiosensitivity of colorectal cancer cells, the current study induced TAM formation from THP‑1 monocyte cells. Sequential treatment of THP‑1 cells with PMA for 72 h and human recombinant interleukin‑4 for 24 h was used to stimulate THP‑1 differentiation to TAMs. Expression of the cell surface markers CD68, CD204 and CD206, and changes to cell morphology were used to confirm successful differentiation. The TAMs were stimulated to promote or inhibit autophagy during co‑culture with LoVo colorectal adenocarcinoma cells. The cells were irradiated, with subsequent measurement of LoVo colony formation and apoptosis. Additionally, the expression of p53, Bcl‑2, survivin and Smac proteins was assessed by western blotting. Monodansylcadaverin staining was used to analyze the presence of autophagic vacuoles in TAM, and western blot analysis was used to assess the expression of Beclin‑1, LC3B I and II, ATG‑3, ‑5 and ‑7. The results demonstrated TAM autophagy to be markedly altered by rapamycin and bafilomycin A1 treatment. Following co‑culture with TAMs, the colony formation rate and survival fraction of LoVo cells were significantly higher than those in the control group (PLoVo colorectal cancer cells. Upregulation of TAM autophagy using rapamycin exhibited more effective inhibition of LoVo colony formation than autophagy downregulation. Notably, apoptosis was significantly increased in LoVo cells when co‑cultured with TAMs only, or with rapamycin‑mediated autophagy upregulated TAMs, compared with LoVo cells cultured alone (PLoVo cells co‑cultured with TAMs, compared with the control group (P<0

  3. Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO-1051 through augmented and sustained DNA damage response

    Science.gov (United States)

    2011-01-01

    Background 1-{4-[Bis(2-chloroethyl)amino]phenyl}-3-[2-methyl-5-(4-methylacridin-9-ylamino)phenyl]urea (BO-1051) is an N-mustard DNA alkylating agent reported to exhibit antitumor activity. Here we further investigate the effects of this compound on radiation responses of human gliomas, which are notorious for the high resistance to radiotherapy. Methods The clonogenic assay was used to determine the IC50 and radiosensitivity of human glioma cell lines (U87MG, U251MG and GBM-3) following BO-1051. DNA histogram and propidium iodide-Annexin V staining were used to determine the cell cycle distribution and the apoptosis, respectively. DNA damage and repair state were determined by γ-H2AX foci, and mitotic catastrophe was measure using nuclear fragmentation. Xenograft tumors were measured with a caliper, and the survival rate was determined using Kaplan-Meier method. Results BO-1051 inhibited growth of human gliomas in a dose- and time-dependent manner. Using the dosage at IC50, BO-1051 significantly enhanced radiosensitivity to different extents [The sensitizer enhancement ratio was between 1.24 and 1.50 at 10% of survival fraction]. The radiosensitive G2/M population was raised by BO-1051, whereas apoptosis and mitotic catastrophe were not affected. γ-H2AX foci was greatly increased and sustained by combined BO-1051 and γ-rays, suggested that DNA damage or repair capacity was impaired during treatment. In vivo studies further demonstrated that BO-1051 enhanced the radiotherapeutic effects on GBM-3-beared xenograft tumors, by which the sensitizer enhancement ratio was 1.97. The survival rate of treated mice was also increased accordingly. Conclusions These results indicate that BO-1051 can effectively enhance glioma cell radiosensitivity in vitro and in vivo. It suggests that BO-1051 is a potent radiosensitizer for treating human glioma cells. PMID:21244709

  4. Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO-1051 through augmented and sustained DNA damage response

    Directory of Open Access Journals (Sweden)

    Chen Ming-Teh

    2011-01-01

    Full Text Available Abstract Background 1-{4-[Bis(2-chloroethylamino]phenyl}-3-[2-methyl-5-(4-methylacridin-9-ylaminophenyl]urea (BO-1051 is an N-mustard DNA alkylating agent reported to exhibit antitumor activity. Here we further investigate the effects of this compound on radiation responses of human gliomas, which are notorious for the high resistance to radiotherapy. Methods The clonogenic assay was used to determine the IC50 and radiosensitivity of human glioma cell lines (U87MG, U251MG and GBM-3 following BO-1051. DNA histogram and propidium iodide-Annexin V staining were used to determine the cell cycle distribution and the apoptosis, respectively. DNA damage and repair state were determined by γ-H2AX foci, and mitotic catastrophe was measure using nuclear fragmentation. Xenograft tumors were measured with a caliper, and the survival rate was determined using Kaplan-Meier method. Results BO-1051 inhibited growth of human gliomas in a dose- and time-dependent manner. Using the dosage at IC50, BO-1051 significantly enhanced radiosensitivity to different extents [The sensitizer enhancement ratio was between 1.24 and 1.50 at 10% of survival fraction]. The radiosensitive G2/M population was raised by BO-1051, whereas apoptosis and mitotic catastrophe were not affected. γ-H2AX foci was greatly increased and sustained by combined BO-1051 and γ-rays, suggested that DNA damage or repair capacity was impaired during treatment. In vivo studies further demonstrated that BO-1051 enhanced the radiotherapeutic effects on GBM-3-beared xenograft tumors, by which the sensitizer enhancement ratio was 1.97. The survival rate of treated mice was also increased accordingly. Conclusions These results indicate that BO-1051 can effectively enhance glioma cell radiosensitivity in vitro and in vivo. It suggests that BO-1051 is a potent radiosensitizer for treating human glioma cells.

  5. Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO-1051 through augmented and sustained DNA damage response

    International Nuclear Information System (INIS)

    1-{4-[Bis(2-chloroethyl)amino]phenyl}-3-[2-methyl-5- (4-methylacridin-9-ylamino)phenyl]urea (BO-1051) is an N-mustard DNA alkylating agent reported to exhibit antitumor activity. Here we further investigate the effects of this compound on radiation responses of human gliomas, which are notorious for the high resistance to radiotherapy. The clonogenic assay was used to determine the IC50 and radiosensitivity of human glioma cell lines (U87MG, U251MG and GBM-3) following BO-1051. DNA histogram and propidium iodide-Annexin V staining were used to determine the cell cycle distribution and the apoptosis, respectively. DNA damage and repair state were determined by γ-H2AX foci, and mitotic catastrophe was measure using nuclear fragmentation. Xenograft tumors were measured with a caliper, and the survival rate was determined using Kaplan-Meier method. BO-1051 inhibited growth of human gliomas in a dose- and time-dependent manner. Using the dosage at IC50, BO-1051 significantly enhanced radiosensitivity to different extents [The sensitizer enhancement ratio was between 1.24 and 1.50 at 10% of survival fraction]. The radiosensitive G2/M population was raised by BO-1051, whereas apoptosis and mitotic catastrophe were not affected. γ-H2AX foci was greatly increased and sustained by combined BO-1051 and γ-rays, suggested that DNA damage or repair capacity was impaired during treatment. In vivo studies further demonstrated that BO-1051 enhanced the radiotherapeutic effects on GBM-3-beared xenograft tumors, by which the sensitizer enhancement ratio was 1.97. The survival rate of treated mice was also increased accordingly. These results indicate that BO-1051 can effectively enhance glioma cell radiosensitivity in vitro and in vivo. It suggests that BO-1051 is a potent radiosensitizer for treating human glioma cells

  6. Targeted radiosensitization of ETS fusion-positive prostate cancer through PARP1 inhibition.

    Science.gov (United States)

    Han, Sumin; Brenner, J Chad; Sabolch, Aaron; Jackson, Will; Speers, Corey; Wilder-Romans, Kari; Knudsen, Karen E; Lawrence, Theodore S; Chinnaiyan, Arul M; Feng, Felix Y

    2013-10-01

    ETS gene fusions, which result in overexpression of an ETS transcription factor, are considered driving mutations in approximately half of all prostate cancers. Dysregulation of ETS transcription factors is also known to exist in Ewing's sarcoma, breast cancer, and acute lymphoblastic leukemia. We previously discovered that ERG, the predominant ETS family member in prostate cancer, interacts with the DNA damage response protein poly (ADP-ribose) polymerase 1 (PARP1) in human prostate cancer specimens. Therefore, we hypothesized that the ERG-PARP1 interaction may confer radiation resistance by increasing DNA repair efficiency and that this radio-resistance could be reversed through PARP1 inhibition. Using lentiviral approaches, we established isogenic models of ERG overexpression in PC3 and DU145 prostate cancer cell lines. In both cell lines, ERG overexpression increased clonogenic survival following radiation by 1.25 (±0.07) fold (mean ± SEM) and also resulted in increased PARP1 activity. PARP1 inhibition with olaparib preferentially radiosensitized ERG-positive cells by a factor of 1.52 (±0.03) relative to ERG-negative cells (P alkaline COMET assays and immunofluorescence microscopy assessing γ-H2AX foci showed increased short- and long-term efficiencies of DNA repair, respectively, following radiation that was preferentially reversed by PARP1 inhibition. These findings were verified in an in vivo xenograft model. Our findings demonstrate that ERG overexpression confers radiation resistance through increased efficiency of DNA repair following radiation that can be reversed through inhibition of PARP1. These results motivate the use of PARP1 inhibitors as radiosensitizers in patients with localized ETS fusion-positive cancers. PMID:24204199

  7. Targeted Radiosensitization of ETS Fusion-Positive Prostate Cancer through PARP1 Inhibition

    Directory of Open Access Journals (Sweden)

    Sumin Han

    2013-10-01

    Full Text Available ETS gene fusions, which result in overexpression of an ETS transcription factor, are considered driving mutations in approximately half of all prostate cancers. Dysregulation of ETS transcription factors is also known to exist in Ewing's sarcoma, breast cancer, and acute lymphoblastic leukemia. We previously discovered that ERG, the predominant ETS family member in prostate cancer, interacts with the DNA damage response protein poly (ADP-ribose polymerase 1 (PARP1 in human prostate cancer specimens. Therefore, we hypothesized that the ERG-PARP1 interaction may confer radiation resistance by increasing DNA repair efficiency and that this radio-resistance could be reversed through PARP1 inhibition. Using lentiviral approaches, we established isogenic models of ERG overexpression in PC3 and DU145 prostate cancer cell lines. In both cell lines, ERG overexpression increased clonogenic survival following radiation by 1.25 (±0.07 fold (mean ± SEM and also resulted in increased PARP1 activity. PARP1 inhibition with olaparib preferentially radiosensitized ERG-positive cells by a factor of 1.52 (±0.03 relative to ERG-negative cells (P < .05. Neutral and alkaline COMET assays and immunofluorescence microscopy assessing γ-H2AX foci showed increased short- and long-term efficiencies of DNA repair, respectively, following radiation that was preferentially reversed by PARP1 inhibition. These findings were verified in an in vivo xenograft model. Our findings demonstrate that ERG overexpression confers radiation resistance through increased efficiency of DNA repair following radiation that can be reversed through inhibition of PARP1. These results motivate the use of PARP1 inhibitors as radiosensitizers in patients with localized ETS fusion-positive cancers.

  8. Electron paramagnetic resonance highlights that the oxygen effect contributes to the radiosensitizing effect of paclitaxel.

    Directory of Open Access Journals (Sweden)

    Fabienne Danhier

    Full Text Available BACKGROUND: Paclitaxel (PTX is a potent anti-cancer chemotherapeutic agent and is widely used in the treatments of solid tumors, particularly of the breast and ovaries. An effective and safe micellar formulation of PTX was used to administer higher doses of PTX than Taxol® (the current commercialized drug. We hypothesize that PTX-loaded micelles (M-PTX may enhance tumor radiosensitivity by increasing the tumor oxygenation (pO(2. Our goals were (i to evaluate the contribution of the "oxygen effect" to the radiosensitizing effect of PTX; (ii to demonstrate the therapeutic relevance of the combination of M-PTX and irradiation and (iii to investigate the underlying mechanisms of the observed oxygen effect. METHODOLOGY AND PRINCIPAL FINDINGS: We used (PEG-p-(CL-co-TMC polymeric micelles to solubilize PTX. pO(2 was measured on TLT tumor-bearing mice treated with M-PTX (80 mg/kg using electron paramagnetic resonance (EPR oximetry. The regrowth delay following 10 Gy irradiation 24 h after M-PTX treatment was measured. The tumor perfusion was assessed by the patent blue staining. The oxygen consumption rate and the apoptosis were evaluated by EPR oximetry and the TUNEL assay, respectively. EPR oximetry experiments showed that M-PTX dramatically increases the pO(2 24 h post treatment. Regrowth delay assays demonstrated a synergy between M-PTX and irradiation. M-PTX increased the tumor blood flow while cells treated with M-PTX consumed less oxygen and presented more apoptosis. CONCLUSIONS: M-PTX improved the tumor oxygenation which leads to synergy between this treatment and irradiation. This increased pO(2 can be explained both by an increased blood flow and an inhibition of O(2 consumption.

  9. Semaphorin3B modulates radiosensitivity of human glioma U-87MG cells

    International Nuclear Information System (INIS)

    This study was to determine the Semaphorin3B (SEMA3B) role in glioma cells responding to irradiation. Two glioma cell lines, which were used here was wild-type p53 (U-87MG), and the other was harboring mutated p53 (U-251). The SEMA3B mRNA could be detected in the two cell lines. The expression level of SEMA3B mRNA was higher in U-87MG cells than in U-251 cells, and increased with time in U-87MG cells after irradiation. Knockdown of SEMA3B expression by shRNA decreased the radiosensitivity of U-87MG cells, this may be associated with the increased G2 accumulation after irradiation. In addition, G2 accumulation after irradiation was enhanced in SEMA3B low-expressing U-87MG cells. These results showed that the SEMA3B was implicated in glioma cells responding to irradiation. (authors)

  10. Association of in vitro radiosensitivity and cancer in a family with acute myelogenous leukemia

    International Nuclear Information System (INIS)

    The γ-ray sensitivity of skin fibroblasts from six members of a cancer family was investigated using a colony-forming assay. Fibroblasts from the three members with cancer (two sisters with acute myelogenous leukemia and the mother with cervical carcinoma) showed a significant ( p > 0.05) increase in radiosensitivity, while three members without cancer (the father and two sons) showed a normal radioresponse. The possiblity that the increased γ-ray sensitivity was due to defective DNA repair was investigated using assays for DNA repair replication, single-strand break rejoining, and removal of enzyme-sensitive sites in γ-irradiated DNA. Results of these assays indicate that the kinetics of enzymatic repair of radiogenic DNA damage in general, and the rejoining of single-strand scissions and excision repair of base and sugar radioproducts in partigular, were the same in the cell lines from the sensitive and clinically normal family members

  11. 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 usin

  12. DNA damage induction and tumour cell radiosensitivity : PFGE and halo measurements

    NARCIS (Netherlands)

    Woudstra, EC; Driessen, C; Konings, AWT; Kampinga, HH

    1998-01-01

    Purpose: To test whether induction of DNA damage is correlated with tumour-cell radiosensitivity. Materials and methods: Initial DNA damage caused by X-irradiation was measured in ten human tumour cell lines, which largely differed in radiosensitivity, using either the pulsed-field gel electrophores

  13. Sex differences in the radiosensitivity of potato epilachnid Henosepilachna vigintioctopunctata (F. ) (Coleoptera, Coccinellidae)

    Energy Technology Data Exchange (ETDEWEB)

    Gupta, J.K.; Ashok Kumar (Himachal Pradesh Univ., Simla (India). Dept. of Bio-sciences)

    1980-07-01

    Sex differences in the radiosensitivity of potato epilachnid, were studied by irradiating 1 to 3 days old adults with ..gamma..-radiation at doses of 0,2,3,5 and 9 Krad. Males were slightly more radiosensitive than females. However, male mortality was significantly higher than that of female throughout the period of observation only at 3 Krad.

  14. Radiosensitivity of AsPC-1 cell to γ-rays enhanced by up-regulation of PUMA induced by targeted Slug gene

    International Nuclear Information System (INIS)

    Objective: To explore the influence of PUMA on radiosensitivity of pancreatic cancer AsPC-1 cells after Slug gene inhibition by transfected short interferencing RNA (siRNA). Methods: The AsPC-1 cells were infected with MOI 10, 50, 100 for 72 h, respectively. The expression of Slug and PUMA was analyzed by Western blotting and immunohistochemistry methods. The transfected and control cells were exposed to 4 Gy γ-rays. The cells inhibition rate was examined by MTT, Hoechst 33342 and IP double staining. DNA ladder and Giemsa staning was used to observe apoptosis. Results: The relative value of Slug expression was 0.831±0.14, 0.546±0.12 and 0.178±0.08 after AsPC-1 was infected with Slug-siRNA (MOI 10, 50, 100) for 72 h, significantly lower than that of control group (F=4.992, P<0.05). The relative value of PUMA was 0.325±0.07, 0.593±0.11 and 0.978±0.12, after AsPC-1 was infected with Slug-siRNA (MOI 10, 50, 100) for 72 h, significantly higher than that of control group (F=4.324, P<0.05). The cell proliferation rate was (78.76±9.36)% in transfection combined with radiosensitivity group, significantly higher than that of transfection group [(43.68±6.71)%] and radiosensitivity group alone [(19.25±3.72)%] (F=5.056, P<0.05). The apoptosis of transfection combined with radiosensitivity group was significantly higher than that of others. Conclusions: Slug gene targeting siRNA could inhibit the expression of Slug, and consequently increase the activation of PUMA expression, and so enhance the radiosensitivity to γ-rays. (authors)

  15. AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells

    Energy Technology Data Exchange (ETDEWEB)

    Raghavan, Pavithra; Tumati, Vasu; Yu Lan [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Chan, Norman [Departments of Medical Biophysics and Radiation Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Ontario (Canada); Tomimatsu, Nozomi [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Burma, Sandeep [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Simmons Comprehensive Cancer Center, Dallas, Texas (United States); Bristow, Robert G. [Departments of Medical Biophysics and Radiation Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Ontario (Canada); Saha, Debabrata, E-mail: debabrata.saha@utsouthwestern.edu [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Simmons Comprehensive Cancer Center, Dallas, Texas (United States)

    2012-11-15

    Purpose: Radiation therapy (RT) is one of the primary modalities for treatment of non-small cell lung cancer (NSCLC). However, due to the intrinsic radiation resistance of these tumors, many patients experience RT failure, which leads to considerable tumor progression including regional lymph node and distant metastasis. This preclinical study evaluated the efficacy of a new-generation cyclin-dependent kinase (Cdk) inhibitor, AZD5438, as a radiosensitizer in several NSCLC models that are specifically resistant to conventional fractionated RT. Methods and Materials: The combined effect of ionizing radiation and AZD5438, a highly specific inhibitor of Cdk1, 2, and 9, was determined in vitro by surviving fraction, cell cycle distribution, apoptosis, DNA double-strand break (DSB) repair, and homologous recombination (HR) assays in 3 NSCLC cell lines (A549, H1299, and H460). For in vivo studies, human xenograft animal models in athymic nude mice were used. Results: Treatment of NSCLC cells with AZD5438 significantly augmented cellular radiosensitivity (dose enhancement ratio rangeing from 1.4 to 1.75). The degree of radiosensitization by AZD5438 was greater in radioresistant cell lines (A549 and H1299). Radiosensitivity was enhanced specifically through inhibition of Cdk1, prolonged G{sub 2}-M arrest, inhibition of HR, delayed DNA DSB repair, and increased apoptosis. Combined treatment with AZD5438 and irradiation also enhanced tumor growth delay, with an enhancement factor ranging from 1.2-1.7. Conclusions: This study supports the evaluation of newer generation Cdk inhibitors, such as AZD5438, as potent radiosensitizers in NSCLC models, especially in tumors that demonstrate variable intrinsic radiation responses.

  16. AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells

    International Nuclear Information System (INIS)

    Purpose: Radiation therapy (RT) is one of the primary modalities for treatment of non-small cell lung cancer (NSCLC). However, due to the intrinsic radiation resistance of these tumors, many patients experience RT failure, which leads to considerable tumor progression including regional lymph node and distant metastasis. This preclinical study evaluated the efficacy of a new-generation cyclin-dependent kinase (Cdk) inhibitor, AZD5438, as a radiosensitizer in several NSCLC models that are specifically resistant to conventional fractionated RT. Methods and Materials: The combined effect of ionizing radiation and AZD5438, a highly specific inhibitor of Cdk1, 2, and 9, was determined in vitro by surviving fraction, cell cycle distribution, apoptosis, DNA double-strand break (DSB) repair, and homologous recombination (HR) assays in 3 NSCLC cell lines (A549, H1299, and H460). For in vivo studies, human xenograft animal models in athymic nude mice were used. Results: Treatment of NSCLC cells with AZD5438 significantly augmented cellular radiosensitivity (dose enhancement ratio rangeing from 1.4 to 1.75). The degree of radiosensitization by AZD5438 was greater in radioresistant cell lines (A549 and H1299). Radiosensitivity was enhanced specifically through inhibition of Cdk1, prolonged G2-M arrest, inhibition of HR, delayed DNA DSB repair, and increased apoptosis. Combined treatment with AZD5438 and irradiation also enhanced tumor growth delay, with an enhancement factor ranging from 1.2-1.7. Conclusions: This study supports the evaluation of newer generation Cdk inhibitors, such as AZD5438, as potent radiosensitizers in NSCLC models, especially in tumors that demonstrate variable intrinsic radiation responses.

  17. Thermal radiosensitization in radiation-sensitive mutant mouse leukemic cells

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Toshikazu (Hiroshima Univ. (Japan). School of Dentistry)

    1994-06-01

    This study investigated thermal, radiation, and combined thermal radiation sensitization of mouse leukemic cells, L5178Y, and radiation-sensitive mutant cells, LX830. Radiation sensitivity (D[sub 0]) values were 0.41 Gy for LX830 and 1.39 Gy for L5178Y, with the ratio of D[sub 0] values in LX830 to in L5178Y being 3.4. Thus, LX830 was more radiosensitive than L5178Y. LX830 showed no shouldered survival curves. Although sublethal damage (SLD) repair was seen to the almost same degree in both LX830 and L5178Y, potential lethal damage (PLD) repair was scarcely observed in LX830. Both cell lines were similar in thermal sensitivity (T[sub 0]). Eosine staining suggested that cell killing due to hyperthermia had occurred in the interphase in both LX830 and L5178Y. L5178Y showed thermal sensitivity low in the G1 phase and high in the S phase; on the contrary, LX830 showed it high in the G1 phase and low in the S phase. Thermal radiosensitization was similar in both cell lines, although there was a great difference in radiation sensitivity between the cell lines. The difference in radiation sensitivity (D[sub 0]) between L5178Y and LX830 became small when radiation was given at the time of the maximum thermal resistance. This seemed to contribute to a decrease in radiation sensitivity in LX830. It can be concluded that thermal radiosensitization depends on thermal sensitivity and that radiation sensitivity decreases in radiation-sensitive cells when exposed to irradiation at the time of thermal resistance. (N.K.).

  18. 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.

  19. Bacterial radiosensitization by using radiation processing in combination with essential oil: Mechanism of action

    Energy Technology Data Exchange (ETDEWEB)

    Lacroix, Monique [Canadian Irradiation Center, Research Laboratory in Sciences Applied to Food, INRS-Institut Armand-Frappier, 531, Boulevard des Prairies, Laval, Quebec, H7V 1B7 (Canada)], E-mail: monique.lacroix@iaf.inrs.ca; Caillet, Stephane [Canadian Irradiation Center, Research Laboratory in Sciences Applied to Food, INRS-Institut Armand-Frappier, 531, Boulevard des Prairies, Laval, Quebec, H7V 1B7 (Canada); Shareck, Francois [INRS-Institut Armand-Frappier, 531, Boulevard des Prairies, Laval, Quebec, H7V 1B7 (Canada)

    2009-07-15

    Spice extracts under the form of essential oils were tested for their efficiency to increase the relative radiosensitivity of Listeria monocytogenes and Escherichia coli O157H7 in culture media. The two pathogens were treated by gamma-irradiation alone or in combination with oregano essential oil to evaluate their mechanism of action. The membrane murein composition, and the intracellular and extracellular concentration of ATP was determined. The bacterial strains were treated with two irradiation doses: 1.2 kGy to induce cell damage and 3.5 kGy to cause cell death for L. monocytogenes. A dose of 0.4 kGy to induce cell damages, 1.1 kGy to obtain viable but nonculturable (VBNC) state and 1.3 kGy to obtain a lethal dose was also applied on E. coli O157H7. Oregano essential oil was used at 0.020% and 0.025% (w/v), which is the minimum inhibitory concentration (MIC) for L. monocytogenes. For E. coli O157H7, a concentration of 0.006% and 0.025% (w/v) which is the minimum inhibitory concentration was applied. The use of essential oils in combination with irradiation has permitted an increase of the bacterial radiosensitization by more than 3.1 times. All treatments had also a significant effect (p{<=}0.05) on the murein composition, although some muropeptides did not seem to be affected by the treatment. Each treatment influenced differently the relative percentage and number of muropeptides. There was a significant (p{<=}0.05) correlation between the reduction of intracellular ATP and increase in extracellular ATP following treatment of the cells with oregano oil. The reduction of intracellular ATP was even more important when essential oil was combined with irradiation, but irradiation of L. monocytogenes alone induced a significant decrease (p{<=}0.05) of the internal ATP without affecting the external ATP.

  20. Bacterial radiosensitization by using radiation processing in combination with essential oil: Mechanism of action

    International Nuclear Information System (INIS)

    Spice extracts under the form of essential oils were tested for their efficiency to increase the relative radiosensitivity of Listeria monocytogenes and Escherichia coli O157H7 in culture media. The two pathogens were treated by gamma-irradiation alone or in combination with oregano essential oil to evaluate their mechanism of action. The membrane murein composition, and the intracellular and extracellular concentration of ATP was determined. The bacterial strains were treated with two irradiation doses: 1.2 kGy to induce cell damage and 3.5 kGy to cause cell death for L. monocytogenes. A dose of 0.4 kGy to induce cell damages, 1.1 kGy to obtain viable but nonculturable (VBNC) state and 1.3 kGy to obtain a lethal dose was also applied on E. coli O157H7. Oregano essential oil was used at 0.020% and 0.025% (w/v), which is the minimum inhibitory concentration (MIC) for L. monocytogenes. For E. coli O157H7, a concentration of 0.006% and 0.025% (w/v) which is the minimum inhibitory concentration was applied. The use of essential oils in combination with irradiation has permitted an increase of the bacterial radiosensitization by more than 3.1 times. All treatments had also a significant effect (p≤0.05) on the murein composition, although some muropeptides did not seem to be affected by the treatment. Each treatment influenced differently the relative percentage and number of muropeptides. There was a significant (p≤0.05) correlation between the reduction of intracellular ATP and increase in extracellular ATP following treatment of the cells with oregano oil. The reduction of intracellular ATP was even more important when essential oil was combined with irradiation, but irradiation of L. monocytogenes alone induced a significant decrease (p≤0.05) of the internal ATP without affecting the external ATP.

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

    Energy Technology Data Exchange (ETDEWEB)

    Negron, Ana C. Valderrama; Silva, Denise de Oliveira [Universidade de Sao Paulo (USP), SP (Brazil). Inst. de Quimica. Dept. de Quimica Fundamental], e-mail: deosilva@iq.usp.br; Rogero, Sizue O. [Instituto de Pesquisas Energeticas e Nucleares (IPEN-CNEN/SP), Sao Paulo, SP (Brazil)], e-mail: sorogero@ipen.br; Cruz, Aurea S. [Instituto Adolfo Lutz, Sao Paulo, SP (Brazil)

    2009-07-01

    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)

  2. Relationship between Radiosensitivity and Telomere Length in Human Carcinoma Cell Lines

    Institute of Scientific and Technical Information of China (English)

    Fu-Xiang ZHOU; Zhi-Guo LUO; Zhen CAO; Yun-Feng ZHOU

    2005-01-01

    @@ 1 Introducion Radiotherapy has long been used as a curative treatment for many cancers. The sensitivity to the irradiation differs in various cancers, and relates to the individual radiotherapy protocol for each patient who suffered from malignancys. So what we will do is to find some definite indicators for radiosensitivity in order to make the individual treatment available. The length of telomere which is known as the "miototic clock" to determine the cell division ability[1]. Radiosensitivity is correlated with the cell division ability, therefore it maybe hypothesized that there is some intrinsic relationship between telomere length and radiosensitivity. In order to explore if the telomere length could be a valid indicator for radiosensitivity, we investigated the correlation between the radiosensitivity and telomere length with or without the pretreatment of azidothymidine (AZT), a telomerase inhibitor which can shorten the telomere, in several carcinoma cell lines.

  3. Nervous system disease associated with dominant cellular radiosensitivity

    International Nuclear Information System (INIS)

    Ionizing radiation sensitivity has been demonstrated in the following neurological diseases: sporadic and familial Alzheimer's disease, familial non-specific dementia, amyotrophic lateral sclerosis and Parkinsonism dementia of Guam, Huntington's disease, multiple sclerosis. Family studies in many cases give data consistent with dominant genetics, as does cell fusion analysis in the one disease so studied. In no case was there an absolute association between radiosensitivity and a given neurological disease. It is proposed that the underlying mutations are in genes controlling facets of nervous or immune system differentiation and development. 15 references, 2 tables

  4. Gadolinium-based nanoparticles for theranostic MRI-radiosensitization.

    Science.gov (United States)

    Lux, François; Sancey, Lucie; Bianchi, Andrea; Crémillieux, Yannick; Roux, Stéphane; Tillement, Olivier

    2015-01-01

    A rapid development of gadolinium-based nanoparticles is observed due to their attractive properties as MRI-positive contrast agents. Indeed, they display high relaxivity, adapted biodistribution and passive uptake in the tumor thanks to enhanced permeability and retention effect. In addition to these imaging properties, it has been recently shown that they can act as effective radiosensitizers under different types of irradiation (radiotherapy, neutron therapy or hadron therapy). These new therapeutic modalities pave the way to therapy guided by imaging and to personalized medicine.

  5. Absence of Radio-Sensitization mediated by Telomerase-inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hee Young; Ju, Yeun Jin; Park, Jeong Eun [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)] (and others)

    2009-05-15

    The radio-therapeutics's problem in tumor is the repeated return of radio-resistant tumor cells during radiotherapy. Therefore, many studies have been accomplished to develop many modulators regulating this mechanism. Besides, sensitizing agents have actively been exploited to enhance the radio-therapeutic efficacy for cancer. The combination anticancer radiotherapeutic cure with telomerase inhibition is useful to sensitize tumor cells to radiation, depending on telomere dysfunction and eventual genomic instability. In our studies, we showed that there was absence of radio-sensitization mediated by telomerase deficiency in clonal cell population.

  6. Radiosensitivity in callus tissues of soybean(glycine max.(L.)merril)

    International Nuclear Information System (INIS)

    Radiosensitivity of soybean as expressed by callus growth was examined after exposure of primary leaf explants with gamma rays.The leaf explants were irradiated 24 hours after incubation on the medium with gamma radiation doses of 0,5,7.5,10,25,50,75 and 100 Gy from Co-60 source. At the 30-day culture of callus the percentage of callus formation from irradiated explants was not different from the percentage of control callus formation. The decreasing average callus fresh weights were in connection with the increasing doses of the radiation and this relationship was significant (P<0.05).The differences between the doses of 5 Gy with 50 Gy and 100 Gy were significant (P<0.05) and the Gr-50 dose was found as 37 Gy for J-357 soybean variety.But the comparison of close doses of radiation was not significant from the point of decreasing average callus fresh weight

  7. Possible role of chromatin alteration in the radiosensitivity of ataxia-telangiectasia

    Energy Technology Data Exchange (ETDEWEB)

    Hittelman, W.N. [Anderson (M.D.) Cancer Center, Houston, TX (United States); Pandita, T.K. [Columbia Univ., New York, NY (United States). Dept. of Radiation Oncology

    1994-12-01

    Cells derived from individuals with ataxia-telangiectasia (A-T) are known to exhibit increased sensitivity to ionizing radiation and certain radiomimetic chemical agents. Here we summarize our findings regarding the role of chromosome damage and repair in this radiosensitivity. Lymphoblastoid cells derived from A-T homozygotes were characterized for initial chromosome (premature chromosome condensation) and DNA (neutral filter elution) damage and repair kinetics in cells from G1 and G2 cell cycle phases. Despite initial levels of DNA damage being similar to normal controls, A-T cells exhibited nearly a two-fold higher initial amount of chromosome damage. Different A-T cell lines exhibited differing chromosome repair capacities compared with control lymphoblastoid cell lines. These results suggest that A-T cells have an altered chromatin structure whereby DNA double-strand breaks are apparently more efficiently converted into chromosome breaks. (author).

  8. Possible role of chromatin alteration in the radiosensitivity of ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Cells derived from individuals with ataxia-telangiectasia (A-T) are known to exhibit increased sensitivity to ionizing radiation and certain radiomimetic chemical agents. Here we summarize our findings regarding the role of chromosome damage and repair in this radiosensitivity. Lymphoblastoid cells derived from A-T homozygotes were characterized for initial chromosome (premature chromosome condensation) and DNA (neutral filter elution) damage and repair kinetics in cells from G1 and G2 cell cycle phases. Despite initial levels of DNA damage being similar to normal controls, A-T cells exhibited nearly a two-fold higher initial amount of chromosome damage. Different A-T cell lines exhibited differing chromosome repair capacities compared with control lymphoblastoid cell lines. These results suggest that A-T cells have an altered chromatin structure whereby DNA double-strand breaks are apparently more efficiently converted into chromosome breaks. (author)

  9. Radiosensitivity of three species of ground orchids (Spathoglottis plicata, S. kimballiana var. angustifolia and S. tomentosa) to acute gamma radiation

    International Nuclear Information System (INIS)

    A radiosensitivity study coupled with tissue culture technique was conducted as preliminary to mutation breeding of the three species of ground orchids (Spathoglottis plicata, S. kimballiana var. angustifolia, and S. tomentosa). It aimed to compare the effects of varying dose levels of gamma radiation applied to the germinated embryos (protocorms) of the three species. Also it sought to determine the lethal dose of gamma radiation on the three species and to determine their optimum dose or the dose level that will lead to production of more mutants. The protocorms of the three species were irradiated at 10 Gy, 20 Gy, 30 Gy, 40 Gy, and 50 Gy dose levels of gamma radiation. Results of the study showed that as the dose level administered increases, percent mortality of seedlings also increases. Further, seedling height, number of roots and root length decreases. However, there was an increase in number of leaves at certain dose levels due to the emergence of furcations, but further increase in the dose levels of radiation decreases the number of leaves.Furthermore, some qualitative characters such as albinism, pigmentation, forked leaves, furcations, and multiple branching came out as responses to gamma radiation. It further shows that the three species have varied radiosensitivity as affected by their individual phenotype. It was found that S. kimballiana var. angustifolia was the least radiosensitive among the species, and could have a great potential for a wide array of genetic variations due to the observed emergence of more morphological mutations that came out as effect of gamma radiation. (Author)

  10. Genetic determination of chromosomal radiosensitivities in G0- and G2-phase human lymphocytes

    International Nuclear Information System (INIS)

    Background and purpose: The radiosensitivity of human lymphocytes measured using a G0- or G2-assay has been linked with an individual's risk of developing normal tissue complications following radiotherapy. This study was performed to increase basic knowledge of the genetics of the human radiation response, and chromosomal aberration induction in particular. Materials and methods: The study was carried out with blood samples taken from 15 monozygotic twin pairs. G0-assay was performed for cells irradiated with 6 Gy counting only deletions and G2-assay for cells irradiated with 0.5 Gy scoring only chromatid breaks. Results: The mean number of deletions measured at 6 Gy for all 30 samples using the G0-assay amounted to 2.96 ± 0.37 (means ± SD), which corresponds to a coefficient of variation (CV) of 13%. There is a highly significant intra-pair correlation for this number among twins (r 2 = 0.911) demonstrating that this parameter is mostly determined by genetic factors. According to the mean number of deletions, a theoretical classification based on the definition =MV + SD as sensitive was made, identifying two pairs as sensitive or resistant, respectively, while nine were normal and two pairs are intermediate. For chromatid breaks measured at 0.5 Gy with the G2-assay the mean number was 1.35 ± 0.42 (means ± SD) corresponding to a CV of 31%. There was again a strong intra-pair correlation among twins with r 2 = 0.837 showing that this sensitivity is also determined mostly by genetic factors. There was, however, no inter-assay correlation between the G0- and G2-sensitivity (r 2 = 0.006) demonstrating that these two sensitivities depend on different genetic factors. Conclusion: The chromosomal radiosensitivity of lymphocytes as defined by G0- or G2-assay is largely determined by different genetic factors, which may allow the use of genetic profiling as an indicator of the respective individual radiosensitivity

  11. The small molecule inhibitor QLT0267 Radiosensitizes squamous cell carcinoma cells of the head and neck.

    Directory of Open Access Journals (Sweden)

    Iris Eke

    Full Text Available BACKGROUND: The constant increase of cancer cell resistance to radio- and chemotherapy hampers improvement of patient survival and requires novel targeting approaches. Integrin-Linked Kinase (ILK has been postulated as potent druggable cancer target. On the basis of our previous findings clearly showing that ILK transduces antisurvival signals in cells exposed to ionizing radiation, this study evaluated the impact of the small molecule inhibitor QLT0267, reported as putative ILK inhibitor, on the cellular radiation survival response of human head and neck squamous cell carcinoma cells (hHNSCC. METHODOLOGY/PRINCIPAL FINDINGS: Parental FaDu cells and FaDu cells stably transfected with a constitutively active ILK mutant (FaDu-IH or empty vectors, UTSCC45 cells, ILK(floxed/floxed(fl/fl and ILK(-/- mouse fibroblasts were used. Cells grew either two-dimensionally (2D on or three-dimensionally (3D in laminin-rich extracellular matrix. Cells were treated with QLT0267 alone or in combination with irradiation (X-rays, 0-6 Gy single dose. ILK knockdown was achieved by small interfering RNA transfection. ILK kinase activity, clonogenic survival, number of residual DNA double strand breaks (rDSB; gammaH2AX/53BP1 foci assay, cell cycle distribution, protein expression and phosphorylation (e.g. Akt, p44/42 mitogen-activated protein kinase (MAPK were measured. Data on ILK kinase activity and phosphorylation of Akt and p44/42 MAPK revealed a broad inhibitory spectrum of QLT0267 without specificity for ILK. QLT0267 significantly reduced basal cell survival and enhanced the radiosensitivity of FaDu and UTSCC45 cells in a time- and concentration-dependent manner. QLT0267 exerted differential, cell culture model-dependent effects with regard to radiogenic rDSB and accumulation of cells in the G2 cell cycle phase. Relative to corresponding controls, FaDu-IH and ILK(fl/fl fibroblasts showed enhanced radiosensitivity, which failed to be antagonized by QLT0267. A

  12. Hypoxic radiosensitization by the antimicrobial methyl paraben

    Energy Technology Data Exchange (ETDEWEB)

    Jacobs, G.P.; Sade, N.

    1984-08-01

    The antimicrobial preservative, methyl paraben (methyl-4-hydroxybenzoate) sensitizes anoxic buffered suspensions of Staphylococcus aureus to gamma-radiation. The maximal response at an 0.5 mM concentration represents a 150 percent increase in response over that for deoxygenated suspensions without additive, and 80 percent of the response for aerated suspensions alone. Methyl paraben is not toxic to the test organism under the present test conditions.

  13. Dexamethasone acts as a radiosensitizer in three astrocytoma cell lines via oxidative stress

    Directory of Open Access Journals (Sweden)

    Sylvia Ortega-Martínez

    2015-08-01

    Full Text Available Glucocorticoids (GCs, which act on stress pathways, are well-established in the co-treatment of different kinds of tumors; however, the underlying mechanisms by which GCs act are not yet well elucidated. As such, this work investigates the role of glucocorticoids, specifically dexamethasone (DEXA, in the processes referred to as DNA damage and DNA damage response (DDR, establishing a new approach in three astrocytomas cell lines (CT2A, APP.PS1 L.1 and APP.PS1 L.3. The results show that DEXA administration increased the basal levels of gamma-H2AX foci, keeping them higher 4 h after irradiation (IR of the cells, compared to untreated cells. This means that DEXA might cause increased radiosensitivity in these cell lines. On the other hand, DEXA did not have an apparent effect on the formation and disappearance of the 53BP1 foci. Furthermore, it was found that DEXA administered 2 h before IR led to a radical change in DNA repair kinetics, even DEXA does not affect cell cycle. It is important to highlight that DEXA produced cell death in these cell lines compared to untreated cells. Finally and most important, the high levels of gamma-H2AX could be reversed by administration of ascorbic acid, a potent blocker of reactive oxygen species, suggesting that DEXA acts by causing DNA damage via oxidative stress. These exiting findings suggest that DEXA might promote radiosensitivity in brain tumors, specifically in astrocytoma-like tumors.

  14. Radiosensitization by 6-aminonicotinamide and 2-deoxy-D-glucose in human cancer cells.

    Science.gov (United States)

    Varshney, R; Dwarakanath, Bs; Jain, V

    2005-05-01

    The aim was to exploit simultaneous inhibition of glycolytic and pentose phosphate pathways of energy production for radiosensitization using 2-deoxy-D-glucose (2-DG) and 6-aminonicotinamide (6-AN) in transformed mammalian cells. Two human tumour cell lines (cerebral glioma, BMG-1 and squamous carcinoma cells 4197) were investigated. 2-DG and/or 6-AN added at the time of irradiation were present for 4 h after radiation. Radiation-induced cell death (macrocolony assay), cytogenetic damage (micronuclei formation), cell cycle delay (bromodeoxyuridne (BrdU) pulse chase), apoptosis (externalization of phosphotidylserine (PS) by annexin V), chromatin-bound proliferation cell nuclear antigen (PCNA) and cellular glutathione (GSH) levels were investigated as parameters of radiation response. The presence of 2-DG (5 mM) during and for 4 h after irradiation increased the radiation-induced micronuclei formation and cell death, and caused a time-dependent decrease in GSH levels in BMG-1 cells while no significant effects could be observed in 4197 cells. 6-AN (5 microM) enhanced the radiosensitivity of both cell lines and reduced the GSH content by nearly 50% in gamma-irradiated 4197 cells. Combining 2-DG and 6-AN caused a profound decrease in the GSH content and enhanced the radiation damage in both the cell lines by increasing mitotic and apoptotic cell death. Further, the combination (2-DG + 6-AN) enhanced the radiation-induced G2 block, besides arresting cells in S phase and inhibited the recruitment of PCNA. The combination of 2-DG and 6-AN enhances radiation damage by modifying damage response pathways and has the potential for improving radiotherapy of cancer. PMID:16076755

  15. Radioprotection and Cell Cycle Arrest of Intestinal Epithelial Cells by Darinaparsin, a Tumor Radiosensitizer

    International Nuclear Information System (INIS)

    Purpose: It was recently reported that the organic arsenic compound darinaparsin (DPS) is a cytotoxin and radiosensitizer of tumor cells in vitro and in subcutaneous xenograft tumors. Surprisingly, it was also found that DPS protects normal intestinal crypt epithelial cells (CECs) from clonogenic death after ionizing radiation (IR). Here we tested the DPS radiosensitizing effect in a clinically relevant model of prostate cancer and explored the radioprotective effect and mechanism of DPS on CECs. Methods and Materials: The radiation modification effect of DPS was tested in a mouse model of orthotopic xenograft prostate cancer and of IR-induced acute gastrointestinal syndrome. The effect of DPS on CEC DNA damage and DNA damage responses was determined by immunohistochemistry. Results: In the mouse model of IR-induced gastrointestinal syndrome, DPS treatment before IR accelerated recovery from body weight loss and increased animal survival. DPS decreased post-IR DNA damage and cell death, suggesting that the radioprotective effect was mediated by enhanced DNA damage repair. Shortly after DPS injection, significant cell cycle arrest was observed in CECs at both G1/S and G2/M checkpoints, which was accompanied by the activation of cell cycle inhibitors p21 and growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A). Further investigation revealed that DPS activated ataxia telangiectasia mutated (ATM), an important inducer of DNA damage repair and cell cycle arrest. Conclusions: DPS selectively radioprotected normal intestinal CECs and sensitized prostate cancer cells in a clinically relevant model. This effect may be, at least in part, mediated by DNA damage response activation and has the potential to significantly increase the therapeutic index of radiation therapy

  16. Radioprotection and Cell Cycle Arrest of Intestinal Epithelial Cells by Darinaparsin, a Tumor Radiosensitizer

    Energy Technology Data Exchange (ETDEWEB)

    Tian, Junqiang; Doi, Hiroshi [Department of Radiation Oncology, School of Medicine, Stanford University, Stanford, California (United States); Saar, Matthias; Santos, Jennifer [Department of Urology, School of Medicine, Stanford University, Stanford, California (United States); Li, Xuejun; Peehl, Donna M. [Department of Radiation Oncology, School of Medicine, Stanford University, Stanford, California (United States); Knox, Susan J., E-mail: sknox@stanford.edu [Department of Radiation Oncology, School of Medicine, Stanford University, Stanford, California (United States)

    2013-12-01

    Purpose: It was recently reported that the organic arsenic compound darinaparsin (DPS) is a cytotoxin and radiosensitizer of tumor cells in vitro and in subcutaneous xenograft tumors. Surprisingly, it was also found that DPS protects normal intestinal crypt epithelial cells (CECs) from clonogenic death after ionizing radiation (IR). Here we tested the DPS radiosensitizing effect in a clinically relevant model of prostate cancer and explored the radioprotective effect and mechanism of DPS on CECs. Methods and Materials: The radiation modification effect of DPS was tested in a mouse model of orthotopic xenograft prostate cancer and of IR-induced acute gastrointestinal syndrome. The effect of DPS on CEC DNA damage and DNA damage responses was determined by immunohistochemistry. Results: In the mouse model of IR-induced gastrointestinal syndrome, DPS treatment before IR accelerated recovery from body weight loss and increased animal survival. DPS decreased post-IR DNA damage and cell death, suggesting that the radioprotective effect was mediated by enhanced DNA damage repair. Shortly after DPS injection, significant cell cycle arrest was observed in CECs at both G1/S and G2/M checkpoints, which was accompanied by the activation of cell cycle inhibitors p21 and growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A). Further investigation revealed that DPS activated ataxia telangiectasia mutated (ATM), an important inducer of DNA damage repair and cell cycle arrest. Conclusions: DPS selectively radioprotected normal intestinal CECs and sensitized prostate cancer cells in a clinically relevant model. This effect may be, at least in part, mediated by DNA damage response activation and has the potential to significantly increase the therapeutic index of radiation therapy.

  17. Is variation in human radiosensitivity real or artifactual?

    International Nuclear Information System (INIS)

    Two methods of producing human T-lymphocyte colonies in vitro are described, as well as dose-survival experiments using these methods for the investigation of possible differential radiosensitivity among individuals. In one method, the cloning efficiency (CE) of nonirradiated lymphocytes was between 10 % and 40 % (method 1), whereas subsequent improvement in assay conditions (method 2) resulted in a CE greater than 30 %. In vitro X-irradiation of colonies produced using method 1 revealed that the dose required to kill 90 % of the cells (D10) was 2.87±0.28 Gy (mean ±SD, n = 18) for repeated examinations of lymphocytes from one reference individual. Using method 2, the D10 values were greater, viz., 3.66±0.21 Gy for 28 repeated tests of the same reference individual and 3.58±0.19 Gy for 31 different individuals. Analysis of variance to compare the data from repeated examinations of one person versus data from single examinations of different persons showed that variation in the D10 value was not significantly greater in the latter group. These results support the hypothesis that individual variation in human radiosensitivity is quite small, if it exists at all, as far as can be determined by the loss of colony-forming ability of irradiated G0 lymphocytes. (author)

  18. Role of Natural Radiosensitizers and Cancer Cell Radioresistance: An Update

    Directory of Open Access Journals (Sweden)

    Arif Malik

    2016-01-01

    Full Text Available Cancer originates from genetic mutations accumulation. Cancer stem cells have been depicted as tumorigenic cells that can differentiate and self-renew. Cancer stem cells are thought to be resistant to conventional therapy like chemotherapy and radiation therapy. Radiation therapy and chemotherapy damage carcinomic DNA cells. Because of the ability of cancer stem cells to self-renew and reproduce malignant tumors, they are the subject of intensive research. In this review, CSCs radioresistant mechanisms which include DNA damage response and natural radiosensitizers have been summed up. Reactive oxygen species play an important role in different physiological processes. ROS scavenging is responsible for regulation of reactive oxygen species generation. A researcher has proved that microRNAs regulate tumor radiation resistance. Ionizing radiation does not kill the cancer cells; rather, IR just slows down the signs and symptoms. Ionizing radiation damages DNA directly/indirectly. IR is given mostly in combination with other chemo/radiotherapies. We briefly described here the behavior of cancer stem cells and radioresistance therapies in cancer treatment. To overcome radioresistance in treatment of cancer, strategies like fractionation modification, treatment in combination, inflammation modification, and overcoming hypoxic tumor have been practiced. Natural radiosensitizers, for example, curcumin, genistein, and quercetin, are more beneficial than synthetic compounds.

  19. The radiosensitizing effect of metronidazole in maize

    International Nuclear Information System (INIS)

    The identification of chemical substances which increase the efficiency of radiation is important to make easier the obtention of plants with structural chromosome aberrations which may be used in an alternative program for hybrid maize production. The present work was carried out to investigate the effect of the chemical substance metronidazole in maize seedlings submitted to gamma radiation. Several treatments were done, soaking the seeds in solutions with varied concentrations of the active substance combined with solution filtration and gamma radiation. On the third day of the experiment, germination percentage, root and stem lengths were evaluated. At a high concentration (1,250 mg/50 mL) metronidazole behaved as a radiosensibilizer in the presence of radiation. Even at a low concentration (250 mg/50 mL; 750 mg/50 mL) and in the absence of radiation, metronidazole behaved as toxic substance. (author)

  20. Nicotinamide as a radiosensitizer in tumours and normal tissues: the importance of drug dose and timing

    International Nuclear Information System (INIS)

    Background and purpose: Nicotinamide is a radiation sensitizer currently undergoing clinical testing. This was an experimental study to determine the importance of drug dose and time interval between drug administration and irradiation for radiosensitization. Materials and methods: Nicotinamide (50-500 mg/kg) was injected intraperitoneally into CDF1 or C3H mice and drug plasma pharmacokinetics were determined by HPLC. Radiosensitization was measured in tumours and normal tissues after local irradiation. The tumours were a C3H mammary carcinoma, the KHT sarcoma and the SCCVII carcinoma. Tumour response was assessed using either growth delay (C3H) or clonogenic survival (KHT/SCCVII). Normal tissue toxicities evaluated included early responding skin (development of moist desquamation of the foot) and late responding bladder (reservoir function estimated by cystometry) and lung (ventilation rate measured by plethysmography). Results: All nicotinamide peak plasma concentrations were seen within 30 min after injection. Irradiating tumours at peak times resulted in enhancement ratios (ERs) of 1.27 (C3H), 1.75 (KHT) and 1.45 (SCCVII) with high nicotinamide doses and 1.27 (C3H), 1.28 (KHT) and 1.36 (SCCVII) after giving clinically relevant doses (100-200 mg/kg). Lower ERs were observed when the time interval between drug injection and irradiation was increased beyond the peak time. Irradiating normal tissues at peak times after injecting 100-200 mg/kg nicotinamide gave ERs of 1.20 (skin), 0.90 (bladder) and 1.02 (lung). Conclusions: Clinically achievable doses of nicotinamide will enhance tumour radiation damage while having minimal effects in normal tissues, but for the best tumour effect radiation should be given at the time of peak plasma drug concentrations

  1. Cytosolic phospholipaseA2 inhibition with PLA-695 radiosensitizes tumors in lung cancer animal models.

    Directory of Open Access Journals (Sweden)

    Dinesh Thotala

    Full Text Available Lung cancer remains the leading cause of cancer deaths in the United States and the rest of the world. The advent of molecularly directed therapies holds promise for improvement in therapeutic efficacy. Cytosolic phospholipase A2 (cPLA2 is associated with tumor progression and radioresistance in mouse tumor models. Utilizing the cPLA2 specific inhibitor PLA-695, we determined if cPLA2 inhibition radiosensitizes non small cell lung cancer (NSCLC cells and tumors. Treatment with PLA-695 attenuated radiation induced increases of phospho-ERK and phospho-Akt in endothelial cells. NSCLC cells (LLC and A549 co-cultured with endothelial cells (bEND3 and HUVEC and pre-treated with PLA-695 showed radiosensitization. PLA-695 in combination with irradiation (IR significantly reduced migration and proliferation in endothelial cells (HUVEC & bEND3 and induced cell death and attenuated invasion by tumor cells (LLC &A549. In a heterotopic tumor model, the combination of PLA-695 and radiation delayed growth in both LLC and A549 tumors. LLC and A549 tumors treated with a combination of PLA-695 and radiation displayed reduced tumor vasculature. In a dorsal skin fold model of LLC tumors, inhibition of cPLA2 in combination with radiation led to enhanced destruction of tumor blood vessels. The anti-angiogenic effects of PLA-695 and its enhancement of the efficacy of radiotherapy in mouse models of NSCLC suggest that clinical trials for its capacity to improve radiotherapy outcomes are warranted.

  2. On differences in radiosensitivity estimation: TCP experiments versus survival curves. A theoretical study

    Science.gov (United States)

    Stavrev, Pavel; Stavreva, Nadejda; Ruggieri, Ruggero; Nahum, Alan

    2015-08-01

    We have compared two methods of estimating the cellular radiosensitivity of a heterogeneous tumour, namely, via cell-survival and via tumour control probability (TCP) pseudo-experiments. It is assumed that there exists intra-tumour variability in radiosensitivity and that the tumour consists predominantly of radiosensitive cells and a small number of radio-resistant cells. Using a multi-component, linear-quadratic (LQ) model of cell kill, a pseudo-experimental cell-survival versus dose curve is derived. This curve is then fitted with a mono-component LQ model describing the response of a homogeneous cell population. For the assumed variation in radiosensitivity it is shown that the composite pseudo-experimental survival curve is well approximated by the survival curve of cells with uniform radiosensitivity. For the same initial cell radiosensitivity distribution several pseudo-experimental TCP curves are simulated corresponding to different fractionation regimes. The TCP model used accounts for clonogen proliferation during a fractionated treatment. The set of simulated TCP curves is then fitted with a mono-component TCP model. As in the cell survival experiment the fit with a mono-component model assuming uniform radiosensitivity is shown to be highly acceptable. However, the best-fit values of cellular radiosensitivity produced via the two methods are very different. The cell-survival pseudo-experiment yields a high radiosensitivity value, while the TCP pseudo-experiment shows that the dose-response is dominated by the most resistant sub-population in the tumour, even when this is just a small fraction of the total.

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

    International Nuclear Information System (INIS)

    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

  4. Opportunities for Radiosensitization in the Stereotactic Body Radiation Therapy (SBRT) Era.

    Science.gov (United States)

    Moding, Everett J; Mowery, Yvonne M; Kirsch, David G

    2016-01-01

    Stereotactic body radiation therapy (SBRT) utilizing a small number of high-dose radiation therapy fractions continues to expand in clinical application. Although many approaches have been proposed to radiosensitize tumors with conventional fractionation, how these radiosensitizers will translate to SBRT remains largely unknown. Here, we review our current understanding of how SBRT eradicates tumors, including the potential contributions of endothelial cell death and immune system activation. In addition, we identify several new opportunities for radiosensitization generated by the move toward high dose per fraction radiation therapy. PMID:27441746

  5. Down-Regulation of EBV-LMP1 Radio-Sensitizes Nasal Pharyngeal Carcinoma Cells via NF-κB Regulated ATM Expression

    OpenAIRE

    Xiaoqian Ma; Lifang Yang; Lanbo Xiao; Min Tang; Liyu Liu; Zijian Li; Mengyao Deng; Lunquan Sun; Ya Cao

    2011-01-01

    BACKGROUND: The latent membrane protein 1 (LMP1) encoded by EBV is expressed in the majority of EBV-associated human malignancies and has been suggested to be one of the major oncogenic factors in EBV-mediated carcinogenesis. In previous studies we experimentally demonstrated that down-regulation of LMP1 expression by DNAzymes could increase radiosensitivity both in cells and in a xenograft NPC model in mice. RESULTS: In this study we explored the molecular mechanisms underlying the radiosens...

  6. Inhibition of cyclooxygenase-2 activity by celecoxib does not lead to radiosensitization of human prostate cancer cells in vitro

    International Nuclear Information System (INIS)

    Purpose: To evaluate the potential radiosensitizing effect of the specific COX-2 inhibitor celecoxib (Celebrex[reg]) on prostate carcinoma cells in vitro. Materials and methods: The influence of celecoxib (concentration range 5 to 75 μM) on radiation-induced cellular and clonogenic survival was investigated in prostate carcinoma cell lines PC-3, DU145, LNCaP and normal prostate epithelial cells (PrEC). Western blot analysis and ELISA were used to determine the impact of radiation alone or radiation combined with celecoxib treatment on COX-2 expression and prostaglandin E2 synthesis. To evaluate induction of celecoxib-induced apoptosis cell cycle analysis has been performed. Results: Celecoxib (5, 10 and 25 μM) in combination with single-dose irradiation of 2 Gy induced a significant radiosensitization in normal prostate epithelial cells which could not be observed for any of the prostate carcinoma cell lines investigated. Increased COX-2 protein expression in PC-3 cells was obvious only after IR with 15 Gy, while PGE2 production was elevated following irradiation (2-15 Gy) in a dose-dependent manner. Treatment with celecoxib alone or in combination with IR led to a dose-dependent increase in COX-2 protein expression. Nevertheless pre-treatment with celecoxib caused a marked reduction of radiation-induced enzyme activity as tested at the level of PGE2 production, both in PC-3 and DU145 cells. Following fractionated irradiation with single doses of 2 Gy, elevated COX-2 protein expression as well as enhanced PGE2 production was observed already after the second fraction in PC-3 cells. Pre-treatment with celecoxib reduced the amount of PGE2 significantly, but not of COX-2 protein. Conclusions: Our data obtained for the human prostate cancer cell lines do not indicate that a marked inhibition of prostaglandin E2 synthesis by celecoxib leads to enhanced radiosensitization. Thus, in terms of radiosensitization the analysed prostate cancer cells can be classified as non

  7. Effect of silencing of ATM expression by siRNA on radiosensitivity of human lung adenocarcinoma A549 cells

    International Nuclear Information System (INIS)

    Objective: To investigate the effect of silencing of ataxia-telangiectasia mutated (ATM) expression by plasmid-mediated RNA interference on the radiosensitivity of human lung adenocarcinoma A549 cells. Methods: Eukaryotic expression plasmid containing ATM small interfering RNA (siRNA) (pSilencer2.1-ATM), as well as pSilencer2.1-nonspecific, was constructed.Lung adenocarcinoma A549 cells were divided into positive group, negative group,and control group to be transfected with pSilencer2.1-ATM, pSilencer2.1-nonspecific, and no plasmid, respectively. The mRNA and protein expression of ATM was measured by RT-PCR and Western blot, respectively. The change in cell radiosensitivity was observed by colony-forming assay. Cell cycle and cell apoptosis were analyzed by flow cytometry. Results: The eukaryotic expression plasmid containing ATM siRNA was successfully constructed. The RT-PCR and Western blot demonstrated that the expression of ATM was down-regulated in the positive group. The sensitization enhancement ratios (D0 ratios) for the positive group and negative group were 1.50 and 1.01, respectively. The flow cytometry revealed that the proportions of A549 cells in G1 and G2/M phases were significantly lower in the positive group than in the control group (51.27% vs 61.85%, P = 0.012; 6.34% vs 10.91%, P = 0.008) and that the apoptosis rate was significantly higher in the positive group than in the control group and negative group (49.31% vs 13.58%, P = 0.000; 49.31% vs 13.17%, P = 0.000). Conclusions: Silencing of ATM expression may increase the radiosensitivity of human lung adenocarcinoma A549 cells, probably by affecting the cell cycle and promoting cell apoptosis. (authors)

  8. MicroRNA-148b enhances the radiosensitivity of non-Hodgkin's lymphoma cells by promoting radiation-induced apoptosis

    International Nuclear Information System (INIS)

    Growing evidence has demonstrated that microRNAs (miRNAs) play an important role in regulating cellular radiosensitivity. This study aimed to explore the role of miRNAs in non-Hodgkin's lymphoma (NHL) radiosensitivity. Microarray was employed to compare the miRNA expression profiles in B cell lymphoma cell line Raji before and after a 2-Gy dose of radiation. A total of 20 differentially expressed miRNAs were identified including 10 up-regulated and 10 down-regulated (defined as P <0.05). Among the differentially expressed miRNAs, miR-148b was up-regulated 1.53-fold in response to radiation treatment. A quantitative real-time polymerase chain reaction (PCR) assay confirmed the up-regulation of miR-148b after radiation. Transient transfection experiments showed that miR-148b was up-regulated by miR-148b mimic and down-regulated by miR-148b inhibitor in the Raji cells. A proliferation assay showed that miR-148b could inhibit the proliferation of Raji cells before and after radiation. A clonogenic assay demonstrated that miR-148b sensitized Raji cells to radiotherapy. MiR-148b did not affect the cell cycle profile of post-radiation Raji cells compared with controls. An apoptosis assay showed that miR-148b enhanced apoptosis of Raji cells after irradiation. Taken together, these results demonstrate that miR-148b increased the radiosensitivity of NHL cells probably by promoting radiation-induced apoptosis, which suggests that miR-148b plays an important role in the response of NHL to ionizing radiation. (author)

  9. Radiosensitivity of tumor cell lines after pretreatment with the EGFR tyrosine kinase inhibitor ZD1839 (Iressa {sup registered})

    Energy Technology Data Exchange (ETDEWEB)

    Burdak-Rothkamm, S. [Dept. of Radiotherapy, Saarland Univ. Hospital, Homburg/Saar (Germany); Gray Cancer Inst., Northwood, Middlesex (United Kingdom); Ruebe, C.E.; Nguyen, T.P.; Ludwig, D.; Ruebe, C. [Dept. of Radiotherapy, Saarland Univ. Hospital, Homburg/Saar (Germany); Feldmann, K. [AstraZeneca GmbH, Wedel (Germany); Wiegel, T. [Dept. of Radiotherapy, Univ. Hospital Benjamin Franklin, Berlin (Germany)

    2005-03-01

    Background and purpose: the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa registered) reduces survival and augments radiation response of certain tumor cells. The aim of this study was to identify cellular events that are associated with the modulation of radiosensitivity by ZD1839. Material and methods: three tumor cell lines (A549, H596, FaDu) were exposed to ionizing radiation, treatment with ZD1839, and combined treatment. Clonogenic cell survival was determined by colony assays, EGFR and transforming growth factor-(TGF-){alpha} expression by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), cell cycle distribution and apoptosis by flow cytometry. Results: in A549 and H596 cells ZD1839 had little effect on clonogenic growth, but survival curves revealed a radiosensitizing effect of 5 {mu}M ZD1839 on A549 cells. Both cell lines expressed moderate amounts of EGFR mRNA and very low levels of TGF-{alpha} mRNA. FaDu cells expressed relatively high amounts of EGFR and TGF-{alpha} transcripts and showed marked inhibition of clonogenic growth, reduction of S-phase cells, and induction of apoptosis after treatment with 1 {mu}M ZD1839 and combined treatment. Surprisingly, the subpopulation of FaDu cells surviving ZD1839 pretreatment was more radioresistant. Exposure to ZD1839 caused a decrease in EGFR mRNA expression in A549 cells, no change in H596, and even an increase in FaDu cells. Conclusion: the sensitivity to ZD1839 correlated with the EGFR expression level, an inhibition of cell proliferation, and induction of apoptosis in the cell lines analyzed. A radiosensitizing effect of ZD1839 was associated with downregulation of EGFR mRNA expression. (orig.)

  10. Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer.

    Science.gov (United States)

    Feng, Felix Y; Speers, Corey; Liu, Meilan; Jackson, William C; Moon, Dominic; Rinkinen, Jacob; Wilder-Romans, Kari; Jagsi, Reshma; Pierce, Lori J

    2014-08-01

    Sustained locoregional control of breast cancer is a significant issue for certain patients. Inhibition of PARP1 is a promising strategy for radiosensitization (RS). We sought to optimize therapy with PARP1 inhibition and radiation (RT) by establishing the most effective treatment schedule, degree of PARP1-mediated RS, and identify early biomarkers predictive of efficacy in breast cancer models. Using clonogenic survival assays, we assessed intrinsic radiosensitivity and RS induced by PARP1 inhibition in breast cancer cell lines. Potential biomarkers of response were evaluated using western blotting, flow cytometry, and immunofluorescence with validation in vivo using tumor xenograft experiments. Across a panel of BC and normal breast epithelial cell lines, the PARP1 inhibitor ABT-888 preferentially radiosensitizes breast cancer (vs. normal) cells with enhancement ratios (EnhR) up to 2.3 independent of intrinsic BC subtype or BRCA mutational status. Concurrent and adjuvant therapy resulted in the highest EnhR of all schedules tested. The degree of RS did not correlate with pretreatment markers of PARP1 activity, DNA damage/repair, or cell cycle distribution. Increases in PARP1 activity 24 h after RT were associated with sensitivity after combination treatment. Findings were confirmed in breast cancer xenograft models. Our study demonstrates that PARP1 inhibition improves the therapeutic index of RT independent of BC subtype or BRCA1 mutational status and that PARP1 activity may serve as a clinically relevant biomarker of response. These studies have led to a clinical trial (TBCRC024) incorporating intratreatment biomarker analyses of PARP1 inhibitors and RT in breast cancer patients. PMID:25104443

  11. Radiosensitizing effect of nitric oxide in tumor cells and experimental tumors irradiated with gamma rays and proton beams

    International Nuclear Information System (INIS)

    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 137Cs 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)

  12. Relationship between radiosensitivity of human neonatal hematopoietic stem/progenitor cells and individual maternal/neonatal obstetric factors

    International Nuclear Information System (INIS)

    Hematopoietic stem/progenitor cells (HSPCs) in placental/umbilical cord blood (CB), which is neonatal peripheral blood, have increasingly been used for hematopoietic stem cell transplantations. It is likely HSPCs are sensitive to extracellular oxidative stresses, such as ionizing radiation and redox-directed chemotherapeutic agents. However, the radiosensitivity of HSPCs and neonatal hematopoietic system remains unclear. This study investigated the potential relationship between the radiosensitivity of HSPCs in CB, which was obtained from singleton and full-term deliveries, and maternal/neonatal obstetric factors. Freshly prepared CB CD34+ cells exposed to 2 Gy X-irradiation were assayed for hematopoietic progenitor cells such as colony-forming unit-granulocyte-macrophage (CFU-GM), burst-forming unit-erythroid (BFU-E), colony-forming unit-granulocyte-erythroid-macrophage-megakaryocyte (CFU-Mix), and colony-forming unit-megakaryocyte (CFU-Meg). As a result, the neonatal weight, placental weight, CB volume, total low-density (LD) cells, and CD34+ cells showed mutually significant positive correlations. The CB volume and total LD cells showed a significant reverse correlation with the surviving fraction of CFU-Meg. The surviving fraction of CFU-GM in spring (March-May) was significantly higher than that in autumn (September-November). The surviving fraction of CFU-Meg in the spring was significantly lower than that in the autumn. Male neonates showed a significantly higher surviving fraction of CFU-GM than female neonates. Contrarily, females showed a significantly higher surviving fraction of CFU-Meg than males. The present results suggest that the obstetric factors, such as the season of birth and neonatal gender, influence the radiosensitivity of neonatal hematopoiesis. (author)

  13. Adenovirus-mediated expression of UHRF1 reduces the radiosensitivity of cervical cancer HeLa cells to γ-irradiation

    Institute of Scientific and Technical Information of China (English)

    Xin-li LI; Qing-hui MENG; Sai-jun FAN

    2009-01-01

    Aim:An in vitro study was carried out to determine the effect of UHRF1 overexpression on radiosensitivity in human cervical cancer HeLa ceUs using adenovirus-mediated UHRF1 gene transfer (Ad5-UHRF1). Methods: Cell survival was evaluated using the clonogenic survival assay and the MTT assay; apoptosis and cell cycle distribution were monitored by flow cytometry. Protein levels were measured by Western blotting. Silencing XRCC4 expression was performed by transfection of small interfering RNA (siRNA).Results: Increased expression of UHRF1 by AdS-UHRF1 significantly reduced the radiosensitivity of HeLa cells. The UHRF1-mediated radioresistance was correlated with increased DNA repair capability and increased expression of the DNA damage repair protein, XRCC4. Knocking down XRCC4 expression in the cells using XRCC4 siRNA markedly reduced the UHRFl-mediated radioresistance. Conclusion: These results provide the first evidence for revealing a functional role of UHRF1 in human cervical cancer cells as a negative regulator of radiosensitivity.

  14. Observations on the radiosensitivity of guppy (Lebistes reticulatus Peters)

    International Nuclear Information System (INIS)

    The ichthyologically well-known teleostean fish, Lebistes reticulatus Peters commonly known as guppy, found abundant in pools, streams and estuaries was studied to establish its sensitivity to radiation and to explore its possible use as a biological indicator organism of radiation effects in the aquatic system. The guppy, Lebistes reticulatus was found to be radiosensitive. Chromosome aberrations were induced by gamma-irradiation of fish in vivo. Through cytogenetic technique the aberrant chromosomes were evaluated. The aberrant chromosomes observed were of various types such as chromatid gaps and breaks, chromosome gaps and breaks, chromatid and chromosome fragments, polycentrics (dicentrics and tricentrics), fusions and translocations. Of the types seen, it is concluded that dicentrics are the most reliable indicator of radiation effects. In the course of this study, the Lethal Radiation Dose in guppy within thirty days was determined. It was found to lie in the dose of 3 krad (LDsub(50/30)). (author)

  15. Radiosensitivity Parameters For Lethal Mutagenesis In Caenorhabditis Elegans

    Energy Technology Data Exchange (ETDEWEB)

    Cucinotta, F.A.; Wilson, J.W.; Katz, R.

    1994-01-01

    For the first time track structure theory has been applied to radiobiological effects in a living organism. Data for lethal mutagenesis in Caenorhabditis elegans, obtained after irradiation with nine different types of ions of atomic number 1-57 and gamma rays have yielded radiosensitivity parameters (E{sub 0}, sigma{sub 0}, Kappa, m = 68 Gy, 2.5 x 10(exp {minus}9) cm (exp 2), 750, 2) comparable with those found for the transformation of C3HT10 1/2 cells (180 Gy, 1.15 x 10(exp {minus}10) cm(exp 2), 750, 2) but remote from those (E{sub 0} and sigma{sub 0} = approx. 2 Gy, approx. 5 x 10(exp {minus}7) cm(exp 2)) for mammalian cell survival.

  16. Acute skin reaction suggestive of pembrolizumab-induced radiosensitization.

    Science.gov (United States)

    Sibaud, Vincent; David, Isabelle; Lamant, Laurence; Resseguier, Sarah; Radut, Roxana; Attal, Justine; Meyer, Nicolas; Delord, Jean-Pierre

    2015-12-01

    The combination of localized radiotherapy and immune checkpoint inhibitors represents a promising therapeutic strategy for various cancers, including metastatic melanoma. Radiation therapy may enhance tumor antigen presentation and cytokine release, which may optimize the systemic antitumor immune response induced by these immunotherapeutic antibodies, with a potential delayed abscopal effect. However, clinical experience of using immune checkpoint inhibitors with concurrent radiotherapy remains scarce. We report here for the first time a case suggestive of acute skin radiosensitization induced by pembrolizumab, with a suggestive time relationship between the completion of ionizing radiation, drug administration, and rapid onset of the skin reaction. This suggests that radiation therapy may also interact rapidly with anti-programmed-death 1 antibodies. Therefore, caution should be exercised when prescribing this combination therapy in advanced cancers.

  17. Effect of medroxyprogesterone acetate (Provera) on ovarian radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Jarrell, J.; YoungLai, E.V.; McMahon, A.; Barr, R.; O' Connell, G.; Belbec, L.

    1989-04-01

    Medroxyprogesterone acetate (Provera) is a drug that is commonly given to young women with cancer during chemotherapy and radiation to control heavy bleeding associated with anovulation. Because hypothalamic-pituitary-ovarian suppression has been associated with ovarian protection from the effects of chemotherapy and medroxyprogesterone acetate has been identified as a radiosensitizing agent, we explored the effects of medroxyprogesterone acetate on a rat model with known radiation injury characteristics. Sprague-Dawley rats were treated with medroxyprogesterone acetate or vehicle from day 22 to day 37 of life and were either irradiated or sham-irradiated on day 30 of life and then killed on day 44. Radiation with medroxyprogesterone acetate administration produced a greater loss in preantral and healthy control follicles than in control follicles. No suppression of luteinizing hormone or follicle-stimulating hormone had occurred by day 30 but ovarian glutathione content was reduced. These findings indicate that the administration of medroxyprogesterone acetate with radiotherapy may enhance ovarian injury.

  18. Autotaxin and LPA receptors represent potential molecular targets for the radiosensitization of murine glioma through effects on tumor vasculature.

    Directory of Open Access Journals (Sweden)

    Stephen M Schleicher

    Full Text Available Despite wide margins and high dose irradiation, unresectable malignant glioma (MG is less responsive to radiation and is uniformly fatal. We previously found that cytosolic phospholipase A2 (cPLA(2 is a molecular target for radiosensitizing cancer through the vascular endothelium. Autotaxin (ATX and lysophosphatidic acid (LPA receptors are downstream from cPLA(2 and highly expressed in MG. Using the ATX and LPA receptor inhibitor, α-bromomethylene phosphonate LPA (BrP-LPA, we studied ATX and LPA receptors as potential molecular targets for the radiosensitization of tumor vasculature in MG. Treatment of Human Umbilical Endothelial cells (HUVEC and mouse brain microvascular cells bEND.3 with 5 µmol/L BrP-LPA and 3 Gy irradiation showed decreased clonogenic survival, tubule formation, and migration. Exogenous addition of LPA showed radioprotection that was abrogated in the presence of BrP-LPA. In co-culture experiments using bEND.3 and mouse GL-261 glioma cells, treatment with BrP-LPA reduced Akt phosphorylation in both irradiated cell lines and decreased survival and migration of irradiated GL-261 cells. Using siRNA to knock down LPA receptors LPA1, LPA2 or LPA3 in HUVEC, we demonstrated that knockdown of LPA2 but neither LPA1 nor LPA3 led to increased viability and proliferation. However, knockdown of LPA1 and LPA3 but not LPA2 resulted in complete abrogation of tubule formation implying that LPA1 and LPA3 on endothelial cells are likely targets of BrP-LPA radiosensitizing effect. Using heterotopic tumor models of GL-261, mice treated with BrP-LPA and irradiation showed a tumor growth delay of 6.8 days compared to mice treated with irradiation alone indicating that inhibition of ATX and LPA receptors may significantly improve malignant glioma response to radiation therapy. These findings identify ATX and LPA receptors as molecular targets for the development of radiosensitizers for MG.

  19. Is 24-color FISH detection of in-vitro radiation-induced chromosomal aberrations suited to determine individual intrinsic radiosensitivity?

    Energy Technology Data Exchange (ETDEWEB)

    Kuechler, A.; Wendt, T.G. [Clinic of Radiology, Jena (Germany). Dept. of Radiotherapy; Neubauer, S.; Grabenbauer, G.G.; Sauer, R. [Erlangen Univ. (Germany). Dept. of Radiotherapy; Claussen, U.; Liehr, T. [Jena Univ. (Germany). Inst. of Human Genetics and Anthropology

    2002-04-01

    Background: Reliable determination of intrinsic radiosensitivity in individual patients is a serious need in radiation oncology. Chromosomal aberrations are sensitive indicators of a previous exposure to ionizing irradiation. Former molecular cytogenetic studies showed that such aberrations as an equivalent of intrinsic radiosensitivity can be detected by fluorescence in-situ hybridization (FISH) techniques using whole chromosome painting (wcp) probes. However, only one up to three randomly chosen wcp probes have been applied for such approaches until now. As a random distribution of chromosomal rearrangements along the chromosomes is up to now still controversial, the power of the 24-color FISH approach should be elucidated in the present study. Methods and Material: Lymphocytes derived from lymphoblastoid cell lines of one patient with Nijmegen breakage syndrome (NBS homozygote) and of two NBS heterozygotes and peripheral blood lymphocytes of two controls were analyzed. Samples of each patient/control were irradiated in vitro with 0.0 Gy, 0.7 Gy or 2.0 Gy prior to cultivation. Chromosomal aberrations were analyzed in detail and quantified by means of 24-color FISH as an expression of the individual intrinsic radiosensitivity. Results: 24-color FISH analyses were done in a total of 1,674 metaphases. After in-vitro irradiation, 21% (0.7 Gy) or 57% (2.0 Gy) of the controls' cells, 15% (0.7 Gy) or 53% (2.0 Gy) of the heterozygotes' cells and 54% (0.7 Gy) or 79% (2.0 Gy) of the homozygote's cells contained aberrations. The highest average rates of breaks per mitosis [B/M] (0.7 Gy: 1.80 B/M, 2.0 Gy: 4.03 B/M) and complex chromosomal rearrangements [CCR] (0.7 Gy: 0.20 CCR/M, 2.0 Gy: 0.47 CCR/M) were observed in the NBS patient. Moreover, the proportion of different aberration types after irradiation showed a distinct increase in the rate of CCR combined with a decrease in dicentrics in the NBS homozygote. Conclusion: To come to a more complete picture of

  20. Expression of hPNAS-4 Radiosensitizes Lewis Lung Cancer

    International Nuclear Information System (INIS)

    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.

  1. Expression of hPNAS-4 Radiosensitizes Lewis Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zeng Hui [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Yuan Zhu [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Zhu Hong [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Li Lei; Shi Huashan [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Wang Zi; Fan Yu; Deng Qian; Zeng Jianshuang; He Yinbo [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Xiao Jianghong [State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China); Li Zhiping, E-mail: lizhiping620312@yahoo.com.cn [Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province (China)

    2012-11-15

    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.

  2. Radiosensitivity of human haematopoietic stem/progenitor cells

    International Nuclear Information System (INIS)

    The haematopoietic system is regenerative tissue with a high proliferative potential; therefore, haematopoietic stem cells (HSCs) are sensitive to extracellular oxidative stress caused by radiation and chemotherapeutic agents. An understanding of this issue can help predict haematopoietic recovery from radiation exposure as well as the extent of radiation damage to the haematopoietic system. In the present study, the radiosensitivity of human lineage-committed myeloid haematopoietic stem/progenitor cells (HSPCs), including colony-forming unit–granulocyte macrophage, burst-forming unit–erythroid and colony-forming unit–granulocyte–erythroid–macrophage–megakaryocyte cells, which are contained in adult individual peripheral blood (PB) and fetus/neonate placental/umbilical cord blood (CB), were studied. The PB of 59 healthy individual blood donors and the CB of 42 neonates were investigated in the present study. HSPCs prepared from PB and CB were exposed to 0.5 or 2 Gy x-irradiation. The results showed that large individual differences exist in the surviving fraction of cells. In the case of adult PB, a statistically significant negative correlation was observed between the surviving fraction observed at a dose of 0.5 Gy and the age of the blood donors; however, none of these correlations were observed after 2 Gy x-irradiation. In addition, seasonal and gender variation were observed in the surviving fraction of CB HSPCs. The present results suggest that there are large individual differences in the surviving fraction of HSPCs contained in both adult PB and fetus/neonate CB. In addition, some factors, including the gender, age and season of birth, affect the radiosensitivity of HSPCs, especially with a relatively low-dose exposure. (paper)

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  4. Comparison of radiosensitivity of rat parotid and submandibular glands after different radiation schedules

    NARCIS (Netherlands)

    Coppes, RP; Vissink, A; Konings, AWT

    2002-01-01

    Background and purpose: To investigate the radiosensitivity of rat parotid and submandibular gland functioning after local single dose, conventional fractionated and accelerated fractionated irradiation. Methods: The salivary glands of male albino Wistar rats were locally irradiated with a single do

  5. Differential radio-sensitivities of human chromosomes 1 and 2 in one donor in interphase- and metaphase-spreads after 60Co γ-irradiation

    International Nuclear Information System (INIS)

    Radiation-induced chromosome aberrations lead to a plethora of detrimental effects at cellular level. Chromosome aberrations provide broad spectrum of information ranging from probability of malignant transformation to assessment of absorbed dose. Studies mapping differences in radiation sensitivities between human chromosomes are seldom undertaken. Consequently, health risk assessment based on radio-sensitivities of individual chromosomes may be erroneous. Our efforts in this article, attempt to demonstrate differences in radio-sensitivities of human chromosome-1 and/or -2, both in interphase and metaphase spreads. Upon blood collection, dosimetry and irradiation were performed. Lymphocytes were isolated after whole-blood irradiation with 60Co γ-rays in the dose range of 0–5 Gy for both interphase, and metaphase aberration studies. Induction of premature chromosome condensation in interphase cells was accomplished using a phosphatase inhibitor, calyculin-A. Metaphase spreads were harvested from short-term peripheral blood lymphocyte cultures following colcemid arrest and using an automated metaphase harvester and spreader. Aberration analysis in both interphase and metaphase spreads were done using FISH. In interphase, aberrant cell and aberration frequency involving chromosome 1 and/or 2 increased linearly with radiation dose. In metaphase, aberrations increased in a linear-quadratic manner with dose. Our studies ascertain that chromosome-2 is more radio-sensitive than chromosome-1 in both interphase and metaphase stages, albeit the DNA content of chromosome-2 is lesser than chromosome-1 by almost 10 million base pairs. Differences in radio-sensitivities of chromosomes have implications in genetic damage, chromosome organization, and chromosome function. Designing research experiments based on our vital findings may bring benefit to radiation-induced risk assessment, therapeutics and development of chromosome specific biomarkers

  6. Quince tree (cydonia oblonga Mill.)-breeding bases:seed propagation, cytogenetics and radiosensitivity

    International Nuclear Information System (INIS)

    The following aspects of the marmeleiro, cydonia oblonga Mill., were, researched: media nad periods to supply the seed chilling requirement in moist cold storage (5-100c); 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)

  7. Enhancement of radiosensitization by metal-based nanoparticles in cancer radiation therapy

    OpenAIRE

    Su, Xiang-Yu; Liu, Pei-Dang; Wu, Hao; Gu, Ning

    2014-01-01

    Radiation therapy performs an important function in cancer treatment. However, resistance of tumor cells to radiation therapy still remains a serious concern, so the study of radiosensitizers has emerged as a persistent hotspot in radiation oncology. Along with the rapid advancement of nanotechnology in recent years, the potential value of nanoparticles as novel radiosensitizers has been discovered. This review summarizes the latest experimental findings both in vitro and in vivo and attempts...

  8. Relationship between Radiosensitivity and Telomere Length in Human Carcinoma Cell Lines

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    1 IntroducionRadiotherapy has long been used as a curative treatment for many cancers. The sensitivity to the irradiation differs in various cancers, and relates to the individual radiotherapy protocol for each patient who suffered from malignancys. So what we will do is to find some definite indicators for radiosensitivity in order to make the individual treatment available. The length of telomere which is known as the “miototic clock” to determine the cell division ability~([1]). Radiosensitivity is corre...

  9. Comet assay study on the radiosensitivity of transplanted tumor models in nude mice

    International Nuclear Information System (INIS)

    Objective: To evaluate the possibility of detecting human solid tumors radiosensitivity by comet assay. Methods: The radiosensitivity of three human tumor xenografts (lung adenocarcinoma, esophageal squamous carcinoma and nasopharyngeal squamous carcinoma) were detected by comet assay with the RTM considered as the end point. Transplanted tumor specimens were taken and digested to single-cell suspensions with a cell concentration of 4 x 104 ml. For each xenograft, the resultant suspensions were divided into five groups and exposed to irradiation on ice to doses of 0 (control group), 2, 5, 10 and 15 Gy, respectively. DNA damage was detected by comet assay immediately after irradiation. Results: For the unirradiated control group, the tail movement (TM) of the three xenografts showed significant differences (F=9.11, Pesophageal squamous carcinoma>nasopharyngeal squamous carcinoma, which is not consistent with the clinical observation. However, the descending trend of the relative radiosensitivity reflected by the adjusted tail moment (RTM) was in the following sequences: esophageal squamous carcinoma>nasopharyngeal squamous carcinoma>lung adenocarcinoma; the esophageal squamous carcinoma was slightly more radiosensitive than nasopharyngeal squamous carcinoma (though without significant difference), which was exactly consistent with clinical observation. Conclusions: 1. The tail movement should undergo background adjustment in order to reflect the difference of the radiosensitivity detected by comet assay in solid tumors. 2. Comet assay could be used for detecting the radiosensitivity of human solid tumors

  10. Re-evaluating gadolinium(III) texaphyrin as a radiosensitizing agent.

    Science.gov (United States)

    Bernhard, E J; Mitchell, J B; Deen, D; Cardell, M; Rosenthal, D I; Brown, J M

    2000-01-01

    Gadolinium(III) texaphyrin (Gd-tex) was recently proposed as a radiosensitizing agent that combines preferential tumor uptake with detection of drug localization by magnetic resonance imaging (S. W. Young et al., Proc. Natl. Acad. Sci. USA, 93: 6610-6615, 1996). In view of the initial report on this compound, four radiobiology laboratories undertook independent efforts to further study radiosensitization by Gd-tex. In addition to repeating the previously reported studies on Gd-tex in HT-29 cells, we tested five other human tumor cell lines (U-87 MG, U251-NCI, SW480, A549, and MCF-7). These studies included a Gd-tex treatment period of 24 h before irradiation (as in the original publication), with concentrations of Gd-tex ranging from 20-500 microM. In neither the HT-29 cells nor any of the other five human cell lines did we see radiation sensitization by Gd-tex. Two cell lines (MCF-7 and U-87 MG) were further tested for radiosensitization by Gd-tex under hypoxic conditions. No radiosensitization was observed in either case. Finally, the radiation response of two tumor lines were assessed in vivo. Neither HT-29 xenografts in severe combined immunodeficient (SCID) mice nor RIF-1 tumors growing in C3H mice demonstrated radiosensitization after Gd-tex treatment before single or fractionated doses of radiation. Our results raise questions about the efficacy of Gd-tex as a radiosensitizing agent. PMID:10646858

  11. Radiosensitivity of CD45RO+ memory and CD45RO- naive T cells in culture

    International Nuclear Information System (INIS)

    Radiosensitivities of various human T-cell subsets were investigated by a proliferation assay and by a single-cell gel electrophoresis assay. Each T-cell subset was purified using a cell sorter and was induced to proliferate by ionomycin and interleukin 2. Unsorted T cells showed biphasic dose-survival curves, indicating the heterogeneity of T cells in terms of radiosensitivity. Purified CD4+ helper and CD8+ killer T cells showed similar biphasic dose-survival curves. Hence both T-cell subsets were composed of cells of different radiosensitivity. The T-cell subsets belonging to different activation stages such as CD45RO+ memory and CD45RO- naive T cells had different dose-survival curves. The former was more radiosensitive than the latter. The high radiosensitivity of CD45RO+ cells was also demonstrated by single-cell gel electrophoresis after irradiation. This is the first demonstration that a particular cell surface marker on T cells is correlated with greater radiosensitivity. 27 refs., 7 figs., 1 tab

  12. Inhibiting CD146 by its Monoclonal Antibody AA98 Improves Radiosensitivity of Cervical Cancer Cells.

    Science.gov (United States)

    Cheng, Huawen

    2016-01-01

    BACKGROUND Cervical cancer is one of the major causes of cancer death of females worldwide. Radiotherapy is considered effective for cervical cancer treatment, but the low radiosensitivity found in some cases severely affects therapeutic outcomes. This study aimed to reveal the role of CD146, an important adhesion molecule facilitating tumor angiogenesis, in regulating radiosensitivity of cervical cancer cells. MATERIAL AND METHODS CD146 protein expression was compared in normal cells, cervical cancer cells with lower radiosensitivity, and cervical cancer cells with higher sensitivity from cervical squamous cell carcinoma patients. Anti-CD146 monoclonal antibody AA98 was used to inhibit CD146 in human cervical cancer SiHa cells with relatively low radiosensitivity, and then the cell survival and apoptosis changes after radiation were detected by colony formation assay and flow cytometry. RESULTS CD146 protein was significantly up-regulated in cervical cancer cells (Pcancer cells with lower radiosensitivity. The SiHa cells treated with AA98 showed more obvious inhibition in cell survival (Papoptosis (Pcancer cells, which might allow improvement in treatment outcome in cervical cancer. Further studies are necessary for understanding the detailed mechanism of CD146 in regulating radiosensitivity. PMID:27647179

  13. 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)

    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

  14. Fluorescence studies on radiation oxidative damage to membranes with implications to cellular radiosensitivity

    Indian Academy of Sciences (India)

    K P Mishra

    2002-12-01

    Radiation oxidative damage to plasma membrane and its consequences to cellular radiosensitivity have received increasing attention in the past few years. This review gives a brief account of radiation oxidative damage in model and cellular membranes with particular emphasis on results from our laboratory. Fluorescence and ESR spin probes have been employed to investigate the structural and functional alterations in membranes after g-irradiation. Changes in the lipid bilayer in irradiated unilamellar liposomes prepared from egg yolk lecithin (EYL) were measured by using diphenylhexatriene (DPH) as a probe. The observed increase in DPH polarization and decrease in fluorescence intensity after g-irradiation of liposomes imply radiationinduced decrease in bilayer fluidity. Inclusion of cholesterol in liposome was found to protect lipids against radiation damage, possibly by modulation of bilayer organization e.g. lipid packing. Measurements on dipalmitoyl phosphatidylcholine (DPPC) liposomes loaded with 6-carboxyfluorescein (CF) showed radiation dose-dependent release of the probe indicating radiation-induced increased permeability. Changes in plasma membrane permeability of thymocytes were monitored by fluorescein diacetate (FDA) and induced intracellular reactive oxygen species (ROS) were determined by 2,7-dichlorodihydro fluorescein diacetate (DCH-FDA). Results suggest a correlation between ROS generation and membrane permeability changes induced by radiation within therapeutic doses (0-10 Gy). It is concluded that increase in membrane permeability was the result of ROS-mediated oxidative reactions, which might trigger processes leading to apoptotic cell death after radiation exposure.

  15. EFFECT OF ADENOVIRUS-MEDIATED p53 GENE TRANSFER ON APOPTOSIS AND RADIOSENSITIVITY OF HUMAN GASTRIC CARCINOMA CELL LINES

    Institute of Scientific and Technical Information of China (English)

    张珊文; 肖绍文; 吕有勇

    2003-01-01

    Objective: To evaluate the effect of adenovirus- mediated p53 gene (Adp53) on apoptosis and radiosensitivity of human gastric carcinoma cell lines. Methods: Recombinant adenovirus expressing wild-type p53 gene was transferred into four human gastric carcinoma cell lines with different p53 genetic status. p53 protein expression was detected by immunohistochemistry assay and western blot assay. Cell survival was assessed using a clonogenic assay. TUNEL assay was used in determination of apoptosis. Four human gastric carcinoma cells infected with Adp53 were irradiated with 4Gy and cell cycle distribution and Sub-G1 peak were assayed by flow cytometry. Results: G2/M arrest, apoptosis and inhibition of tumor cell proliferation were induced by infection at Adp53 at 100 MOI which caused high transfer rate of wild-type p53 and strong expression of p53 protein in four human gastric carcinoma cells. The radio-enhancement ratio of Adp53 at 4Gy were 3.0 for W cell, 3.6 for M cell, 2.2 for neo cell and 2.5 for 823 cell in vitro. Conclusion: This study demonstrated that Adp53 transfer increased cellular apoptosis and radiosensitivity of human gastric carcinoma cell lines in vitro independently on cellular intrinsic p53 status thus supporting the combination of p53 gene therapy with radiotherapy in clinical trials.

  16. Radio-sensitivities and angiogenic signaling pathways of irradiated normal endothelial cells derived from diverse human organs

    International Nuclear Information System (INIS)

    The purpose of the present investigation was to study the effects of ionizing radiation on endothelial cells derived from diverse normal tissues. We first compared the effects of radiation on clonogenic survival and tube formation of endothelial cells, and then investigated the molecular signaling pathways involved in endothelial cell survival and angiogenesis. Among the different endothelial cells studied, human hepatic sinusoidal endothelial cells (HHSECs) were the most radio-resistant and human dermal microvascular endothelial cells were the most radio-sensitive. The radio-resistance of HHSECs was related to adenosine monophosphate-activated protein kinase and p38 mitogen-activated protein kinase-mediated expression of MMP-2 and vascular endothelial growth factor receptor-2 (VEGFR-2), whereas the increased radio-sensitivity of HDMECs was related to extracellular signal-regulated kina0se-mediated generation of angiostatin. These observations demonstrate that there are distinct differences in the radiation responses of normal endothelial cells obtained from diverse organs, which may provide important clues for protection of normal tissue from radiation exposure. (author)

  17. A correlation between DNA-nuclear matrix binding and relative radiosensitivity in two human squamous cell carcinoma cell lines

    International Nuclear Information System (INIS)

    Three aspects of DNA topology were examined in two human squamous cell carcinoma lines of differing radiosensitivity (SQ-9G, D0 = 1.46 Gy; and SQ-20B, D0 = 2.36 Gy). High-salt-extracted nuclei (nucleoids) were taken from γ-irradiated cells, stained with ethidium bromide and examined by flow cytometry. After 5 Gy, nucleoids from SQ-9G cells became 30% less efficient at adopting positive DNA supercoils than were unirradiated controls. Only a 4% difference was found with the radioresistant SQ-20B line. Both lines produced positive supercoils more efficiently after irradiation if first exposed to the topoisomerase II inhibitor VP16. Ethidium bromide titration of nucleoids was consistent with each containing similar numbers and sizes of DNA loops. In each line approximately 30-35% of DNA was accessible to trioxsalen, shown by inter-strand crosslinking after UV photo-activation. Exhaustive digestion of nuclear DNA by DNase I removed more DNA from the radiosensitive than from the radioresistant cell line (12% vs 28% remaining), thought to be due to the increased accessibility of SQ-9G DNA in vitro. (author)

  18. Ectopically hTERT expressing adult human mesenchymal stem cells are less radiosensitive than their telomerase negative counterpart

    International Nuclear Information System (INIS)

    During the past several years increasing evidence indicating that the proliferation capacity of mammalian cells is highly radiosensitive, regardless of the species and the tissue of origin of the cells, has accumulated. It has also been shown that normal bone marrow cells of mice have a similar radiosensitivity to other mammalian cells so far tested. In this study, we investigated the genetic effects of ionizing radiation (2.5-15 Gy) on normal human mesenchymal stem cells and their telomerised counterpart hMSC-telo1. We evaluated overall genomic integrity, DNA damage/repair by applying a fluorescence-detected alkaline DNA unwinding assay together with Western blot analyses for phosphorylated H2AX and Q-FISH was applied for investigation of telomeric damage. Our results indicate that hMSC and TERT-immortalized hMSCs can cope with relatively high doses of γ-rays and that overall DNA repair is similar in the two cell lines. The telomeres were extensively destroyed after irradiation in both cell types suggesting that telomere caps are especially sensitive to radiation. The TERT-immortalized hMSCs showed higher stability at telomeric regions than primary hMSCs indicating that cells with long telomeres and high telomerase activity have the advantage of re-establishing the telomeric caps

  19. Effect of oxygen-radiosensitizer mixtures on the radiation response of Chinese hamster cells, line V-79-753B, in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Millar, B.C.; Fielden, E.M.; Steele, J.J.

    1980-07-01

    The present data show that the maximum yield of single-strand breaks (ssb) in the cellular DNA of Chinese hamster cells V-79-753B is produced at a concentration of oxygen that produces an enhancement ratio for cell survival of 1.9. The relationship between the oxygen concentration and enhancement ratio for survival in this cell line is biphasic with a plateau at ER = 1.9 over the range of 1.5 to 7 ..mu..M O/sub 2/. For concetrations of oxygen below 1.5 ..mu..M a linear relationship between 1/D/sub 0/ and the initial yield of ssb is found. Electron affinic and free radical radiosensitizers operate by different mechanisms which are reflected at the level of ssb production; electron affinic compounds increase the yield of ssb in anoxia and in the presence of low concentrations of oxygen, whereas free radical radiosensitizers do not. The observation that TMPN can compete with oxygen or misonidazole in reactions that lead to changes in radiosensitivity but not ssb production indicates that the relationship between the two parameters must be casual and not casual.

  20. Genetic variations in DNA repair genes, radiosensitivity to cancer and susceptibility to acute tissue reactions in radiotherapy-treated cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Chistiakov, Dimitry A. (Dept. of Pathology, Univ. of Pittsburgh, Pittsburgh (US)); Voronova, Natalia V. (Dept. of Molecular Diagnostics, National Research Center GosNIIgenetika, Moscow (RU)); Chistiakov, Pavel A. (Dept. of Radiology, Cancer Research Center, Moscow (RU))

    2008-06-15

    Ionizing radiation is a well established carcinogen for human cells. At low doses, radiation exposure mainly results in generation of double strand breaks (DSBs). Radiation-related DSBs could be directly linked to the formation of chromosomal rearrangements as has been proven for radiation-induced thyroid tumors. Repair of DSBs presumably involves two main pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). A number of known inherited syndromes, such as ataxia telangiectasia, ataxia-telangiectasia like-disorder, radiosensitive severe combined immunodeficiency, Nijmegen breakage syndrome, and LIG4 deficiency are associated with increased radiosensitivity and/or cancer risk. Many of them are caused by mutations in DNA repair genes. Recent studies also suggest that variations in the DNA repair capacity in the general population may influence cancer susceptibility. In this paper, we summarize the current status of DNA repair proteins as potential targets for radiation-induced cancer risk. We will focus on genetic alterations in genes involved in HR- and NHEJ-mediated repair of DSBs, which could influence predisposition to radiation-related cancer and thereby explain interindividual differences in radiosensitivity or radioresistance in a general population

  1. Influence of pEgr1-hsTRAIL plasmid on radiosensitivity and DR4 and DR5 expression levels in lung adencarcinoma A549 cells

    International Nuclear Information System (INIS)

    Objective: To measure the changes of the radiosensitivity in human lung adenocarcinoma A549 cells transfected with pEgr1-hsTRAIL plasmid and the effect on death receptor (DR) 4 and DR5 expressions, and to explore the radiosensitizing effect of pEgr1-hsTRAIL plasmid and possible mechanism on inducing apoptosis. Methods: There were normal control, pEgr1-hsTRAIL, 6 Gy X-rays, and pEgr1-hsTRAIL + 6 Gy X-rays groups in the experiment. After the A549 cells were transfected with liposome, and irradiated with X-rays, colony formation assay was used to measure the radiosensitivity, and reverse transcription PCR (RT-PCR) was performed to detect the DR4 and DR5 mRNA expressions, and Western blotting was applied to determine the DR4 and DR5 protein expressions. Results: The D0 values of A549 cells in normal control group and pEgr1-hsTRAIL group were 3.26 and 1.91 Gy, respectively, it indicated that pEgr1-hsTRAIL plasmid could enhance the radiosensitivity in A549 cells. The RT-PCR results showed that as compared with normal control group, the DR4 and DR5 mRNA expression levels in pEgr1-hsTRAIL group had no significant change, but those in 6 Gy X-rays group were increased significantly (P<0.05), and those in pEgr1-hsTRAIL + 6 Gy X-rays group were also increased significantly (P<0.05); the DR5 mRNA expression level in pEgr1-hsTRAIL + 6 Gy X-rays group was higher than that in 6 Gy X-rays group (P<0.05). The Western blotting results showed that the DR4 and DR5 protein expressions in pEgr1-hsTRAIL group did not change obviously compared with normal control group, but those in 6 Gy X-rays and pEgr1-hsTRAIL + 6 Gy X-rays groups were increased, and the DR5 protein expression in pEgr1-hsTRAIL + 6 Gy X-rays group was increased mostly. Conclusion: The recombinant plasmid pEgr1-hsTRAIL can enhance the radiosensitivity of A549 cells, and has the enhancing effect on DR5 expression induced by radiation, but no same effect on DR4 expression. (authors)

  2. Proteomics analysis of apoptosis-regulating proteins in tissues with different radiosensitivity

    International Nuclear Information System (INIS)

    The aim of this study was to identify of radiosusceptibility proteins in tissues with different radiosensitivity. C3H/HeJ mice were exposed to 10 Gy. The tissues were processed for proteins extraction and were analyzed by 2-dimensional electrophoresis. The proteins were identified by matrix-assisted laser desorption ionizing time-of-flight mass spectrometry and validated by immunohistochemical staining and Western blotting. The peaks of apoptosis levels were 35.3±1.7% and 0.6±0.2% in the spleen and the liver, respectively, after ionizing radiation. Analysis of liver tissue showed that the expression level of reactive oxygen species (ROS) related proteins such as cytochrome c, glutathione S transferase, NADH dehydrogenase and peroxiredoxin VI increased after radiation. The expression level of cytochrome c increased to 3-fold after ionizing radiation in both tissues. However in spleen tissue, the expression level of various kinds of apoptosis regulating proteins increased after radiation. These involved iodothyronine, CD 59A glycoprotein precursor, fas antigen and tumor necrosis factor -inducible protein TSG-6nprecursor after radiation. The difference in the apoptosis index between the liver and spleen tissues is closely associated with the expression of various kinds of apoptosis-related proteins. The result suggests that the expression of apoptosis-related protein and redox proteins play important roles in this radiosusceptibility. (author)

  3. Effects of some hypoxic cell radiosensitizers on the decay of potentially lethal oxygen-dependent damage in fully hydrated spores

    International Nuclear Information System (INIS)

    Using a stopped-flow mixing and pulsed irradiation apparatus, a study has been made of the decay, to a harmless form, of radiation-induced species that would otherwise be lethal to spores on contact with oxygen. Aqueous suspensions of Bacillus megaterium spores were irradiated with electrons for approximately 1 s; at various times after irradiation oxygen in solution was added. As the interval between anoxic irradiation and introduction of oxygen increased, the fraction of spores surviving increased. This change in survival reflects the decay of potentially lethal species. The presence of electron-affinic radiosensitizers during irradiation enhanced the decay rate of this damage, the greatest enhancement being seen with sensitizers of the highest electron affinity. In contrast, the nitroxyl-free radical sensitizer TAN fixed the radiation-induced damage so that no increase in survival, and hence no decay, was seen. (author)

  4. Modified comet assay prediction of radiosensitivity in 105 nasopharyngeal cancer patients

    International Nuclear Information System (INIS)

    Objective: To evaluate the value of modified comet assay for predicting clinical radiosensitivity of nasopharyngeal cancers (NPC). Methods: Biopsy samples were collected and analyzed by alkaline comet assay in 105 NPC patients before radiotherapy. The biopsy material from the primary tumor, having been prepared as isolated cell suspension, was divided into two items: control and 5 Gy per fraction irradiation. All tumors had been examined by spiral CT or MRI before treatment and up until 50 Gy of radiation by conventional fraction, so as to measured the S0 and S50 of the maximum tumor cross-section area. Regression rate was used to evaluate the clinical tumor radiosensitivity, and expressed as regression ratio (Rs=[S0-S50 ]/S0). The tumor radiosensitivity was set as high sensitivity (Rs≥0.9), intermediate sensitivity (0.7≤Rss<0.7). According to the cell DNA photos in modified comet assay, I A, I B, II A II B graphs were classified and the radiosensitivity was decided by the value of RTM and absorption of light density (A). Statistical analysis software SPSS10.0 was used. Kappa analytical method was used for consistency test between clinical results and laboratory results. Results: In the assay of clinical radiosensitivity, 41 highly sensitive, 21 intermediate sensitive and 43 low sensitive tumors were found. In the modified comet assay, 58 sensitive and 47 insensitive tumors were found. The sensitivity, specificity and accuracy were 71.0%, 67.4% and 69.5%. The results of modified comet assay were similar to the clinical results in 73 patients. Kappa analytical result neared moderate-high consistency (Kappa=0.38) between modified comet assay and clinical radiosensitivity. Conclusions: Our study demonstrates that evident correlation is present between results of modified comet assay and clinical radiosensitivity of NPC. The modified comet assay is potentially favored in clinical application due to its convenience and short cycle of assay

  5. RELATIONSHIP BETWEEN TELOMERE LENGTH AND RADIOSENSITIVITY IN VARIOUS HUMAN CANCER CELL LINES

    Institute of Scientific and Technical Information of China (English)

    CAO Zhen; ZHOU Yun-feng; LUO Zhi-guo; XIAO Chuang-ying; DAI Jing; PAN Dong-feng; ZHOU Fu-xiang; XIE Cong-hua; ZHANG Gong; LIU Shi-quan

    2005-01-01

    Objective: To investigate the relationship between telomere length and radiosensitivity in various human cancer cell lines with the expectation to find a valid and common predictor of radiosensitivity for different cancers. Methods: Eight human cancer cell lines were used, including five human breast cancer cell lines (ZR-75-30, MCF-7, MDA-MB-435S, T-47-D,F539-1590), two human larynx squamous carcinoma cell lines (Hep-2 and Hep-2R) and a human malignant glioma cell line(U251). Among them, the radioresistant cell line Hep-2R was isolated and established from a radiosensitive human larynx squamous carcinoma cell line Hep-2 by our center. The radiobiological characteristics of the eight lines were analyzed by the method of colony-forming assay and the radiosensitivity parameters were calculated. Telomere length was analyzed by TRF(mean Telomere Restriction Fragments) length assay. Results: The radioresistance of Hep-2R cell line proved to be stable in long-term passaged cultures as well as in frozen samples. Radiosensitivity parameters are different among those lines. The SF2 values of Hep-2 and U251 are 0.4148 and 0.7520, respectively; The SF2 values of breast cancer cell lines are between those of Hep-2 and U251. The TRF of Hep-2R is 11.12Kb, longer than three times that of its parental counterpart. There is a positive correlation both between SF2 and TRF (r=0.786, P<0.05), and between Do and TRF (r=0.905, P<0.01). Conclusion:It is concluded that radiosensitivity and telomere length (TRF) are negatively correlated, TRF could be a valid predictor for radiosensitivity.

  6. The effect of nitroimidazole and nitroxyl radiosensitizers on the post-irradiation synthesis of DNA

    International Nuclear Information System (INIS)

    The modification of DNA damage by three radiosensitizing drugs, present during γ-irradiation of hypoxic Chinese hamster cells, was investigated. Both 2-methyl-5-nitroimidazole-1-ethanol (metronidazole) and 1-(2-nitro-1-imidazole)-3-methoxy-2-propanol (Ro-07-0582) were found to cause large increases in the yield of DNA single-strand breaks (SSB); triacetoneamine-N-oxyl (TAN) was found to have only a small effect on SSB production. The three drugs tested did not inhibit the rejoining of SSB. A pulse label and chase procedure was used to examine post-irradiation DNA synthesis. TAN present during irradiation under hypoxia was found to cause interruptions in subsequent DNA synthesis. Metronidazole and Ro-07-0582 had no effect on post-irradiation DNA synthesis. In addition, the effects of pre- and post-irradiation exposure to TAN were investigated, since these treatments have shown increased cell-killing in survival studies. TAN pre- and post-treatments were found to have no significant effect on subsequent DNA synthesis. (author)

  7. Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers

    Directory of Open Access Journals (Sweden)

    Jayant S Goda

    2016-01-01

    Full Text Available Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor, RAS (rat sarcoma oncogene or loss of PTEN (phosphatase and tensin homologue which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells, it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies.

  8. Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers.

    Science.gov (United States)

    Goda, Jayant S; Pachpor, Tejaswini; Basu, Trinanjan; Chopra, Supriya; Gota, Vikram

    2016-02-01

    Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor), RAS (rat sarcoma) oncogene or loss of PTEN (phosphatase and tensin homologue) which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K)/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells), it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs) known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies.

  9. Radiosensitivity of angiogenic and mitogenic factors in human amniotic membrane

    International Nuclear Information System (INIS)

    Amniotic membrane as a temporary biological dressing remains as a beneficial and cost-effective means of treating burns in developing countries. This medical application is attributed mainly to placental structural and biochemical features that are important for maintaining proper embryonic development. Since fresh amnions are nevertheless for straightforward clinical use and for preservation, radiation-sterilization is been performed to improve the safety of this placental material. However, like any other sterilization method, gamma-radiation may induce physical and chemical changes that may influence the biological property of the material. Thus, the aim of this study is to compare the effects of various levels of radiation-sterilization protocols for human amnions on angiogenic (neovascularization) and epithelial-mitogenic activities, both of which are physiological processes fundamental to wound healing. Water-soluble extract of non-irradiated amnions demonstrates a strong stimulatory effect on both cell proliferation and angiogenesis. No change in biological activity is seen in amnions irradiated at 25 kGy, the sterilization dose used by the Philippine Nuclear Research Institute (PNRI) for the production of radiation-sterilized human amniotic membranes (RSHAM). However, it appears that amniotic angiogenic factors are more radiosensitive than its mitogenic components, evident from the depressed vascularization of the chorioallantoic membrane (CAM) exposed to 35 kGy-irradiated amnions. The dose of 35 kGy is at present the medical sterilization dose used at the Central Tissue Bank in Warsaw (Poland) for the preparation of their amnion allografts. (Authors)

  10. Cytogenetic radio-sensitivity in wild and laboratory rats

    International Nuclear Information System (INIS)

    Radiation-induced chromosomal aberrations have been found differ considerably between different species and also between individuals of the same species (Andrews, 1958; Carlson, 1954; Scott and Bigger, 1974). The work of Blumel (1950) on drosophila and crowley and curtis (1963) on mice represent few examples of the vast differences in frequencies of radiation-induced chromosomal aberrations in different species. however, in most cases, all experimental work on the genetic effects of radiation has been carried out on laboratory stocks that have been living under artificial conditions. Domestication of many organisms has been found to be associated with many genetical changes (Berry, 1969). Searle, berry and Beechey (1970) have reported significant differences between irradiated wild and laboratory mice in the frequency of translocations in spermatocyte ,metaphases. Badr and Badr (1971 a, b) have found that the responses of two different populations of rats, a laboratory albino strain (Rattus norvegicus) and a wild type (Rattus Rattus) to various doses of X-ray irradiation in terms of mitotic activity, mortality rate and mean survival times are significantly different. In this report, the differential response of two populations of the rat (Rattus norvegicus), wild and laboratory types, to X-ray irradiation in bone marrow cells has been studied. These comparative studies are needed to supplement the now available information on the response of the wild form of experimental animals and thereby to provide a better understanding of the magnitude of radiosensitivities within a species. 4 tabs., 1 tab

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

    Directory of Open Access Journals (Sweden)

    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

  13. Radiosensitizing efficiency of sodium glycididazole on V79 cells in vitro

    International Nuclear Information System (INIS)

    Radiosensitizing effect of sodium glycididazole (SGDD) on the hypoxic V79 cells by standard in vitro colon formation method has been further studied. The results showed its toxicity was low. Its ID50 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 (p1.6 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

  14. Cytological factors and their predictive role in comparative radiosensitivity: a general summary

    International Nuclear Information System (INIS)

    Various cytological factors, including interphase chromosome volume (ICV), nuclear volume (NV), cell volume, DNA content per nucleus and per chromosome, have been reviewed to determine their usefulness as indices to predict radiosensitivity. Fourteen topics are discussed. They are: a historical development of the concept of using karyotypic features to estimate radiosensitivity; interrelationships between cellular parameters; relationship of the karyotype to the duration of mitosis and meiosis; relationships between chronic and acute irradiation and ICV using several radiobiological end points for woody and herbaceous species; correlations between dose and cellular parameters for end points involving reproductive processes; correlations between chromosome aberrations and cellular characteristics after chronic irradiation; polyploidy and plant radiosensitivity; radiation-induced petal mutations in plants and their relationship to cellular parameters; correlations betwen mean survival time after irradiation and cellular parameters in amphibians and higher plants; correlations between radiobiological end points and cellular parameters after whole-body irradiation in amphibians, insects and mammals; correlations between radiosensivity and cellular parameters in diverse single-cell ogranisms; correlations between radiobiological end points and cellular parameters in higher plants irradiated with neutrons and the value of cell parameters to estimate relative biological effectiveness (RBE); and energy absorption and trends in radiosensitivity among species and radiobiological end points. It is concluded that ICV is usually the most useful parameter for predicting radiosensitivity. (Auth.)

  15. Radiosensitivity of the in vitro cultured young plants for sport mutation induction of stevia rebaudiana bert

    International Nuclear Information System (INIS)

    Due to the increasing incidence of diabetes, obesity and hypertensive, stevia has been placed great attentions as the sweetener to substitute sucrose in the world. Stevia was introduced to Korea in 1970's, but it has not been an attractive crop in that time. However, recently it has more attention for the natural food sweet additives. Because stevia have many problems for cultivation especially cultivar, seed germination, fertility, uniformity and glycoside quality, the sport mutation was attempted to in vitro plants for the improvement of some characteristics. The young in vitro plants was nursed on MS medium supplemented with 1 mg 1-1 GA3. Shoots of 10 cm height were irradiated with 0 ∼ 200 Gy of gamma ray and the every node was separated and inoculated on MS basic medium. The lethality, number and length of shoot, numbers of node and branch were investigated for the evaluation of radiosensitivity. The optimum dose of gamma ray seemed to be around 80 Gy for the sport mutation induction in stevia. The lower node was more sensitive than higher node to radiation

  16. A methodological study on modified comet assay in predicting solid tumor radiosensitivity

    International Nuclear Information System (INIS)

    Objective: To improve the method of 'modified comet assay' in predicting the radiosensitivity of solid tumor. Methods: A single cell suspension from biopsy sample was irradiated on ice with a dose of 5 Gy. The microscope slide was spread with agarose, lysed for 50 minutes, rinsed 3 times in rinse solution, and given electrophoresis for 20 minutes. After being stained with PI, cell images were collected through the microscope and analyzed with Lucia G software (Version 4.6). In order to check system/background errors, every sample was made into control slide and irradiation slide. The end-points were cell DNA contents and tail moment. Results: The factors influencing the results included: (1) Sample was faulty for the biopsy taken from mucosa and no tumor cells were contained. (2) The slides with a high background (induced by necrosis) disturbed the measurement of comet assay. (3) Setting lymphocytes as control to check system errors was very important. (4) To separately collect images of the normal tissue cells and tumor cells from the biopsy sample improved the conformity between the clinical observation and the lab resuit. Conclusions: To increase the correlation between comet assay and clinical response, it is very helpful to set double control for checking system/background errors and to collect images of the normal tissue cells and tumor cells through the microscope, respectively. (authors)

  17. Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells.

    Science.gov (United States)

    Cheng, Gang; Zielonka, Jacek; Ouari, Olivier; Lopez, Marcos; McAllister, Donna; Boyle, Kathleen; Barrios, Christy S; Weber, James J; Johnson, Bryon D; Hardy, Micael; Dwinell, Michael B; Kalyanaraman, Balaraman

    2016-07-01

    Metformin (Met) is an approved antidiabetic drug currently being explored for repurposing in cancer treatment based on recent evidence of its apparent chemopreventive properties. Met is weakly cationic and targets the mitochondria to induce cytotoxic effects in tumor cells, albeit not very effectively. We hypothesized that increasing its mitochondria-targeting potential by attaching a positively charged lipophilic substituent would enhance the antitumor activity of Met. In pursuit of this question, we synthesized a set of mitochondria-targeted Met analogues (Mito-Mets) with varying alkyl chain lengths containing a triphenylphosphonium cation (TPP(+)). In particular, the analogue Mito-Met10, synthesized by attaching TPP(+) to Met via a 10-carbon aliphatic side chain, was nearly 1,000 times more efficacious than Met at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC). Notably, in PDAC cells, Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in nontransformed control cells. Moreover, Mito-Met10 potently triggered G1 cell-cycle phase arrest in PDAC cells, enhanced their radiosensitivity, and more potently abrogated PDAC growth in preclinical mouse models, compared with Met. Collectively, our findings show how improving the mitochondrial targeting of Met enhances its anticancer activities, including aggressive cancers like PDAC in great need of more effective therapeutic options. Cancer Res; 76(13); 3904-15. ©2016 AACR. PMID:27216187

  18. Radiosensitivity of different aged human lymphocytes following electron irradiation in vitro

    International Nuclear Information System (INIS)

    Cytochalasin B-blocking micronucleus test and chromosomal aberration analysis were used in this study to estimate the yield of individual variability in radiation response of different aged human lymphocytes. Both analyses were performed in three groups of adults, aged 18-65 years, on two sampling times, following irradiation by therapeutical dose of 2 G in vitro. No statistically significant difference in the induced yield of exchange aberrations between individuals under consideration was found. The yield of total aberration data showed greater variability and was statistically significant in the oldest group against two other adult groups. Regarding to fixation times no statistically significant differences in the induced yield of chromosomal aberration (exchanges as well as total aberrations) were observed. The study has shown a slight increase in spontaneously occurring micronuclei with age. Almost equal mean number of radiation induced micronuclei was observed in the groups of adult aged 18-20 and 45-55 years. The highest mean number was observed in the oldest group. Evident variation in number of radiation induced micronuclei among individuals from the same age group was observed. The results of micronuclei assay for for all individuals under consideration show statistically significant difference in the yield of radiation-induced micronuclei regarding the second fixation time. This study has shown that cytochalasin-B blocking micronucleus test is more sensitive assay than chromosomal aberration analysis for the estimation of individual radiosensitivity. (author)

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

    International Nuclear Information System (INIS)

    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.)

  20. Radiosensitivity of the in vitro cultured young plants for sport mutation induction of stevia rebaudiana bert

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Tai Young; Kim, Ee Youb; Hyun, Kyung Sup; Jo, Han Jig; Lee, Young Il; Ju, Sun Ah; Oh, Seung Cheol [Korea Stevia Research Institute, Jeongeup (Korea, Republic of); Kim, Dong Sub; Kang, Si Yong [Korea Atomic Energy Research Institute, Jeongeup (Korea, Republic of); Ko, Jeong Ae [Chonbuk National University, Jeonju (Korea, Republic of)

    2010-12-15

    Due to the increasing incidence of diabetes, obesity and hypertensive, stevia has been placed great attentions as the sweetener to substitute sucrose in the world. Stevia was introduced to Korea in 1970's, but it has not been an attractive crop in that time. However, recently it has more attention for the natural food sweet additives. Because stevia have many problems for cultivation especially cultivar, seed germination, fertility, uniformity and glycoside quality, the sport mutation was attempted to in vitro plants for the improvement of some characteristics. The young in vitro plants was nursed on MS medium supplemented with 1 mg 1{sup -1} GA{sub 3}. Shoots of 10 cm height were irradiated with 0 {approx} 200 Gy of gamma ray and the every node was separated and inoculated on MS basic medium. The lethality, number and length of shoot, numbers of node and branch were investigated for the evaluation of radiosensitivity. The optimum dose of gamma ray seemed to be around 80 Gy for the sport mutation induction in stevia. The lower node was more sensitive than higher node to radiation.

  1. ZnFe{sub 2}O{sub 4} nanoparticles as radiosensitizers in radiotherapy of human prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Meidanchi, Alireza [Department of Physics, Payame Noor University (PNU), P.O. Box 19395-3697, Tehran (Iran, Islamic Republic of); Department of Physics, Sharif University of Technology, P.O. Box 11155-9161, Tehran (Iran, Islamic Republic of); Akhavan, Omid, E-mail: oakhavan@sharif.edu [Department of Physics, Sharif University of Technology, P.O. Box 11155-9161, Tehran (Iran, Islamic Republic of); Institute for Nanoscience and Nanotechnology, Sharif University of Technology, P.O. Box 14588-89694, Tehran (Iran, Islamic Republic of); Khoei, Samideh [Department of Medical Physics, Iran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Shokri, Ali A. [Department of Physics, Payame Noor University (PNU), P.O. Box 19395-3697, Tehran (Iran, Islamic Republic of); Computational Physical Sciences Research Laboratory, School of Nano-Science, Institute for Studies in Theoretical Physics and Mathematics (IPM), PO Box 19395-5531, Tehran (Iran, Islamic Republic of); Hajikarimi, Zahra [Department of Medical Physics, Iran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Khansari, Nakisa [Department of Cardiology, Hamadan University of Medical Sciences, Hamadan (Iran, Islamic Republic of)

    2015-01-01

    Nanoparticles of high-Z elements exhibit stronger photoelectric effects than soft tissues under gamma irradiation. Hence, they can be used as effective radiosensitizers for increasing the efficiency of current radiotherapy. In this work, superparamagnetic zinc ferrite spinel (ZnFe{sub 2}O{sub 4}) nanoparticles were synthesized by a hydrothermal reaction method and used as radiosensitizers in cancer therapy. The magnetic nanoparticles showed fast separation from solutions (e.g., ∼ 1 min for 2 mg mL{sup −1} of the nanoparticles in ethanol) by applying an external magnetic field (∼ 1 T). The ZnFe{sub 2}O{sub 4} nanoparticles were applied in an in vitro radiotherapy of lymph node carcinoma of prostate cells (as high radioresistant cells) under gamma irradiation of {sup 60}Co source. The nanoparticles exhibited no significant effects on the cancer cells up to the high concentration of 100 μg mL{sup −1}, in the absence of gamma irradiation. The gamma irradiation alone (2 Gy dose) also showed no significant effects on the cells. However, gamma irradiation in the presence of 100 μg mL{sup −1} ZnFe{sub 2}O{sub 4} nanoparticles resulted in ∼ 53% inactivation of the cells (∼ 17 times higher than the inactivation that occurred under gamma irradiation alone) after 24 h. The higher cell inactivation was assigned to interaction of gamma radiation with nanoparticles (photoelectric effect), resulting in a high level electron release in the media of the radioresistant cells. Our results indicated that ZnFe{sub 2}O{sub 4} nanoparticles not only can be applied in increasing the efficiency of radiotherapy, but also can be easily separated from the cell environment by using an external magnetic field after the radiotherapy. - Highlights: • Synthesis of magnetic ZnFe{sub 2}O{sub 4} nanoparticles with high-Z elements as radiosensitizers • Fast separation of the nanoparticles from solutions by applying a magnetic field • Application of the nanoparticles in efficient

  2. Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo

    Energy Technology Data Exchange (ETDEWEB)

    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

  3. Radiosensitizing effect of conjugated linoleic acid in MCF-7 and MDA-MB-231 breast cancer cells

    International Nuclear Information System (INIS)

    Apoptotic pathways in breast cancer cells are frequently altered, reducing the efficiency of radiotherapy. Conjugated linoleic acid (CLA), known to trigger apoptosis, was tested as radiosensitizer in breast cancer cells MCF-7 and MDA-MB-231. The CLA-mix, made up of the isomers CLA-9cis 11trans and CLA-10trans 12cis, was compared to three purified isomers, i.e., the CLA-9cis 11cis, CLA-9cis 11trans, and CLA-10trans 12cis. Using the apoptotic marker YO-PRO-1, the CLA-9cis 11cis at 50 μmol/L turned out to be the best apoptotic inducer leading to a 10-fold increase in MCF-7 cells and a 2,5-fold increase in MDA-MB-231 cells, comparatively to the CLA-mix. Contrary to previous studies on colorectal and prostate cancer cells, CLA-10trans 12cis does not lead to an apoptotic response on breast cancer cell lines MCF-7 and MDA-MB-231. Our results also suggest that the main components of the CLA-mix (CLA-9cis 11trans and CLA-10trans 12cis) are not involved in the induction of apoptosis in the breast cancer cells studied. A dose of 5 Gy did not induce apoptosis in MCF-7 and MDA-MB-231 cells. The addition of CLA-9cis 11cis or CLA-mix has allowed us to observe a radiation-induced apoptosis, with the CLA-9cis 11cis being about 8-fold better than the CLA-mix. CLA-9cis 11cis turned out to be the best radiosensitizer, although the isomers CLA-9cis 11trans and CLA-10trans 12cis have also reduced the cell survival following irradiation, but using a mechanism not related to apoptosis. In conclusion, the radiosensitizing property of CLA-9cis 11cis supports its potential as an agent to improve radiotherapy against breast carcinoma. (author)

  4. Comet assay as a predictive assay for radiosensitivity of two human brain tumor cell lines

    International Nuclear Information System (INIS)

    Micronucleus assay and comet assay were compared as a predictive assay for radiosensitivity of tumors. Two human brain tumor cell lines, Becker (derived from astrocytoma) and ONS76 (derived from medulloblastoma) were used. Colony methods as the gold standard showed ONS76 as radiosensitive and Becker as radioresistant cell lines. Micronucleus assay revealed no different radiosensitivity between them. With comet assay, Becker cells received irradiation showed less damage to the DNA and faster repair of the damage than ONS76 cells did. The results correlate with those from colony methods. Comet assay is simple and rapid method for clinical use and it has an advantage not to establish the primary culture. Moreover, the results of comet assay showed not only DNA damage but also repair from the damage. It is concluded that comet assay is a superior method than micronucleus assay and has a potent candidate for clinical predictive assay. (author)

  5. Radiosensitivity of different tissues from carrot root at different phases of growth in culture

    International Nuclear Information System (INIS)

    The present work compares the effect of γ-radiation dose and time in culture on the growth of cambium and phloem carrot (Daucus carota) root explants. It was found that the phloem is more radiosensitive than the cambium and that both tissues were more radiosensitive when irradiated on excision at the G1 phase rather than at the end of the lag phase on the ninth day of growth in culture when cells were predominantly at the G2 phase. The nuclear volumes of cells from both tissues were similar but were larger at the end of the more radioresistant lag phase than those of the G1 phase on excision. However, nuclear volume could not account for the differences in radiosensitivity between either the tissues or irradiation times in culture

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Microwave hyperthermia radiosensitized iridium-192 for recurrent brain malignancy.

    Science.gov (United States)

    Borok, T L; Winter, A; Laing, J; Paglione, R; Sterzer, F; Sinclair, I; Plafker, J

    1988-03-01

    Twenty-one patients whose solitary detectable biopsy proven recurrent brain malignancies produced Central Nervous System (CNS) symptoms warranting further intervention received 60-minute 43 degrees C (180 degree-minute) interstitial 2450 MHz microwave hyperthermia fractions. All received brain teletherapy prior to recurrence. The first 15 received no brachytherapy and served as a toxicity pilot. All 15 enjoyed neurologic improvement, 12 symptomatic improvement, and 12 objective response as mass reduction and/or tumor necrosis. The next 6 patients were selected with more favorable Karnofsky performance status, no known active malignancy elsewhere, and received afterloading Ir-192 interstitial implantation juxtaposed to radiosensitizing hyperthermia. Volume dose varied from 1000 to 2245 rad, and dose rate from 40 to 100 rad/hr. Dose selected varied as a function of pre-recurrence teletherapy dose, general condition, histologic type, and volume. Neurosurgical debulking, if technically indicated through no additional aperture or trauma, was permitted if consistent with preservation of neurological function. Six enjoyed neurologic improvement, symptom reduction, and objective tumor response; three remain alive, and one experienced transient improvement. Complications, histologic subtypes, autopsy findings, stereotactic approach, thermal monitoring methods and CT follow-up of objective response are presented along with computer dosimetry and isotherm chart. Our microtraumatic universal catheter technique for CT guided stereotactic biopsy, aspiration, decompression, thermal sensory loop, thermalization antennae, and brachytherapy without multiple trauma nor changing catheters is stressed. The rationale for combined modes peculiar to the CNS will be outlined.2+ Proposal for incorporating controlled-release ARA-C chemotherapy polymer micro-rods into the interstitial format will be offered. The preceeding is an FDA-approved controlled clinical trial.(ABSTRACT TRUNCATED AT

  8. Intra-arterial bromodeoxyuridine radiosensitization of malignant gliomas

    International Nuclear Information System (INIS)

    In the 1950's it was first observed that mammalian cells exposed to the halogenated deoxyuridines were more sensitive to ultraviolet light and radiation than untreated cells. This prompted early clinical trials with bromodeoxyuridine (BUdR) which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR (400-600 mg/m2/day X 8 1/2 weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6 1/2 weeks). Following initial biopsy/surgery the infusion pump system was implanted; BUdR infusion began 2 weeks prior to and continued throughout the 6 1/2 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall Kaplan-Meier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognostically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas

  9. Radiosensitization dependent on p53 function in bronchial carcinoma cells by the isoflavone genistein and estradiol in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Hermann, R.M.; Fest, J.; Christiansen, H.; Hille, A.; Rave-Fraenk, M.; Nitsche, M. [Goettingen Univ. (Germany). Dept. of Radiotherapy and Radiooncology; Gruendker, C.; Viereck, V. [Goettingen Univ. (Germany). Dept. of Gynecology; Jarry, H. [Goettingen Univ. (Germany). Dept. of Experimental Endocrinology; Schmidberger, H. [University Hospital Mainz (Germany). Dept. of Radiooncology and Radiotherapy

    2007-04-15

    Background and Purpose: Simultaneous radiotherapy with chemotherapy is a standard treatment for inoperable non-small cell lung cancer (NSCLC), but the clinical outcome still remains poor. To further intensify treatment, substances need to be identified, which increase the effect of radiation on tumor cells without further enhancing toxicity to normal tissue. Hormones have a different toxicity profile than radiation or cytostatic drugs. As NSCLC often express estrogen receptors (ERs), the combination of genistein or estradiol and radiation in vitro was investigated. Material and Methods: A549 NSCLC cells with an inducible expression of a mutated TP53 and fibroblasts of a male donor (DF-18) were examined. ER expression was immunocytologically confirmed in all studied cell lines. Clonogenic survival was measured after incubation of the cells with genistein or estradiol (0.01 {mu}M and 10 {mu}M as maximum clinically applicable dose) and irradiation with different doses (0-4 Gy). The differentiation state of fibroblasts after combined therapy was analyzed. Results: A549 cells expressing mutated TP53 were more radioresistant than TP53 wild-type cells. Incubation of nonfunctional TP53 cells with genistein or estradiol increased radiosensitivity in both tested concentrations. By contrast, radiosensitivity of A549 with wild-type TP53 and DF-18 was not altered by hormonal incubation. In DF-18 radiation induced growth arrest that was not increased by additional hormonal incubation. Conclusion: NSCLC cells with nonfunctional TP53 might be sensitized against radiation by genistein or estradiol. As genistein is better tolerable than estradiol in patients, additional studies are warranted to assess potential gains of this combination therapy.

  10. In Vitro and In Vivo Radiosensitizing Effect of Valproic Acid on Fractionated Irradiation

    OpenAIRE

    Chie, Eui Kyu; Shin, Jin Hee; Kim, Jin Ho; Kim, Hak Jae; Kim, In Ah; Kim, Il Han

    2014-01-01

    Purpose This study was conducted in order to validate the radiosensitization effect of valproic acid, a biologically available histone deacetylase inhibitor, for fractionated radiation. Materials and Methods Radiosensitization effect of valproic acid was tested for the A549 cell line and U87MG cell line in vitro. Fractionated irradiation of 12 Gy in four fractions was administered on D2-5 with valproic acid, 150 mg/Kg, ip, bid for six consecutive days (D1-6) to A549 and U87MG tumors implanted...

  11. Usefulness of DNA repair genes in prediction and potentiation of radiosensitivity in tumor cells

    International Nuclear Information System (INIS)

    Radiotherapy is one of the common treatment modalities for cancer. However, owing to the differences in intrinsic radiosensitivity of the different tumor types, a significant variation in therapeutic response is observed during radiotherapy leading to ineffective killing of tumor cells or occasional adverse effects in normal tissues. Hence, an optimization of radiation dose in clinical practice based on the radiosensitivity of individual patients and tumor types is of paramount importance. From this perspective, prediction of radiosensitivity of tumor tissues and understanding about molecular determinants of radiosensitivity can help in improving the efficacy of radiation therapy. Therefore, in the present study, expression of genes which are involved in DNA damage response and cytoprotective pathways were studied to evaluate their use in predicting the radiosensitivity of tumor cells using six different tumor cells (HT1080, DU145, MCF7, A549, PC3 and HT29). Initially the radiosensitivity profile of these tumor cells has been studied using clonogenic survival assay. Then the expression profile of genes, which are involved in crucial radiation response pathways like, DNA damage, repair, apoptosis and redox regulation were analyzed by real time q-PCR (either 2 Gy or 6 Gy). The fold change in expression was calculated for different genes and was correlated with clonogenic survival. Out of 15 genes analyzed, three genes (HSP70, KU80 and RAD51) showed change in gene expression in accordance with their radiosensitivity. The expression of these three genes also showed a significant positive correlation with survival fraction. The 'r' values observed were 0.97, 0.99, and 0.97 for HSP70, KU80 and RAD51, respectively. Since these genes are involved in DNA repair pathways, we have investigated the effect of inhibition of DNA-PK (a protein involved in the non-homologous end joining and consists of Ku70/KU80 complex and DNA-PKcs), in potentiating the radiation induced damage in

  12. Size-dependent radiosensitization of PEG-coated gold nanoparticles for cancer radiation therapy

    OpenAIRE

    Zhang, Xiao-Dong; Wu, Di; Shen, Xiu; Chen, Jie; Sun, Yuan-Ming; Liu, Pei-Xun; Liang, Xing-Jie

    2012-01-01

    Gold nanoparticles have been conceived as a radiosensitizer in cancer radiation therapy, but one of the important questions for primary drug screening is what size of gold nanoparticles can optimally enhance radiation effects. Herein, we perform in vitro and in vivo radiosensitization studies of 4.8, 12.1, 27.3, and 46.6 nm PEG-coated gold nanoparticles. In vitro results show that all sizes of the PEG-coated gold nanoparticles can cause a significant decrease in cancer cell survival after gam...

  13. Cytogenetic monitoring, radiosensitivity study and adaptive response of workers exposed to low level ionizing radiation

    International Nuclear Information System (INIS)

    The objectives of the present study were: To determine the frequencies of chromosome aberrations in lymphocytes from individuals belonging to professionally exposed groups, under normal conditions; to determine the possible differences in radiosensitivity between the lymphocytes of technicians and controls after in vitro irradiation with gamma rays during the G1 phase of the cell cycle (radiosensitivity study), and to examine the influence of in vivo and in vitro pre-exposure to low doses of radiation on the frequency of chromosome aberrations induced in vitro by high doses (study of the adaptive response) in a group of technicians (T) compared to controls (C). (author)

  14. The PCC assay can be used to predict radiosensitivity in biopsy cultures irradiated with different types of radiation.

    Science.gov (United States)

    Suzuki, Masao; Tsuruoka, Chizuru; Nakano, Takashi; Ohno, Tatsuya; Furusawa, Yoshiya; Okayasu, Ryuichi

    2006-12-01

    The aim of this study was to identify potential biomarkers for radiosensitivity using the relationship between cell killing and the yield of excess chromatin fragments detected with the premature chromosome condensation (PCC) technique. This method was applied to primary cultured cells obtained from biopsies from patients. Six primary culture biopsies were obtained from 6 patients with carcinoma of the cervix before starting radiotherapy. The cultures were irradiated with two different LET carbon-ion beams (LET = 13 keV/microm, 77.1+/-2.8 keV/microm) and 200 kV X-rays. The carbon-ion beams were produced by Heavy Ion Medical Accelerator in Chiba (HIMAC). PCC was performed using the polyethylene glycol-mediated cell fusion technique. The yield of excess chromatin fragments were measured by counting the number of unrejoined chromatin fragments detected with the PCC technique after a 24-h post-irradiation incubation period. Obtained results indicated that cultures which were more sensitive to killing were also more susceptible to the induction of excess chromatin fragments. Furthermore there was a good correlation between cell killing and excess chromatin fragments among the 6 cell cultures examined. There is also evidence that the induction of excess chromatin fragments increased with increasing LET as well as cell-killing effect in the same cell culture. The data reported here support the idea that the yield of excess chromatin fragments detected with the PCC technique might be useful for predicting the radiosensitivity of cells contained in tumor tissue, and to predict responses to different radiation types. PMID:17089052

  15. 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)

    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

  16. Sustained radiosensitization of hypoxic glioma cells after oxygen pretreatment in an animal model of glioblastoma and in vitro models of tumor hypoxia.

    Directory of Open Access Journals (Sweden)

    Ryon H Clarke

    Full Text Available Glioblastoma multiforme (GBM is the most common and lethal form of brain cancer and these tumors are highly resistant to chemo- and radiotherapy. Radioresistance is thought to result from a paucity of molecular oxygen in hypoxic tumor regions, resulting in reduced DNA damage and enhanced cellular defense mechanisms. Efforts to counteract tumor hypoxia during radiotherapy are limited by an attendant increase in the sensitivity of healthy brain tissue to radiation. However, the presence of heightened levels of molecular oxygen during radiotherapy, while conventionally deemed critical for adjuvant oxygen therapy to sensitize hypoxic tumor tissue, might not actually be necessary. We evaluated the concept that pre-treating tumor tissue by transiently elevating tissue oxygenation prior to radiation exposure could increase the efficacy of radiotherapy, even when radiotherapy is administered after the return of tumor tissue oxygen to hypoxic baseline levels. Using nude mice bearing intracranial U87-luciferase xenografts, and in vitro models of tumor hypoxia, the efficacy of oxygen pretreatment for producing radiosensitization was tested. Oxygen-induced radiosensitization of tumor tissue was observed in GBM xenografts, as seen by suppression of tumor growth and increased survival. Additionally, rodent and human glioma cells, and human glioma stem cells, exhibited prolonged enhanced vulnerability to radiation after oxygen pretreatment in vitro, even when radiation was delivered under hypoxic conditions. Over-expression of HIF-1α reduced this radiosensitization, indicating that this effect is mediated, in part, via a change in HIF-1-dependent mechanisms. Importantly, an identical duration of transient hyperoxic exposure does not sensitize normal human astrocytes to radiation in vitro. Taken together, these results indicate that briefly pre-treating tumors with elevated levels of oxygen prior to radiotherapy may represent a means for selectively targeting

  17. Antitumor and radiosensitizing effects of withaferin A on mouse Ehrlich ascites carcinoma in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Sharada, A.C. [Dept. of Radiobiology, Kasturba Medical Coll., Manipal (India); Solomon, F.E. [Dept. of Radiobiology, Kasturba Medical Coll., Manipal (India); Uma Devi, P. [Dept. of Radiobiology, Kasturba Medical Coll., Manipal (India); Udupa, N. [Coll. of Pharmaceutical Sciences, Manipal (India); Srinivasan, K.K. [Coll. of Pharmaceutical Sciences, Manipal (India)

    1996-06-01

    The antitumor and radiosensitizing effects of withaferin A (WA), a steroidal lactone from Withania somnifera, was studied on Ehrlich ascites carcinoma in vivo. The acute LD{sub 50(14)} for WA in Swiss mice was {proportional_to}80 mg/kg. Twenty-four hours after i.p. inoculation of 10{sup 6} tumor cells, WA was injected i.p. at different dose fractions (5 or 7.5 mg/kg x 8, 10 mg/kg x 5, 20 or 30 mg/kg x 2) with or without abdominal gamma irradiation (RT, 7.5 Gy) after the first drug dose. Increase in life span and tumor-free survival were studied up to 120 days. The drug inhibited tumor growth and increased survival, which was dependent on the WA dose per fraction rather than the total dose. Combination of RT with all the drug schedules increased tumor cure and tumor-free survival, the best effect seen after 2 fractions of 30 mg/kg each. In another experiment WA was given as 2 (40 mg/kg x 2), 3 (30 mg/kg x 3) or 4 (20 mg/kg x 4) fractions at 5, 7 or 10 days after tumor inoculation with or without RT after the first drug dose. At 7 and 10 days after inoculation the drug was effective only at 40 mg/kg x 2, but with RT 30 mg/kg x 3 produced an equal effect (20% survival) on 7 day old tumors. (orig.).

  18. Evaluation of the effect of change in the radiosensitive tissue weights listed in the ICRP in estimate of effective dose

    Energy Technology Data Exchange (ETDEWEB)

    Vieira, Jose W.; Leal Neto, Viriato; Lopes Filho, Ferdinand J.; Lima Filho, Jose M.; Santana, Ivan E., E-mail: jose.wilson@recife.ifpe.edu.br [Instituto Federal de Educacao, Ciencia e Tecnologia de Pernambuco, (IFPE), Recife, PE (Brazil); Andrade, Pedro H.A.; Cabral, Manuela O.M. [Universidade Federal de Pernambuco (DEN/UFPE), Recife, PE (Brazil). Departamento de Energia Nuclear; Lima, Vanildo J.M. [Universidade Federal de Pernambuco (DA/UFPE), Recife, PE (Brazil). Departamento de Anatomia; Lima, Fernando R.A., E-mail: falima@cnen.gov.br [Centro Regional de Ciencias Nucleares do Nordeste (CRCN/CNEN-NE), Recife, PE (Brazil)

    2015-07-01

    For photons and electrons, the effective dose by gender is a weighted sum of the absorbed doses in radiosensitive organs and tissue of the human body. Effective dose is estimated using Exposure Computational Models (ECM) of both genders for the same age group. The FSTA and MSTA ECMs were developed by researchers from DEN/UFPE and consist of voxel phantoms representing adults coupled to EGSnrc Monte Carlo Code, which, in the folder designed for users of EGS, codes were added to simulate some radioactive sources. The reports 60 and 103 of the ICRP provide the factors that weigh the radiosensitivity of organs and tissues (W{sub T}) required to estimate the effective dose. The two lists were placed in the FSTA and MSTA to simulate radiodiagnostic examination in different regions of the body (cranium, abdomen and thorax). The dosimetric data produced allowed an analysis of the effect of the change in the w{sub T} from the report 60 to the 103. The highest mean percent relative error, 64.3%, occurred in the results for the cranium due to the increase of the w{sub T} for most of the organs and tissues in the head and trunk in the updated list. In this case, it can be concluded that the values of the effective dose with the wT of the ICRP 60 were underestimated. Other types of simulators of radioactive sources can be used in investigating this problem and other variables related to the phantom can be considered for that proposes a W{sub T}'s list specific for the Brazilian population or recommend unrestricted use the ICRP data. (author)

  19. Evaluation of the effect of change in the radiosensitive tissue weights listed in the ICRP in estimate of effective dose

    International Nuclear Information System (INIS)

    For photons and electrons, the effective dose by gender is a weighted sum of the absorbed doses in radiosensitive organs and tissue of the human body. Effective dose is estimated using Exposure Computational Models (ECM) of both genders for the same age group. The FSTA and MSTA ECMs were developed by researchers from DEN/UFPE and consist of voxel phantoms representing adults coupled to EGSnrc Monte Carlo Code, which, in the folder designed for users of EGS, codes were added to simulate some radioactive sources. The reports 60 and 103 of the ICRP provide the factors that weigh the radiosensitivity of organs and tissues (WT) required to estimate the effective dose. The two lists were placed in the FSTA and MSTA to simulate radiodiagnostic examination in different regions of the body (cranium, abdomen and thorax). The dosimetric data produced allowed an analysis of the effect of the change in the wT from the report 60 to the 103. The highest mean percent relative error, 64.3%, occurred in the results for the cranium due to the increase of the wT for most of the organs and tissues in the head and trunk in the updated list. In this case, it can be concluded that the values of the effective dose with the wT of the ICRP 60 were underestimated. Other types of simulators of radioactive sources can be used in investigating this problem and other variables related to the phantom can be considered for that proposes a WT's list specific for the Brazilian population or recommend unrestricted use the ICRP data. (author)

  20. Radiosensitization effect of folate-conjugated gold nanoparticles on HeLa cancer cells under orthovoltage superficial radiotherapy techniques

    Science.gov (United States)

    Khoshgard, Karim; Hashemi, Bijan; Arbabi, Azim; Javad Rasaee, Mohammad; Soleimani, Masoud

    2014-05-01

    Due to the high atomic number of gold nanoparticles (GNPs), they are known as new radiosensitizer agents for enhancing the efficiency of superficial radiotherapy techniques by increasing the dose absorbed in tumor cells wherein they can be accumulated selectively. The aim of this study was to compare the effect of various common low energy levels of orthovoltage x-rays and megavoltage γ-rays (Co-60) on enhancing the therapeutic efficiency of HeLa cancer cells in the presence of conjugated folate and non-conjugated (pegylated) GNPs. To achieve this, GNPs with an average diameter of 52 nm were synthesized and conjugated to folic acid molecules. Pegylated GNPs with an average diameter of 47 nm were also synthesized and used as non-conjugated folate GNPs. Cytotoxicity assay of the synthesized folate-conjugated and pegylated GNPs was performed using different levels of nanoparticle concentration incubated with HeLa cells for 24 h. The radiosensitizing effect of both the conjugated and pegylated GNPs on the cells at a concentration of 50 µM was compared using MTT as well as clonogenic assays after exposing them to 2 Gy ionizing radiation produced by an orthovoltage x-ray machine at four different kVps and γ-rays of a Co-60 unit. Significant differences were noted among various irradiated groups with and without the folate conjugation, with an average dose enhancement factor (DEF) of 1.64 ± 0.05 and 1.35 ± 0.05 for the folate-conjugated and pegylated GNPs, respectively. The maximum DEF was obtained with the 180 kVp x-ray beam for both of the GNPs. Folate-conjugated GNPs can significantly enhance the cell killing potential of orthovoltage x-ray energies (especially at 180 kVp) in folate receptor-expressing cancer cells, such as HeLa, in superficial radiotherapy techniques.

  1. Genistein Enhances the Radiosensitivity of Breast Cancer Cells via G2/M Cell Cycle Arrest and Apoptosis

    Directory of Open Access Journals (Sweden)

    Li Gong

    2013-10-01

    Full Text Available The aim of the present study was to investigate the radiosensitizing effect of genistein, and the corresponding mechanisms of action on breast cancer cells with different estrogen receptor (ER status. Human breast cancer cell lines such as MCF-7 (ER-positive, harboring wild-type p53 and MDA-MB-231 (ER-negative, harboring mutant p53 were irradiated with X-rays in the presence or absence of genistein. Cell survival, DNA damage and repair, cell cycle distribution, cell apoptosis, expression of proteins related to G2/M cell cycle checkpoint and apoptosis were measured with colony formation assays, immunohistochemistry, flow cytometry and western blot analysis, respectively. Genistein showed relatively weak toxicity to both cell lines at concentrations in the range of 5–20 μM. Using the dosage of 10 μM genistein, the sensitizer enhancement ratios after exposure to X-rays at a 10% cell survival (IC10 were 1.43 for MCF-7 and 1.36 for MDA-MB-231 cells, respectively. Significantly increased DNA damages, arrested cells at G2/M phase, decreased homologous recombination repair protein Rad51 foci formation and enhanced apoptotic rates were observed in both cell lines treated by genistein combined with X-rays compared with the irradiation alone. The combined treatment obviously up-regulated the phosphorylation of ATM, Chk2, Cdc25c and Cdc2, leading to permanent G2/M phase arrest, and up-regulated Bax and p73, down-regulated Bcl-2, finally induced mitochondria-mediated apoptosis in both cell lines. These results suggest that genistein induces G2/M arrest by the activation of the ATM/Chk2/Cdc25C/Cdc2 checkpoint pathway and ultimately enhances the radiosensitivity of both ER+ and ER- breast cancer cells through a mitochondria-mediated apoptosis pathway.

  2. Radiosensitivity in vitro of clonogenic and non-clonogenic glioblastoma cells obtained from a human brain tumour

    Energy Technology Data Exchange (ETDEWEB)

    Buronfosse, A.; Thomas, C.P.; Ginestet, C.; Dore, J.F. [Centre de Lutte Contre le Cancer Leon-Berard, 69 - Lyon (France)

    1994-11-01

    Cells obtained from a human glioblastoma (G5) were characterized and used to develop an assay measuring their radiosensitivity in vitro. Surviving fractions were estimated 12 days after irradiation by image analysis of the total surface occupied by the cells. This report evaluates 4 experimental factors which may influence the radiosensitivity in vitro of G5 cells: passage number, delay between plating and irradiation, cell density and clonal heterogeneity. The radiosensitivity of the G5 cell line was found to be passage-independent at least between passages 12 and 75. Experimental conditions influence the radiosensitivity as surviving fraction at 2 Gy (SF2) range from 90% (5 000 cells/well, irradiation 72 h after seeding) to 49% (2 500 cells per well, irradiation 24 h after seeding). The heterogeneity of the radiosensitivity is large at the clonal level as SF2 of six clones isolated from the G5 line were 45%, 50%, 72%, 74%, 79% and 84%. Finally, when G5 cells were irradiated at low cell density and at the beginning of the growth phase, the radiosensitivity measured with this assay is comparable to that obtained with a standard colony assay. We propose that this assay may be useful to determine the intrinsic radiosensitivity of cells obtained from human tumours. (authors). 24 refs., 8 figs., 2 tabs.

  3. Mitochondrial DNA and Functional Investigations into the Radiosensitivity of Four Mouse Strains

    Directory of Open Access Journals (Sweden)

    Steven B. Zhang

    2014-01-01

    Full Text Available We investigated whether genetic radiosensitivity-related changes in mtDNA/nDNA ratios are significant to mitochondrial function and if a material effect on mtDNA content and function exists. BALB/c (radiosensitive, C57BL/6 (radioresistant, and F1 hybrid mouse strains were exposed to total body irradiation. Hepatic genomic DNA was extracted, and mitochondria were isolated. Mitochondrial oxygen consumption, ROS, and calcium-induced mitochondrial swelling were measured. Radiation influenced strain-specific survival in vivo. F1 hybrid survival was influenced by maternal input. Changes in mitochondrial content corresponded to survival in vivo among the 4 strains. Calcium-induced mitochondrial swelling was strain dependent. Isolated mitochondria from BALB/c mice were significantly more sensitive to calcium overload than mitochondria from C57BL/6 mice. Maternal input partially influenced the recovery effect of radiation on calcium-induced mitochondrial swelling in F1 hybrids; the hybrid with a radiosensitive maternal lineage exhibited a lower rate of recovery. Hybrids had a survival rate that was biased toward maternal input. mtDNA content and mitochondrial permeability transition pores (MPTP measured in these strains before irradiation reflected a dominant input from the parent. After irradiation, the MPTP opened sooner in radiosensitive and hybrid strains, likely triggering intrinsic apoptotic pathways. These findings have important implications for translation into predictors of radiation sensitivity/resistance.

  4. Cellular radiosensitivity of primary and metastatic human uveal melanoma cell lines

    NARCIS (Netherlands)

    G.J.M.J. van den Aardweg (Gerard J. M.); N.C. Naus (Nicole); A.C. Verhoeven; J.E.M.M. de Klein (Annelies); G.P.M. Luyten (Gré)

    2002-01-01

    textabstractPURPOSE: To investigate the radiosensitivity of uveal melanoma cell lines by a clonogenic survival assay, to improve the efficiency of the radiation regimen. METHODS: Four primary and four metastatic human uveal melanoma cell lines were cultured in the presence of condi

  5. Hormonal and cellular factors affecting immature sertoli cells radiosensitivity in rat fetus

    International Nuclear Information System (INIS)

    Immature Sertoli cells population was studied after irradiation either in hypophysectomised (decapited) or in germ cell free foetus (busulfan treated embryo). Decapitation did not modify the 10 % reduction of immature Sertoli cells after 1.5 Gy irradiation. But, without germ cells, immature Sertoli cells were more radiosensitive

  6. The study of radiosensitivity in left handed compared to right handed healthy women

    International Nuclear Information System (INIS)

    Radiosensitivity is an inheriting trait that mainly depends on genetic factors. it is well known in similar dose of ionizing radiation and identical biological characteristics 9–10 percent of normal population have higher radiation response. Some reports indicate that distribution of breast cancer, immune diseases including autoimmune diseases as example lupus, Myasthenia Gravies and even the rate of allergy are more frequent in left handed individuals compared to right handed individuals. The main goal of the present study is determination of radiosensitivity in left handed compared to right handed in healthy women by cytokinesis blocked micronuclei [CBMN] assay. 5 ml peripheral fresh blood sample was taken from 100 healthy women including 60 right handed and 40 left handed. The age of participants was between 20–25 old years and they had been matched by sex. After blood sampling, blood samples were divided to 2 groups including irradiated and non-irradiated lymphocytes that irradiated lymphocytes were exposed to 2 Gy CO-60 Gama rays source then chromosomal aberrations was analyzed by CBMN [Cytokinesis Blocked Micronuclei Assay]. Our results have shown radiosensitivity index [RI] in left-handers compared to right-handers is higher. Furthermore, the mean MN frequency is elevated in irradiated lymphocytes of left-handers in comparison with right-handers. Our results from CBMN assay have shown radiosensitivity in the left handed is higher than right handed women but more attempts need to prove this hypothesis

  7. Simultaneous Inhibition of EGFR and PI3K Enhances Radiosensitivity in Human Breast Cancer

    International Nuclear Information System (INIS)

    Purpose: Mutations in the epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase (PI3K)/Akt signaling transduction pathway are common in cancer. This pathway is imperative to the radiosensitivity of cancer cells. We aimed to investigate the radiosensitizing effects of the simultaneous inhibition of EGFR and PI3K in breast cancer cells. Methods and Materials: MCF-7 cell lines with low expression of EGFR and wild-type PTEN and MDA-MB-468 cell lines with high expression of EGFR and mutant PTEN were used. The radiosensitizing effects by the inhibition of EGFR with AG1478 and/or PI3K with Ly294002 were determined by colony formation assay, Western blot was used to investigate the effects on downstream signaling. Flow cytometry was used for apoptosis and cell cycle analysis. Mice-bearing xenografts of MDA-MB-468 breast cancer cells were also used to observe the radiosensitizing effect. Results: Simultaneous inhibition of EGFR and PI3K greatly enhanced radiosensitizing effect in MDA-MB-468 in terms of apoptosis and mitotic death, either inhibition of EGFR or PI3K alone could enhance radiosensitivity with a dose-modifying factor (DMFSF2) of 1.311 and 1.437, radiosensitizing effect was further enhanced by simultaneous inhibition of EGFR and PI3K with a DMFSF2 at 2.698. DNA flow cytometric analysis indicated that dual inhibition combined with irradiation significantly induced G0/G1 phase arrest in MDA-MB-468 cells. The expression of phosphor-Akt and phosphor-Erk1/2 (induced by irradiation and PI3K inhibitor) were fully attenuated by simultaneous treatment with both inhibitors in combination with irradiation. In addition, dual inhibition combined with irradiation induced dramatic tumor growth delay in MDA-MB-468 xenografts. Conclusions: Our study indicated that simultaneous inhibition of EGFR and PI3K could further sensitize the cancer cells to irradiation compared to the single inhibitor with irradiation in vitro and in vivo. The approach may have important

  8. Simultaneous Inhibition of EGFR and PI3K Enhances Radiosensitivity in Human Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Li Ping; Zhang Qing [Department of Radiation Oncology, 6th People' s Hospital of Jiao Tong University, Shanghai 200233 (China); Torossian, Artour [Vanderbilt University, School of Medicine, Nashville, TN (United States); Li Zhaobin; Xu Wencai [Department of Radiation Oncology, 6th People' s Hospital of Jiao Tong University, Shanghai 200233 (China); Lu Bo [Department of Radiation Oncology, Thomas Jefferson University and Hospitals, Inc. Philadelphia, PA (United States); Fu Shen, E-mail: fushen1117@gmail.com [Department of Radiation Oncology, 6th People' s Hospital of Jiao Tong University, Shanghai 200233 (China)

    2012-07-01

    Purpose: Mutations in the epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase (PI3K)/Akt signaling transduction pathway are common in cancer. This pathway is imperative to the radiosensitivity of cancer cells. We aimed to investigate the radiosensitizing effects of the simultaneous inhibition of EGFR and PI3K in breast cancer cells. Methods and Materials: MCF-7 cell lines with low expression of EGFR and wild-type PTEN and MDA-MB-468 cell lines with high expression of EGFR and mutant PTEN were used. The radiosensitizing effects by the inhibition of EGFR with AG1478 and/or PI3K with Ly294002 were determined by colony formation assay, Western blot was used to investigate the effects on downstream signaling. Flow cytometry was used for apoptosis and cell cycle analysis. Mice-bearing xenografts of MDA-MB-468 breast cancer cells were also used to observe the radiosensitizing effect. Results: Simultaneous inhibition of EGFR and PI3K greatly enhanced radiosensitizing effect in MDA-MB-468 in terms of apoptosis and mitotic death, either inhibition of EGFR or PI3K alone could enhance radiosensitivity with a dose-modifying factor (DMF{sub SF2}) of 1.311 and 1.437, radiosensitizing effect was further enhanced by simultaneous inhibition of EGFR and PI3K with a DMF{sub SF2} at 2.698. DNA flow cytometric analysis indicated that dual inhibition combined with irradiation significantly induced G0/G1 phase arrest in MDA-MB-468 cells. The expression of phosphor-Akt and phosphor-Erk1/2 (induced by irradiation and PI3K inhibitor) were fully attenuated by simultaneous treatment with both inhibitors in combination with irradiation. In addition, dual inhibition combined with irradiation induced dramatic tumor growth delay in MDA-MB-468 xenografts. Conclusions: Our study indicated that simultaneous inhibition of EGFR and PI3K could further sensitize the cancer cells to irradiation compared to the single inhibitor with irradiation in vitro and in vivo. The approach may have

  9. Simulation on the molecular radiosensitization effect of gold nanoparticles in cells irradiated by x-rays

    International Nuclear Information System (INIS)

    Abundant studies have focused on the radiosensitization effect of gold nanoparticles (GNPs) in the cellular environment with x-ray irradiation. To better understand the physical foundation and to initially study the molecular radiosensitization effect within the nucleus, a simple cell model with detailed DNA structure in the central nucleus was set up and complemented with different distributions of single and multiple GNPs in this work. With the biophysical Monte Carlo simulation code PARTRAC, the radiosensitization effects on both physical quantities and primary biological responses (DNA strand breaks) were simulated. The ratios of results under situations with GNPs compared to those without GNPs were defined as the enhancement factors (EFs). The simulation results show that the presence of GNP can cause a notable enhancement effect on the energy deposition within a few micrometers from the border of GNP. The greatest upshot appears around the border and is mostly dominated by Auger electrons. The enhancement effect on the DNA strand breakage becomes smaller because of the DNA distribution inside the nucleus, and the corresponding EFs are between 1 and 1.5. In the present simulation, multiple GNPs on the nucleus surface, the 60 kVp x-ray spectrum and the diameter of 100 nm are relatively more effective conditions for both physical and biological radiosensitization effects. These results preliminarily indicate that GNP can be a good radiosensitizer in x-ray radiotherapy. Nevertheless, further biological responses (repair process, cell survival, etc) need to be studied to give more accurate evaluation and practical proposal on GNP’s application in clinical treatment. (paper)

  10. Garcinol, a Histone Acetyltransferase Inhibitor, Radiosensitizes Cancer Cells by Inhibiting Non-Homologous End Joining

    Energy Technology Data Exchange (ETDEWEB)

    Oike, Takahiro [Division of Multistep Carcinogenesis, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma (Japan); Ogiwara, Hideaki [Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Torikai, Kohta [Gunma University Heavy Ion Medical Center, Maebashi, Gunma (Japan); Nakano, Takashi [Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma (Japan); Yokota, Jun [Division of Multistep Carcinogenesis, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Kohno, Takashi, E-mail: tkkohno@ncc.go.jp [Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan)

    2012-11-01

    Purpose: Non-homologous end joining (NHEJ), a major pathway used to repair DNA double-strand breaks (DSBs) generated by ionizing radiation (IR), requires chromatin remodeling at DSB sites through the acetylation of histones by histone acetyltransferases (HATs). However, the effect of compounds with HAT inhibitory activities on the DNA damage response (DDR), including the NHEJ and cell cycle checkpoint, as well as on the radiosensitivity of cancer cells, remains largely unclear. Here, we investigated whether garcinol, a HAT inhibitor found in the rinds of Garcinia indica fruit (called mangosteens), has effects on DDR, and whether it can be used for radiosensitization. Methods and Materials: The following assays were used to examine the effect of garcinol on the inhibition of DSB repair, including the following: a conventional neutral comet assay; a cell-based assay recently developed by us, in which NHEJ repair of DSBs on chromosomal DNA was evaluated; the micrococcal nuclease sensitivity assay; and immunoblotting for autophosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We assessed the effect of garcinol on the cell cycle checkpoint after IR treatment by analyzing the phosphorylation levels of checkpoint kinases CHK1 and CHK2 and histone H3, and by cell cycle profile analysis using flow cytometry. The radiosensitizing effect of garcinol was assessed by a clonogenic survival assay, whereas its effects on apoptosis and senescence were examined by annexin V and senescence-associated {beta}-galactosidase (SA-{beta}-Gal) staining, respectively. Results: We found that garcinol inhibits DSB repair, including NHEJ, without affecting cell cycle checkpoint. Garcinol radiosensitized A549 lung and HeLa cervical carcinoma cells with dose enhancement ratios (at 10% surviving fraction) of 1.6 and 1.5, respectively. Cellular senescence induced by IR was enhanced by garcinol. Conclusion: These results suggest that garcinol is a radiosensitizer that

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

    Science.gov (United States)

    Lawton, Patricia Ann

    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. Established tumour cell lines were used to validate and optimise the ATCCS. Success rates with human tumour biopsy specimens were initially poor with both assay methods but further modifications led to success rates of ~70%. In a comparison of the modified Courtenay-Mills assay and the ATCCS there was close agreement between the measurements of surviving fraction at 2 Gy (SF2) for established tumour cell lines but with primary tumour cultures the SF2 values were significantly lower in the ATCCS. The main limitations of the ATCCS for clinical use were inter-experimental variability and fibroblast contamination. Using antibody-coated magnetic beads as a method for removing fibroblasts from tumour cell suspensions, some selectivity for fibroblasts was shown, but the specificity was too low for this method to be of value in its current form. The multiwell assay was found to be a satisfactory method for measuring fibroblast radiosensitivity although inter-experimental variability may limit its clinical use as a predictive test for normal tissue damage in patients.

  12. 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.

  13. Garcinol, a Histone Acetyltransferase Inhibitor, Radiosensitizes Cancer Cells by Inhibiting Non-Homologous End Joining

    International Nuclear Information System (INIS)

    Purpose: Non-homologous end joining (NHEJ), a major pathway used to repair DNA double-strand breaks (DSBs) generated by ionizing radiation (IR), requires chromatin remodeling at DSB sites through the acetylation of histones by histone acetyltransferases (HATs). However, the effect of compounds with HAT inhibitory activities on the DNA damage response (DDR), including the NHEJ and cell cycle checkpoint, as well as on the radiosensitivity of cancer cells, remains largely unclear. Here, we investigated whether garcinol, a HAT inhibitor found in the rinds of Garcinia indica fruit (called mangosteens), has effects on DDR, and whether it can be used for radiosensitization. Methods and Materials: The following assays were used to examine the effect of garcinol on the inhibition of DSB repair, including the following: a conventional neutral comet assay; a cell-based assay recently developed by us, in which NHEJ repair of DSBs on chromosomal DNA was evaluated; the micrococcal nuclease sensitivity assay; and immunoblotting for autophosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We assessed the effect of garcinol on the cell cycle checkpoint after IR treatment by analyzing the phosphorylation levels of checkpoint kinases CHK1 and CHK2 and histone H3, and by cell cycle profile analysis using flow cytometry. The radiosensitizing effect of garcinol was assessed by a clonogenic survival assay, whereas its effects on apoptosis and senescence were examined by annexin V and senescence-associated β-galactosidase (SA-β-Gal) staining, respectively. Results: We found that garcinol inhibits DSB repair, including NHEJ, without affecting cell cycle checkpoint. Garcinol radiosensitized A549 lung and HeLa cervical carcinoma cells with dose enhancement ratios (at 10% surviving fraction) of 1.6 and 1.5, respectively. Cellular senescence induced by IR was enhanced by garcinol. Conclusion: These results suggest that garcinol is a radiosensitizer that inhibits NHEJ

  14. Simulation on the molecular radiosensitization effect of gold nanoparticles in cells irradiated by x-rays.

    Science.gov (United States)

    Xie, W Z; Friedland, W; Li, W B; Li, C Y; Oeh, U; Qiu, R; Li, J L; Hoeschen, C

    2015-08-21

    Abundant studies have focused on the radiosensitization effect of gold nanoparticles (GNPs) in the cellular environment with x-ray irradiation. To better understand the physical foundation and to initially study the molecular radiosensitization effect within the nucleus, a simple cell model with detailed DNA structure in the central nucleus was set up and complemented with different distributions of single and multiple GNPs in this work. With the biophysical Monte Carlo simulation code PARTRAC, the radiosensitization effects on both physical quantities and primary biological responses (DNA strand breaks) were simulated. The ratios of results under situations with GNPs compared to those without GNPs were defined as the enhancement factors (EFs). The simulation results show that the presence of GNP can cause a notable enhancement effect on the energy deposition within a few micrometers from the border of GNP. The greatest upshot appears around the border and is mostly dominated by Auger electrons. The enhancement effect on the DNA strand breakage becomes smaller because of the DNA distribution inside the nucleus, and the corresponding EFs are between 1 and 1.5. In the present simulation, multiple GNPs on the nucleus surface, the 60 kVp x-ray spectrum and the diameter of 100 nm are relatively more effective conditions for both physical and biological radiosensitization effects. These results preliminarily indicate that GNP can be a good radiosensitizer in x-ray radiotherapy. Nevertheless, further biological responses (repair process, cell survival, etc) need to be studied to give more accurate evaluation and practical proposal on GNP's application in clinical treatment.

  15. Gefitinib Radiosensitizes Stem-Like Glioma Cells: Inhibition of Epidermal Growth Factor Receptor-Akt-DNA-PK Signaling, Accompanied by Inhibition of DNA Double-Strand Break Repair

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Khong Bee, E-mail: dmskkb@nccs.com.sg [Brain Tumour Research Laboratory, Division of Medical Sciences, National Cancer Centre Singapore (Singapore); Zhu Congju; Wong Yinling; Gao Qiuhan; Ty, Albert; Wong, Meng Cheong [Brain Tumour Research Laboratory, Division of Medical Sciences, National Cancer Centre Singapore (Singapore)

    2012-05-01

    Purpose: We compared radiosensitivity of brain tumor stem cells (BTSCs) with matched nonstem glioma cells, and determined whether gefitinib enhanced BTSC radiosensitivity by inhibiting epidermal growth factor receptor (EGFR)-Akt-DNA-dependent protein kinase (DNA-PK) signaling, followed by enhanced DNA double-stand breaks (DSBs) and inhibition of DSB repair. Methods and Materials: Radiosensitivity of stem-like gliomaspheres and nonstem glioma cells (obtained at patient neurosurgical resection) were evaluated by clonogenic assays, {gamma}-H{sub 2}AX immunostaining and cell cycle distribution. Survival of irradiated and nonirradiated NOD-SCID mice intracranially implanted with stem-like gliomaspheres were monitored. Glioma cells treated with gefitinib, irradiation, or both were assayed for clonogenic survival, {gamma}-H{sub 2}AX immunostaining, DNA-PKcs expression, and phosphorylation of EGFR and Akt. Results: Stem-like gliomaspheres displayed BTSC characteristics of self-renewal; differentiation into lineages of neurons, oligodendrocytes, and astrocytes; and initiation of glioma growth in NOD-SCID mice. Irradiation dose-dependently reduced clonogenic survival, induced G{sub 2}/M arrest and increased {gamma}-H{sub 2}AX immunostaining of nonstem glioma cells, but not stem-like gliomaspheres. There was no difference in survival of irradiated and nonirradiated mice implanted with stem-like gliomaspheres. The addition of gefitinib significantly inhibited clonogenic survival, increased {gamma}-H{sub 2}AX immunostaining, and reduced DNA-PKcs expression of irradiated stem-like gliomaspheres, without affecting irradiated-nonstem glioma cells. Gefitinib alone, and when combined with irradiation, inhibited phosphorylation of EGFR (Y1068 and Y1045) and Akt (S473) in stem-like gliomaspheres. In nonstem glioma cells, gefitinib alone inhibited EGFR Y1068 phosphorylation, with further inhibition by combined gefitinib and irradiation. Conclusions: Stem-like gliomaspheres are

  16. Gefitinib Radiosensitizes Stem-Like Glioma Cells: Inhibition of Epidermal Growth Factor Receptor-Akt-DNA-PK Signaling, Accompanied by Inhibition of DNA Double-Strand Break Repair

    International Nuclear Information System (INIS)

    Purpose: We compared radiosensitivity of brain tumor stem cells (BTSCs) with matched nonstem glioma cells, and determined whether gefitinib enhanced BTSC radiosensitivity by inhibiting epidermal growth factor receptor (EGFR)–Akt-DNA–dependent protein kinase (DNA-PK) signaling, followed by enhanced DNA double-stand breaks (DSBs) and inhibition of DSB repair. Methods and Materials: Radiosensitivity of stem-like gliomaspheres and nonstem glioma cells (obtained at patient neurosurgical resection) were evaluated by clonogenic assays, γ-H2AX immunostaining and cell cycle distribution. Survival of irradiated and nonirradiated NOD-SCID mice intracranially implanted with stem-like gliomaspheres were monitored. Glioma cells treated with gefitinib, irradiation, or both were assayed for clonogenic survival, γ-H2AX immunostaining, DNA-PKcs expression, and phosphorylation of EGFR and Akt. Results: Stem-like gliomaspheres displayed BTSC characteristics of self-renewal; differentiation into lineages of neurons, oligodendrocytes, and astrocytes; and initiation of glioma growth in NOD-SCID mice. Irradiation dose-dependently reduced clonogenic survival, induced G2/M arrest and increased γ-H2AX immunostaining of nonstem glioma cells, but not stem-like gliomaspheres. There was no difference in survival of irradiated and nonirradiated mice implanted with stem-like gliomaspheres. The addition of gefitinib significantly inhibited clonogenic survival, increased γ-H2AX immunostaining, and reduced DNA-PKcs expression of irradiated stem-like gliomaspheres, without affecting irradiated-nonstem glioma cells. Gefitinib alone, and when combined with irradiation, inhibited phosphorylation of EGFR (Y1068 and Y1045) and Akt (S473) in stem-like gliomaspheres. In nonstem glioma cells, gefitinib alone inhibited EGFR Y1068 phosphorylation, with further inhibition by combined gefitinib and irradiation. Conclusions: Stem-like gliomaspheres are resistant to irradiation-induced cytotoxicity, G2/M

  17. Radiosensitization by fullerene-C60 dissolved in squalene on human malignant melanoma through lipid peroxidation and enhanced mitochondrial membrane potential

    Science.gov (United States)

    Kato, Shinya; Kimura, Masatsugu; Miwa, Nobuhiko

    2014-04-01

    We examined fullerene-C60 dissolved in squalene (C60/Sqe) for the ability to potentiate the radiosensitization under X-ray irradiation on human malignant melanoma HMV-II cells, which were treated with C60/Sqe and thereafter irradiated with X-ray. The cell proliferation for C60/Sqe was inhibited more markedly than for Sqe alone. Meanwhile, cell proliferation was almost unaltered for C60/squalane (Sqa) or Sqa, a hydrogenated form of Sqe, as compared to no-additive control. Thus radiosensitization of C60/Sqe is attributed to peroxidation of unsaturated bonds of squalene by X-ray-excited C60 in contrast to squalane. The fluorescence images of HMV-II cells stained with Rhodamine123, an indicator for mitochondrial membrane potential, were monitored for 6 h after X-ray irradiation. C60/Sqe obviously exhibited more augmented fluorescence intensity on perinuclear region of HMV-II cells than Sqe alone. TBARS assay showed that the lipid peroxidation level as malondialdehyde-equivalent increased by combination of C60/Sqe and X-ray dose-dependently on X-ray doses. C60/Sqe exhibited lipid peroxidation more markedly by 1.2-fold than Sqe alone. Thus the level of lipid peroxidation of squalene was sufficiently higher in C60/Sqe than in Sqe in the absence of C60 under X-ray irradiation, suggesting the combination of C60/Sqe and X-ray irradiation induced radiosensitization on HMV-II cells by peroxidation of absorbed Sqe in mitochondrial membrane via oxidative stress mediated by fullerene-C60.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Radiosensitizing Effect of a Phenylbutyrate-Derived Histone Deacetylase Inhibitor in Hepatocellular Carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Yen-Shen [Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan (China); Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan (China); Chou, Chia-Hung [Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Tzen, Kai-Yuan [Department of Nuclear Medicine, National Taiwan University Hospital, Taipei, Taiwan (China); Gao, Ming [Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Cheng, Ann-Lii [Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan (China); Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan (China); Graduate Institutes of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan (China); Kulp, Samuel K. [Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH (United States); Cheng, Jason Chia-Hsien, E-mail: jasoncheng@ntu.edu.tw [Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan (China); Graduate Institutes of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan (China)

    2012-06-01

    Purpose: Radiotherapy is integrated into the multimodal treatment of localized hepatocellular carcinoma (HCC) refractory to conventional treatment. Tumor control remains unsatisfactory and the sublethal effect associates with secondary spread. The use of an effective molecularly targeted agent in combination with radiotherapy is a potential therapeutic approach. Our aim was to assess the effect of combining a phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, AR-42, with radiotherapy in in vitro and in vivo models of human HCC. Methods and Materials: Human HCC cell lines (Huh-7 and PLC-5) were used to evaluate the in vitro synergism of combining AR-42 with irradiation. Flow cytometry analyzed the cell cycle changes, whereas Western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with AR-42 and/or radiotherapy for the in vivo response. Results: AR-42 significantly enhanced radiation-induced cell death by the inhibition of the DNA end-binding activity of Ku70, a highly versatile regulatory protein for DNA repair, telomere maintenance, and apoptosis. In ectopic xenografts of Huh-7 and PLC-5, pretreatment with AR-42 significantly enhanced the tumor-suppressive effect of radiotherapy by 48% and 66%, respectively. A similar combinatorial effect of AR-42 (10 and 25 mg/kg) and radiotherapy was observed in Huh-7 orthotopic model of tumor growth by 52% and 82%, respectively. This tumor suppression was associated with inhibition of intratumoral Ku70 activity as well as reductions in markers of HDAC activity and proliferation, and increased apoptosis. Conclusion: AR-42 is a potent, orally bioavailable inhibitor of HDAC with therapeutic value as a radiosensitizer of HCC.

  20. Downregulation of peroxiredoxin-1 by β-elemene enhances the radiosensitivity of lung adenocarcinoma xenografts.

    Science.gov (United States)

    Li, Guoquan; Xie, Bingbing; Li, Xiaolong; Chen, Yinghai; Xu, Yinghui; Xu-Welliver, Meng; Zou, Lijuan

    2015-03-01

    β-elemene, the active component of elemene (1-methyl-1-vinyl-2,4-diisopropenyl-cyclohexane), is a naturally occurring compound isolated from the traditional Chinese medicinal herb Curcuma wenyujin. Studies have confirmed that β-elemene enhances the radiosensitivity of lung cancer cell lines such as A549, by multiple pathways; however, their underlying mechanisms and pathways are yet to be elucidated. In the present study, two-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry were used to profile the different proteins in A549 cell xenograft models of both treatment groups. The protein/mRNA expression was assessed by reverse transcription-polymerase chain reaction and western blotting techniques in tumor samples from all treatment groups. As a critical player in redox regulation of cancer cells, inhibition of peroxiredoxin-1 (Prx-1) may be an effective option for enhancing the tumor response to radiation. We further verified Prx-1 expression at the transcription and translation levels. β-elemene at a dose of 45 mg/kg had little effect on the Prx-1 protein expression, which was correlated with a moderate antitumor effect. However, a 45 mg/kg dose of β-elemene significantly inhibited the Prx-1 mRNA expression, thereby suggesting a possible influence on the transcriptional process, and radiation significantly increased the Prx-1 mRNA/protein expression compared to the control group (p<0.01). Notably, Prx-1 mRNA/protein expression was significantly lower in the β-elemene/radiation co-treatment group compared to the baseline levels in the control group (p<0.01). These results suggest that radiation-induced Prx-1 expression is directly or indirectly suppressed by β-elemene, thus suggesting a new pathway by which to reverse radioresistance.

  1. Standard sub-thermoneutral caging temperature influences radiosensitivity of hematopoietic stem and progenitor cells.

    Directory of Open Access Journals (Sweden)

    Benjamin J Povinelli

    Full Text Available The production of new blood cells relies on a hierarchical network of hematopoietic stem and progenitor cells (HSPCs. To maintain lifelong hematopoiesis, HSPCs must be protected from ionizing radiation or other cytotoxic agents. For many years, murine models have been a valuable source of information regarding factors that either enhance or reduce the survival of HSPCs after exposure of marrow to ionizing radiation. In a recent series of studies, however, it has become clear that housing-related factors such as the cool room temperature required for laboratory mice can exert a surprising influence on the outcome of experiments. Here we report that the mild, but chronic cold-stress endured by mice housed under these conditions exerts a protective effect on HSPCs after both non-lethal and lethal doses of total body irradiation (TBI. Alleviation of this cold-stress by housing mice at a thermoneutral temperature (30°C resulted in significantly greater baseline radiosensitivity to a lethal dose of TBI with more HSPCs from mice housed at thermoneutral temperature undergoing apoptosis following non-lethal TBI. Cold-stressed mice have elevated levels of norepinephrine, a key molecule of the sympathetic nervous system that binds to β-adrenergic receptors. We show that blocking this signaling pathway in vivo through use of the β-blocker propanolol completely mitigates the protective effect of cold-stress on HSPC apoptosis. Collectively this study demonstrates that chronic stress endured by the standard housing conditions of laboratory mice increases the resistance of HSPCs to TBI-induced apoptosis through a mechanism that depends upon β-adrenergic signaling. Since β-blockers are commonly prescribed to a wide variety of patients, this information could be important when predicting the clinical impact of HSPC sensitivity to TBI.

  2. Costunolide causes mitotic arrest and enhances radiosensitivity in human hepatocellular carcinoma cells

    International Nuclear Information System (INIS)

    This work aimed to investigate the effect of costunolide, a sesquiterpene lactone isolated from Michelia compressa, on cell cycle distribution and radiosensitivity of human hepatocellular carcinoma (HCC) cells. The assessment used in this study included: cell viability assay, cell cycle analysis by DNA histogram, expression of phosphorylated histone H3 (Ser 10) by flow cytometer, mitotic index by Liu's stain and morphological observation, mitotic spindle alignment by immunofluorescence of alpha-tubulin, expression of cell cycle-related proteins by Western blotting, and radiation survival by clonogenic assay. Our results show that costunolide reduced the viability of HA22T/VGH cells. It caused a rapid G2/M arrest at 4 hours shown by DNA histogram. The increase in phosphorylated histone H3 (Ser 10)-positive cells and mitotic index indicates costunolide-treated cells are arrested at mitosis, not G2, phase. Immunofluorescence of alpha-tubulin for spindle formation further demonstrated these cells are halted at metaphase. Costunolide up-regulated the expression of phosphorylated Chk2 (Thr 68), phosphorylated Cdc25c (Ser 216), phosphorylated Cdk1 (Tyr 15) and cyclin B1 in HA22T/VGH cells. At optimal condition causing mitotic arrest, costunolide sensitized HA22T/VGH HCC cells to ionizing radiation with sensitizer enhancement ratio up to 1.9. Costunolide could reduce the viability and arrest cell cycling at mitosis in hepatoma cells. Logical exploration of this mitosis-arresting activity for cancer therapeutics shows costunolide enhanced the killing effect of radiotherapy against human HCC cells

  3. 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. PMID:27207779

  4. Costunolide causes mitotic arrest and enhances radiosensitivity in human hepatocellular carcinoma cells

    Directory of Open Access Journals (Sweden)

    Chen Chih-Jen

    2011-05-01

    Full Text Available Abstract Purpose This work aimed to investigate the effect of costunolide, a sesquiterpene lactone isolated from Michelia compressa, on cell cycle distribution and radiosensitivity of human hepatocellular carcinoma (HCC cells. Methods The assessment used in this study included: cell viability assay, cell cycle analysis by DNA histogram, expression of phosphorylated histone H3 (Ser 10 by flow cytometer, mitotic index by Liu's stain and morphological observation, mitotic spindle alignment by immunofluorescence of alpha-tubulin, expression of cell cycle-related proteins by Western blotting, and radiation survival by clonogenic assay. Results Our results show that costunolide reduced the viability of HA22T/VGH cells. It caused a rapid G2/M arrest at 4 hours shown by DNA histogram. The increase in phosphorylated histone H3 (Ser 10-positive cells and mitotic index indicates costunolide-treated cells are arrested at mitosis, not G2, phase. Immunofluorescence of alpha-tubulin for spindle formation further demonstrated these cells are halted at metaphase. Costunolide up-regulated the expression of phosphorylated Chk2 (Thr 68, phosphorylated Cdc25c (Ser 216, phosphorylated Cdk1 (Tyr 15 and cyclin B1 in HA22T/VGH cells. At optimal condition causing mitotic arrest, costunolide sensitized HA22T/VGH HCC cells to ionizing radiation with sensitizer enhancement ratio up to 1.9. Conclusions Costunolide could reduce the viability and arrest cell cycling at mitosis in hepatoma cells. Logical exploration of this mitosis-arresting activity for cancer therapeutics shows costunolide enhanced the killing effect of radiotherapy against human HCC cells.

  5. 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)

    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.

  6. 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.

  7. Radiosensitivity enhancement of typical 15 nm polyethylene-glycol-coated Au nanoparticles on HepG2 cell

    International Nuclear Information System (INIS)

    Objective: To investigate the radiosensitivity enhancement of Au nanoparticles to HepG2 cell. Methods: 15 nm polyethylene-glycol-coated(PEG) Au nanoparticles were synthesized, and then blood stability were tested by using the UV-vis optical absorption. Meanwhile, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide methods were used to investigate the cell viability after 24 and 48 hours treatments, and cloning formation were used to investigate the radiosensitivity enhancement. Results: It was found that PEG-coated Au nanoparticles presented a high blood stability, and surface plasmon response has not shown significant changes after 24 hours. Cell viability was decreased after 24 hours treatment, but it was recovered to 90% after 48 hours. Cloning formation showed Au nanoparticles presented a significant radiosensitivity enhancement. Conclusion: 15 nm PEG-coated Au nanoparticles presented a good blood stability, low cytotoxicity and high radiosensitivity enhancement. (authors)

  8. Rigosertib Is a More Effective Radiosensitizer Than Cisplatin in Concurrent Chemoradiation Treatment of Cervical Carcinoma, In Vitro and In Vivo

    International Nuclear Information System (INIS)

    Purpose: To compare rigosertib versus cisplatin as an effective radiosensitizing agent for cervical malignancies. Methods and Materials: Rigosertib and cisplatin were tested in cervical cancer cell lines, HeLa and C33A. A 24-hour incubation with rigosertib and cisplatin, before irradiation (2-8 Gy), was used for clonogenic survival assays. Cell cycle analysis (propidium iodide staining) and DNA damage (γ-H2AX expression) were evaluated by fluorescence-activated cell sorter cytometry. Rigosertib was also tested in vivo in tumor growth experiments on cervical cancer xenografts. Results: Rigosertib was demonstrated to induce a G2/M block in cancer cells. Survival curve comparison revealed a dose modification factor, as index of radiosensitization effect, of 1.1-1.3 for cisplatin and 1.4-2.2 for rigosertib. With 6-Gy irradiation, an increase in DNA damage of 15%-25% was achieved in both HeLa and C33A cells with cisplatin pretreatment, and a 71-108% increase with rigosertib pretreatment. In vivo tumor growth studies demonstrated higher performance of rigosertib when compared with cisplatin, with 53% longer tumor growth delay. Conclusions: Rigosertib was more effective than cisplatin when combined with radiation and caused minimal toxicity. These data support the need for clinical trials with rigosertib in combination therapy for patients with cervical carcinoma

  9. Silencing of osteopontin promotes the radiosensitivity of breast cancer cells by reducing the expression of hypoxia inducible factor 1 and vascular endothelial growth factor

    Institute of Scientific and Technical Information of China (English)

    YANG Li; ZHAO Wei; ZUO Wen-shu; WEI Ling; SONG Xian-rang; WANG Xing-wu; ZHENG Gang; ZHENG Mei-zhu

    2012-01-01

    Background Osteopontin (OPN) is a secreted phosphoglycoprotein (SSP) that is overexpressed in a variety of tumors and was regarded as a molecular marker of tumors.In this study,we intended to demonstrate the role of OPN in human breast cancer cell line MDA-MB-231.Methods Recombinant plasmid expressing small interfering RNA (siRNA) specific to OPN mRNA was transfected into MDA-MB-231 cells to generate the stable transfected cell line MDA-MB-343,and the empty plasmid tansfected cells (MDA-MB-neg) or wildtype MDA-MB-231 cells were used as control cells respectively.Expression of OPN,hypoxia inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) proteins was analyzed by Western blotting analysis.The radiosensitivity of cells was determined by detecting cell apoptosis,cell proliferation and cell senescence.Results HIF-1 and VEGF proteins in MDA-MB-343 cells were significantly downregulated upon the efficient knockdown of OPN expression under either hypoxia or normoxia environment.Moreover,expression of OPN protein was upregualted upon hypoxic culture.Stable OPN-silencing also decreased cell invasion,increased cell apoptosis and cell senescence,as well as reduced clonogenic survival,resulting in increase radiation tolerance.Conclusions Suppression of OPN gene expression can enhance radiosensitivity and affect cell apoptosis in breast cancer cells.OPN seems to be an attractive target for the improvement of radiotherapy.

  10. Safety and radiosensitizing efficacy of sanazole (AK 2123) in oropharyngeal cancers: Randomized controlled double blind clinical trial

    OpenAIRE

    MRSM Pai; Chowta M; Adiga SMN; Dinesh M; Shenoy K; Kamath A; Ullal S; Kotian M; Pai D

    2006-01-01

    Oropharynx is an important site of cancer in India. Global comparison indicates higher incidences in India. Radiotherapy remains an important treatment modality. Efforts to improve loco-regional treatment and prolong survival are areas of focus. Radiosensitizers in hypoxic tumors have shown promise. Aim:0 To study the safety and radiosensitizing efficacy of sanazole in oropharyngeal squamous cell carcinoma (stage T2-4, N0-3, M0) as phase-II double blind controlled trial in patients treated ...

  11. Prediction of radiosensitivity in tumour cells: use of the alkaline comet assay to assess radiosensitivity in bladder and colorectal tumour cell lines

    International Nuclear Information System (INIS)

    Radiotherapy is the treatment of choice for a wide range of solid tumours yet it is impossible to predict which tumours will show a good response. We have investigated the radiosensitivity of a number of tumour cell lines (5 bladder and 4 colorectal) to verify whether the alkaline comet assay (ACA) can be used to predict tumour radiosensitivity. Preliminary studies showed that it is essential to carry out irradiations on cells pre-embedded in agarose to ensure that repair, prior to lysis, is kept to a minimum. Cells were embedded prior to irradiation, lysed and the comet tail moment analysed; this was compared to cell survival measured using a clonogenic assay. For all doses (0 - 6Gy) there was a good correlation between the two measures: r2 0.897 for bladder tumour cells and r2 = 0.929 for colorectal tumour cells. We also irradiated cells with 4Gy X-rays and measured initial damage, repair rate and residual damage. In both groups initial DNA damage and residual damage correlated with clonogenic survival; repair rate was very similar for the cell lines and was not predictive. One cell line (T24) had a pronounced shoulder on the radiation dose response curve such that there was a radioresistant response at 2 Gy and a radiosensitive response at 4 Gy. This change in response within the clinically relevant range emphasises that for a predictive test to have validity in the clinic it must be carried out in the clinically relevant range. The finding that initial damage varies between individual cell lines is consistent with some, but not all reports in the literature. We have also carried out nuclear texture analysis to measure phenotypic changes in DNA distribution and chromatin organisation. The results support the contention that organisation of nuclear chromatin is inherently different in different cell lines and may be significant in determining their response to radiation damage

  12. Radiosensitivity of CD45RO{sup +} memory and CD45RO{sup {minus}} naive T cells in culture

    Energy Technology Data Exchange (ETDEWEB)

    Uzawa, Akiko; Suzuki, Gen; Nakata, Yukiko; Akashi, Makoto; Ohyama, Harumi; Akanuma, Atsuo [National Institute of Radiological Sciences, Chiba (Japan)

    1994-01-01

    Radiosensitivities of various human T-cell subsets were investigated by a proliferation assay and by a single-cell gel electrophoresis assay. Each T-cell subset was purified using a cell sorter and was induced to proliferate by ionomycin and interleukin 2. Unsorted T cells showed biphasic dose-survival curves, indicating the heterogeneity of T cells in terms of radiosensitivity. Purified CD4{sup +} helper and CD8{sup +} killer T cells showed similar biphasic dose-survival curves. Hence both T-cell subsets were composed of cells of different radiosensitivity. The T-cell subsets belonging to different activation stages such as CD45RO{sup +} memory and CD45RO{sup {minus}} naive T cells had different dose-survival curves. The former was more radiosensitive than the latter. The high radiosensitivity of CD45RO{sup +} cells was also demonstrated by single-cell gel electrophoresis after irradiation. This is the first demonstration that a particular cell surface marker on T cells is correlated with greater radiosensitivity. 27 refs., 7 figs., 1 tab.

  13. Comet-electrophoresis assay as a method for determining radiosensitivities of tumor cells

    International Nuclear Information System (INIS)

    Objective: To explore the feasibility of applying comet-electrophoresis to determining the radiosensitivity of tumor cells. Methods: The residual rates of DNA damage at 30 minute after 2 Gy gamma irradiation in four human tumor cell lines (WM9839, KB, LS-T-117, PC3M) were determined with the comet assay. The cell survival fraction of tumor cell after 2 Gy gamma ray-irradiation was determined with clonogenic assay. Results: There were good correlations between cell survival fraction (SF2 ) and residual rate of DNA damage at 30 minute after 2 Gy gamma ray-irradiation in these four human tumor cell lines, separately. Conclusion: The comet-electrophoresis assay may be used as a repaid and sensitive method for determining inherent radiosensitivities of tumor cells

  14. The relationship of DNA double-strand break induction to radiosensitivity in human tumour cell lines

    International Nuclear Information System (INIS)

    Recent data suggest that differences in radiosensitivity between cell lines can be related to differences in dsb induction (Radford 1986). The current authors set out to assess the extent to which differences in radiation survival between nine human tumour cell lines could be attributed to differences in dsb induction. The lines varied widely in sensitivity, ranging from a sensitive neuroblastoma (surviving fraction at 2 Gy, SF2 = 0.13) to a resistant bladder carcinoma (SF2 = 0.62). Dsb induction was found to vary between the cell lines, such that resistant cells generally suffered less damage than sensitive ones. The data suggest that, in human tumour cell lines, differences in radiosensitivity may at least in part be due to different levels of damage induction, but that some lines may vary in their tolerance of damage due to differences in biological characteristics such as repair capacity. (author)

  15. Quantitative and comparative proteomics analysis of radiosensitivity for colorectal cancer cells

    International Nuclear Information System (INIS)

    To identify the related proteins about radiosensitivity (RS) of colorectal cancers,as well as make the personal therapeutics for patients, the specimen of transplanted tumor raised by the colorectal cancer cells, LOVO and SW480 with different radiosensitivity, were examined by the fluorescence differential in-gel electrophoresis (DIGE) after labeled with CyDye DIGE fluors Cy3, Cy5 and Cy2. As the result, intensity changes of 35 spots were detected with statistical significance. 18 protein spots of them are up-regulated in tumor specimen of LOVO, otherwise 17 are up-regulated in specimen of SW480. And 27 of them were identified by MALDI-TOF-MS successfully including 17 in LOVO and 15 in SW480. These differential expressed proteins may become the mocular markers and have a key role in predicting the RS of colorectal cancer. (authors)

  16. A search for radiosensitive mouse mutants by use of the micronucleus technique.

    Science.gov (United States)

    van Buul, P P; Tuinenburg-Bolraap, A; Searle, A G; Natarajan, A T

    1987-01-01

    In order to identify radiosensitive mutations in mice, 26 genetically well defined mutations in 26 different combinations of homozygous, hemizygous or heterozygous conditions, together with normal mice and mutagen-sensitive MS/Ae mice were analysed for the induction of micronuclei by X-rays in bone-marrow cells. For each mutant two doses of 0.5 and 1.0 Gy, two sampling times of 18 and 27 h after irradiation and unirradiated controls were studied. Using our criteria, homozygous contrasted allele of steel (Slcon), scabby (scb), viable dominant spotting (Wv), quaking (qk), fidget (fi) and postaxial hemimelia (px), heterozygous lurcher (Lc), hemizygous gyro (Gy), the compounds Slcon/grizzle-belly (SlgbH) and Wv/rump-white (Rw) and MS/Ae mice, were regarded as radiosensitive, with Slcon/Slcon the highest in rank order. Homozygous wabbler-lethal (wl) and wasted (wst) showed hyposensitivity which for the latter may be connected with enhanced cell killing.

  17. A haplotype common to intermediate radiosensitivity variants of ataxia-telangiectasia in the UK

    Energy Technology Data Exchange (ETDEWEB)

    Taylor, A.M.R.; McConville, C.M.; Byrd, P.J. [Birmingham Univ. (United Kingdom). Medical School; Rotman, G.; Shiloh, Y. [Tel Aviv Univ. (Israel). Sackler School of Medicine

    1994-12-01

    In a study of ataxia-telangiectasia (A-T) in the UK, patients in10 out of 60 families were shown to have a much lower level of chromosomal radiosensitivity compared with the majority of patients. In some patients the level of radiosensitivity was hardly distinguishable from normal. Patients in this group, however, could be distinguished clinically from the majority either by the later onset of severe cerebellar features or the slower rate of progress of the disorder. By using highly polymorphic microsatellite repeat markers a chromosome 11q22-23 haplotype common to the majority of these patients, and not occurring in any non-A-T chromosome in 60 families, was identified on one chromosome. The haplotype probably defines the region of the A-T gene in these families and the mutation associated with this haplotype may be much less severe than the second mutation thereby producing the slightly milder phenotype. (author).

  18. High expression of the circadian gene mPer2 diminishes the radiosensitivity of NIH 3T3 cells

    Energy Technology Data Exchange (ETDEWEB)

    Chang, L.; Liu, Y.Y.; Zhu, B.; Li, Y.; Hua, H.; Wang, Y.H.; Zhang, J.; Jiang, Z.; Wang, Z.R. [Sichuan University, Chengdu (China). West China Medical Center. Health Ministry Key Lab. of Chronobiology], e-mail: wangzhengrong@126.com

    2009-10-15

    Period2 is a core circadian gene, which not only maintains the circadian rhythm of cells but also regulates some organic functions. We investigated the effects of mPeriod2 (mPer2) expression on radiosensitivity in normal mouse cells exposed to {sup 60}Co-{gamma}-rays. NIH 3T3 cells were treated with 12-O-tetradecanoyl phorbol-13-acetate (TPA) to induce endogenous mPer2 expression or transfected with pcDNA3.1(+)-mPer2 and irradiated with {sup 6}0Co-{gamma}-rays, and then analyzed by several methods such as flow cytometry, colony formation assay, RT-PCR, and immunohistochemistry. Flow cytometry and colony formation assay revealed that irradiated NIH 3T3 cells expressing high levels of mPer2 showed a lower death rate (TPA: 24 h 4.3% vs 12 h 6.8% and control 9.4%; transfection: pcDNA3.1-mPer2 3.7% vs pcDNA3.1 11.3% and control 8.2%), more proliferation and clonogenic survival (TPA: 121.7 {+-} 6.51 vs 66.0 {+-} 3.51 and 67.7 {+-} 7.37; transfection: 121.7 {+-} 6.50 vs 65.3 {+-} 3.51 and 69.0 {+-} 4.58) both when treated with TPA and transfected with mPer2. RT-PCR analysis showed an increased expression of bax, bcl-2, p53, cmyc, mre11, and nbs1, and an increased proportionality of bcl-2/bax in the irradiated cells at peak mPer2 expression compared with cells at trough mPer2 expression and control cells. However, no significant difference in rad50 expression was observed among the three groups of cells. Immunohistochemistry also showed increased protein levels of P53, BAX and proliferating cell nuclear antigen in irradiated cells with peak mPer2 levels. Thus, high expression of the circadian gene mPer2 may reduce the radiosensitivity of NIH 3T3 cells. For this effect, mPer2 may directly or indirectly regulate the expressions of cell proliferation- and apoptosis-related genes and DNA repair-related genes. (author)

  19. Cytosine Deaminase/5-Fluorocytosine Exposure Induces Bystander and Radiosensitization Effects in Hypoxic Glioblastoma Cells in vitro

    International Nuclear Information System (INIS)

    Purpose: Treatment of glioblastoma (GBM) is limited by therapeutic ratio; therefore, successful therapy must be specifically cytotoxic to cancer cells. Hypoxic cells are ubiquitous in GBM, and resistant to radiation and chemotherapy, and, thus, are logical targets for gene therapy. In this study, we investigated whether cytosine deaminase (CD)/5-fluorocytosine (5-FC) enzyme/prodrug treatment induced a bystander effect (BE) and/or radiosensitization in hypoxic GBM cells. Methods and Materials: We stably transfected cells with a gene construct consisting of the SV40 minimal promoter, nine copies of a hypoxia-responsive element, and the yeast CD gene. During hypoxia, a hypoxia-responsive element regulates expression of the CD gene and facilitates the conversion of 5-FC to 5-fluorouracil, a highly toxic antimetabolite. We used colony-forming efficiency (CFE) and immunofluorescence assays to assess for BE in co-cultures of CD-expressing clone cells and parent, pNeo- or green fluorescent protein-stably transfected GBM cells. We also investigated the radiosensitivity of CD clone cells treated with 5-FC under hypoxic conditions, and we used flow cytometry to investigate treatment-induced cell cycle changes. Results: Both a large BE and radiosensitization occurred in GBM cells under hypoxic conditions. The magnitude of the BE depended on the number of transfected cells producing CD, the functionality of the CD, the administered concentration of 5-FC, and the sensitivity of cell type to 5-fluorouracil. Conclusion: Hypoxia-inducible CD/5-FC therapy in combination with radiation therapy shows both a pronounced BE and a radiosensitizing effect under hypoxic conditions

  20. Potentiation of cytotoxicity and radiosensitization of (E)-2'-deoxy-2' (fluoromethylene) cytidine by pentoxifylline in vitro.

    OpenAIRE

    Li, Y-X; Sun, L-Q; Paschoud, N; Weber-Johnson, K.; Coucke, Philippe

    1999-01-01

    (E)-28-deoxy-28-(fluoromethylene) cytidine (FMdC), a novel inhibitor of ribonucleotide-diphosphate reductase, has been shown to have anti-tumor activity against solid tumors and sensitize tumor cells to ionizing radiation. Pentoxifylline (PTX) can potentiate the cell killing induced by DNAdamaging agents through abrogation of DNA-damagedependent G2 checkpoint. We investigated the cytotoxic, radiosensitizing and cell-cycle effects of FMdC and PTX in a human colon-cancer...

  1. Days on radiosensitivity: individual variability and predictive tests; Radiosensibilite: variabilite individuelle et tests predictifs

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2008-07-01

    The radiosensitivity is a part of usual clinical observations. It is already included in the therapy protocols. however, some questions stay on its individual variability and on the difficulty to evaluate it. The point will be stocked on its origin and its usefulness in predictive medicine. Through examples on the use of predictive tests and ethical and legal questions that they raise, concrete cases will be presented by specialists such radio biologists, geneticists, immunologists, jurists and occupational physicians. (N.C.)

  2. Radiosensitivity studies in rice I, M1 injury in seedling stage

    International Nuclear Information System (INIS)

    Radiosensitivity of indigeneous rice are discussed in this paper. The popular varieties of rice were irradiated with gamma rays using 60Co source at 35, 92.9 R/min dose rate. Germination percentage, seedling height and root length were studied under laboratory conditions conducted in controlled environment growth room at 25+-10. The seedlings were raised and data of seeds were recorded after a fortnight. (A.B.)

  3. Inhibition of Hsp27 Radiosensitizes Head-and-Neck Cancer by Modulating Deoxyribonucleic Acid Repair

    Energy Technology Data Exchange (ETDEWEB)

    Guttmann, David M.; Hart, Lori [Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Du, Kevin [Department of Radiation Oncology, New York University School of Medicine, New York, New York (United States); Seletsky, Andrew [Department of Biology, Drexel University, Philadelphia, Pennsylvania (United States); Koumenis, Constantinos, E-mail: koumenis@xrt.upenn.edu [Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States)

    2013-09-01

    Purpose: To present a novel method of tumor radiosensitization through Hsp27 knockdown using locked nucleic acid (LNA) and to investigate the role of Hsp27 in DNA double strand break (DSB) repair. Methods and Materials: Clonogenic survival assays, immunoblotting, the proximity ligation assay, and γH2AX foci analysis were conducted in SQ20B and FaDu human head-and-neck cancer cell lines treated with Hsp27 LNA and Hsp27 short hairpin RNA (shRNA). Additionally, nude mice with FaDu flank tumors were treated with fractionated radiation therapy after pretreatment with Hsp27 LNA and monitored for tumor growth. Results: Hsp27 LNA and Hsp27 shRNA radiosensitized head-and-neck cancer cell lines in an Hsp27-dependent manner. Ataxia-Telangectasia Mutated-mediated DNA repair signaling was impaired in irradiated cells with Hsp27 knockdown. ATM kinase inhibition abrogated the radiosensitizing effect of Hsp27. Furthermore, Hsp27 LNA and shRNA both attenuated DNA repair kinetics after radiation, and Hsp27 was found to colocalize with ATM in both untreated and irradiated cells. Last, combined radiation and Hsp27 LNA treatment in tumor xenografts in nude mice suppressed tumor growth compared with either treatment alone. Conclusions: These results support a radiosensitizing property of Hsp27 LNA in vitro and in vivo, implicate Hsp27 in double strand break repair, and suggest that Hsp27 LNA might eventually serve as an effective clinical agent in the radiotherapy of head-and-neck cancer.

  4. Cabazitaxel-induced stabilization of microtubules enhances radiosensitivity in ovarian cancer cells

    Directory of Open Access Journals (Sweden)

    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

  5. Vegetable seed radiosensitivity and kinetic analysis of super-weak bioluminescence

    International Nuclear Information System (INIS)

    Bioluminescence of several vegetable seeds induced by γ-rays was studied. The results show that positive relation exists between seeds bioluminescence and irradiation dose, which fits with equation Y=Y0eKD. The higher the K value is, the more intense the bioluminescence induced by γ-rays is. Significant differences among K values were found with different varieties. The bioluminescence and exterior measurement value of seed radiosensitivity showed good consistency

  6. Effects of halogen substitution on Watson-Crick base pairing: a possible mechanism for radiosensitivity.

    Science.gov (United States)

    Heshmati, Emran; Abdolmaleki, Parviz; Mozdarani, Hossein; Sarvestani, Amir Sabet

    2009-09-01

    The halogen substituent effect on geometries and charge distributions of the A-T base pair derivatives was evaluated using density functional theory at B3LYP/6-31G* level. The results indicate that all of the substitutions affect geometries and charge distributions of the atoms contributing hydrogen bonds. These changes would be the reason of the radiosensitization of these compounds incorporating DNA. PMID:19643605

  7. Radiosensitivity of the reproductive organs exposed to the flow of cassava mixed neutron/gamma

    International Nuclear Information System (INIS)

    A preliminary study of seeds and cuttings radiosensitivity for Cassava mutation breeding was performed. Three Cassava clones were irradiated at different times morder to determine the maximum mutagenic treatment. Data obtained show that treatments of which irradiated time is greater than 6 seconds are lethals for cutting regeneration. Duration inferior or equal to 6 seconds have no negative effect. The cutting regeneration is maximum for 3 seconds treatment and decreases with irradiation time. For irradiated seeds, germination has been completely inhibited.

  8. Ocular absorption and toxicity of a radiosensitizer and its effect on hypoxic cells

    International Nuclear Information System (INIS)

    The recurrence of retinoblastoma after radiation treatment may be related to hypoxic cell radioresistance. Radiosensitizing drugs acting on hypoxic cells without affecting the response of oxygenated cells could improve treatment of ocular tumors while minimizing complications of radiotherapy. A desmethyl derivative of misonidazole is as effective a radiosensitizer as misonidazole (as measured in vitro) and is better suited to ocular administration, since it is more soluble than misonidazole. We studied the ocular toxic effects of a desmethyl derivative of misonidazole after subconjunctival administration of 140 and 70 mg. The higher dose produced an intolerable ocular toxic effect, but at the lower dose, the toxic effect was moderate and reversible. We compared ocular pharmacokinetics of the desmethyl derivative of misonidazole after subconjunctival and intravenous (IV) injections. Subconjunctival administration yielded vitreous and anterior chamber concentrations of the radiosensitizer sufficient to produce a notable dose-modifying effect (as high as 1.8 in the anterior chamber and 1.25 in the vitreous at 70-mg doses). In contrast, even at doses of 140 mg, IV injections of the desmethyl derivative of misonidazole did not result in therapeutically useful ocular levels

  9. The relationship between cellular radiosensitivity and radiation-induced DNA damage measured by the comet assay

    International Nuclear Information System (INIS)

    The relationship between deoxyribonucleic acid (DNA) damage and the cell death induced by γ-irradiation was examined in three kinds of cells, Chinese hamster ovary fibroblast CHO-K1, human melanoma HMV-II and mouse leukemia L5178Y. Cell survival was determined by a clonogenic assay. The induction and rejoining of DNA strand breaks induced by radiation were measured by the alkaline and neutral comet assay. L5178Y cells were the most radiosensitive, while CHO-K1 cells and HMV-II cells were radioresistant. There was an inverse relationship between the survival fraction at 2 Gy (SF2) and the yield of initial DNA strand breaks per unit dose under the alkaline condition of the comet assay, and also a relationship between SF2 and the residual DNA strand breaks (for 4 hr after irradiation) under the neutral condition for the comet assay, the latter being generally considered to be relative to cellular radiosensitivity. In the present analysis, it was considered that the alkaline condition for the comet assay was optimal for evaluating the initial DNA strand breaks, while the neutral condition was optimal for evaluating the residual DNA strand breaks. Since the comet assay is simpler and more rapid than other methods for detecting radiation-induced DNA damage, this assay appears to be a useful predictive assay for evaluating cellular clonogenic radiosensitivity of tumor cells. (author)

  10. Low Dose Rate Radiosensitization of Hepatocellular Carcinoma In Vitro and in Patients

    Directory of Open Access Journals (Sweden)

    Kyle C. Cuneo

    2014-08-01

    Full Text Available Transarterial radioembolization (TARE with 90Y microspheres delivers low dose rate radiation (LDR to intrahepatic tumors. In the current study, we examined clonogenic survival, DNA damage, and cell cycle distribution in hepatocellular carcinoma (HCC cell lines treated with LDR in combination with varying doses and schedules of 5-fluorouracil (5-FU, gemcitabine, and sorafenib. Radiosensitization was seen with 1 to 3 μM 5-FU (enhancement ratio 2.2–13.9 and 30 to 100 nM gemcitabine (enhancement ratio 1.9–2.9 administered 24 hours before LDR (0.26 Gy/h to 4.2 Gy. Sorafenib radiosensitized only at high concentrations (3–10 μM when administered after LDR. For a given radiation dose, greater enhancement was seen with LDR compared to standard dose rate therapy. Summarizing our clinical experience with low dose rate radiosensitization, 13 patients (5 with HCC, 8 with liver metastases were treated a total of 16 times with TARE and concurrent gemcitabine. Six partial responses and one complete response were observed with a median time to local failure of 7.1 months for all patients and 9.9 months for patients with HCC. In summary, HCC is sensitized to LDR with clinically achievable concentrations of gemcitabine and 5-FU in vitro. Encouraging responses were seen in a small cohort of patients treated with TARE and concurrent gemcitabine. Future studies are needed to validate the safety and efficacy of this approach.

  11. Radiosensitization by misonidazole, pimonidazole and azomycin and intracellular uptake in human tumour cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Watts, M.E.; Dennis, M.F.; Roberts, I.J. (Mount Vernon Hospital, Northwood (UK). Gray Lab.)

    1990-02-01

    Radiosensitization of two human tumour cell lines, HT-1080 and LoVo was compared with Chinese hamster line V73-379A. Although the two human lines were more radiosensitive than V79, enhancement ratios for misonidazole, pimonidazole and azomycin were similar for all three. In all cells uptake of misonidazole and azomycin was very rapid; that of pimonidazole was initially much slower before reaching a plateau. The ratios of intracellular concentration of radiosensitizer to extracellular concentration (C{sub i} to C{sub e})for misonidazole were 0.8 (HT-1080) and 0.7 (LoVo and V79); for azomycin 0.9 (HT-1080 and LoVo) and 0.8 (V79). C{sub i}C{sub e} for pimonidazole varied with cell line (1.8 (LoVo), 2.6 (HT-1080) and 3.3 (V79)). When average cell volume was taken into consideration, concentrations of non-protein sulphydryl were very similar (4.2 (HT-1080), 5.6 (LoVo), 5.7 (V79) m mol dm{sup -3}). MPSH levels expressed as n mol/mg protein were also similar. (author).

  12. Chromosomal Radiosensitivity in Lymphocytes of Cervix Cancer Patients—Correlation with Side Effect after Radiotherapy

    Science.gov (United States)

    Wegierek-Ciuk, Aneta; Lankoff, Anna; Lisowska, Halina; Banasik-Nowak, Anna; Arabski, Michał; Kedzierawski, Piotr; Florek, Agnieszka; Wojcik, Andrzej

    2010-01-01

    It is well known that cancer patients receiving similar radiotherapy treatments differ widely in normal tissue reactions ranging from undetectable to unacceptably severe levels. Therefore, an important goal of radiobiological research is to establish a test which would allow identifying individual radiosensitivity of patients prior to radiotherapy. The aim of the presented study is to assess the relationship between lymphocyte intrinsic radiosensitivity in vitro and early reaction of normal tissue in cervix cancer patients treated by radiotherapy. The following endpoints are analyzed in vitro: frequency of micronuclei, the kinetics of DNA repair and apoptosis. Acute normal tissue reaction to radiotherapy in the skin, bladder and rectum are scored according to the EORTC/RTOG scale. Our results show a wide inter-individual variability in chromosomal radiosensitivity in vitro. The majority of patients show a Grade 0, 1 or 2 reaction for all organs studied. No statistically significant correlation has been observed between the in vitro results in lymphocytes and the degree of early normal tissue and organ reaction.

  13. Prediction value of radiosensitivity of hepatocarcinoma cells for apoptosis and micronucleus assay

    Institute of Scientific and Technical Information of China (English)

    Zhi-Zhong Liu; Wen-Ying Huang; Xiao-Sheng Li; Ju-Sheng Lin; Xiao-Kun Cai; Kuo-Huang Lian; He-Jun Zhou

    2005-01-01

    AIM: To investigate the prediction value of radiosensitivity of hepatocarcinoma cells for apoptosis and micronucleus assay.METHODS: Clonogenic assay, flow cytometry, and CB micronuclei assay were used to survey the cell survival rate, radiation-induced apoptosis and micronucleus frequency of hepatocarcinoma cell lines SMMC-7721,HL-7702, and HepG2 after being irradiated by X-ray at the dosage ranging 0-8 Gy.RESULTS: After irradiation, there was a dose-effect relationship between micronucleus frequency and radiation dosage among the three cell lines (P<0.05). A positive relationship was observed between apoptosis and radiation dosage among the three cell lines. The HepG2 cells had a significant correlation (P<0.05) but apoptosis incidence had a negative relationship with micronucleus frequency. There was a positive relationship between apoptosis and radiation dosage and the correlation between SMMC-7721 and HL-7702 cell lines had a significant difference (P<0.01). After irradiation,a negative relationship between cell survival rate and radiation dosages was found among the three cell lines(P<0.01). There was a positive relationship between cell survival rate and micronucleus frequency (P<0.01). No correlation was observed between apoptosis and cell survival rate.CONCLUSION: The radiosensitivity of hepatocarcinoma cells can be reflected by apoptosis and micronuclei.Detection of apoptosis and micronuclei could enhance the accuracy for predicting radiosensitivity.

  14. Low levels of ATM in breast cancer patients with clinical radiosensitivity

    Directory of Open Access Journals (Sweden)

    Fang Zhiming

    2010-06-01

    Full Text Available Abstract Background and Purpose Adjuvant radiotherapy for cancer can result in severe adverse side effects for normal tissues. In this respect, individuals with anomalies of the ATM (ataxia telangiectasia protein/gene are of particular interest as they may be at risk of both breast cancer and clinical radiosensitivity. The association of specific ATM gene mutations with these pathologies has been well documented, however, there is uncertainty regarding pathological thresholds for the ATM protein. Results Semi-quantitative immuno-blotting provided a reliable and reproducible method to compare levels of the ATM protein for a rare cohort of 20 cancer patients selected on the basis of their severe adverse normal tissue reactions to radiotherapy. We found that 4/12 (33% of the breast cancer patients with severe adverse normal tissue reactions following radiotherapy had ATM protein levels Conclusions ATM mutations are generally considered low risk alleles for breast cancer and clinical radiosensitivity. From results reported here we propose a tentative ATM protein threshold of ~55% for high-risk of clinical radiosensitivity for breast cancer patients.

  15. Radiosensitivity of mice and its modifiers based on the endogeneous spleen colony formation

    Energy Technology Data Exchange (ETDEWEB)

    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.

  16. Hypoxia-selective radiosensitization of mammalian cells by nitracrine, an electron-affinic DNA intercalator

    International Nuclear Information System (INIS)

    NC (1-nitroacridine nitracine) radiosensitization was evaluated in CHO cultures at 40C. Under hypoxia, submicromolar concentrations resulted in sensitization (SER=1.6 at μ mol dm-3). In aerobic conditions, a concentration more than 10-fold higher was required. In aerobic cultures, NC radiosensitization was independent of time of exposure. Postirradiation sensitization was not observed under hypoxia. Time dependence of NC uptake and development of radiosensitization were similar, suggesting that sensitization is due to unmetabolized drug. NC was about 1700 times more potent than misonidazole, (accounted for by the electron affinity of NC (E(1) value at pH 7 of -275 mV versus NHE)) and by its accumulation in cells to give intracellular concentrations approximately 30 times greater than in the medium. Concentrations of free NC appear to be low in AA8 cells, presumably due to DNA binding. If radioisensitization by NC is due to bound rather than free drug, it is suggested that intercalated NC can interact efficiently with DNA target radicals, despite a binding ratio in the cell, estimated as less than 1 NC molecule/400 base pairs under conditions providing efficient sensitization. (U.K.)

  17. Effect of Recombinant Human Endostatin on Radiosensitivity in Patients With Non–Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Purpose: To observe the effects of recombinant human endostatin (RHES) on the radiosensitivity of non-small cell lung cancer (NSCLC). Methods and Materials: First, 10 hypoxia-positive cases of pathology-diagnosed NSCLC selected from 15 patients were used to determine the normalization window, a period during which RHES improves NSCLC hypoxia. Second, 50 hypoxia-positive cases of pathology-diagnosed NSCLC (Stages I–III) were randomly divided into a RHES plus radiotherapy group (25 cases) and a radiotherapy-alone group (25 cases). Intensity = modulated radiotherapy with a total dose of 60 Gy in 30 fractions for 6 weeks was adopted in the two groups. The target area included primary foci and metastatic lymph nodes. In the RHES plus radiotherapy group, RHES (15 mg/day) was intravenously given during the normalization window. Results: After RHES administration, the tumor-to=normal tissue radioactivity ratio and capillary permeability surface were first decreased and then increased, with their lowest points on the fifth day compared with the first day (all p < 0.01). Blood flow was first increased and then decreased, with the highest point on the fifth day, compared with the first and tenth day (all p < 0.01). In the RHES plus radiotherapy group and the radiotherapy-alone group, the total effective rates (complete response plus partial response) were 80% and 44% (p = 0.009), respectively. The median survival times were 21.1 ± 0.97 months and 16.5 ± 0.95 months (p = 0.004), respectively. The 1-year and 2-year local control rates were 78.9 ± 8.4% and 68.1 ± 7.8% (p = 0.027) and 63.6 ± 7.2% and 43.4 ± 5.7% (p = 0.022), respectively. The 1-year and 2-year overall survival rates were 83.3 ± 7.2% and 76.6 ± 9.3% (p = 0.247) and 46.3 ± 2.4% and 37.6 ± 9.1% (p = 0.218), respectively. Conclusion: The RHES normalization window is within about 1 week after administration. RHES combined with radiotherapy within the normalization window has better short-term therapeutic

  18. 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

  19. 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

  20. Evaluation of radiosensitivity of human tumor cells after irradiation of γ-rays based on G2-chromosome aberrations

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    The aim of the present investigation is to determine initial G2-chromosome aberrations and to validate whether the G2-chromosome aberrations can predict the cellular clonogenic survival in human tumor cell lines. Cell lines of human ovary carcinoma cells (HO8910) and human hepatoma cells (HepG2) were irradiated with a range of doses and assessed both for initial G2-chromosome aberrations and for cell survival after γ-irradiation. The initial G2-chromosome aberrations were measured by counting the number of G2-chromatid breaks after irradiation, detected by the premature chromosome condensation technique, and the G2-assay method. Cell survival was documented by a colony formation assay. A linear-quadratic survival curve was observed in both cell lines. The dose-response results show that the numbers of G2-chromatid breaks increase with the increase in dose in the two cell lines. At higher doses (higher than 4 Gy) of irradiation, the number of G2-chromatid breaks for the G2-assay method cannot be determined because too few cells reach mitosis, and hence their detection is difficult. A good correlation is found between the clonogenic survival and the radiation-induced initial G2-chromatid breaks per cell (r=0.9616). The present results suggest that the premature chromosome condensation technique may be useful for determining chromatid breaks in G2 cells, and the number of initial G2-chromatid breaks holds promise for predicting the radiosensitivity of tumor cells.

  1. Polyfunctional radiosensitizers: VI. Dexamethasone inhibits shoulder modification by uncharged nitroxyl biradicals in mammalian cells irradiated in vitro

    International Nuclear Information System (INIS)

    Overnight exposure of Chinese hamster cells (V.79-753B) in vitro to 1 μg/ml dexamethasone increases the radiation resistance of the cells by about 20% both in air and in hypoxia, while having no appreciable effect on the oxygen enhancement ratio (OER). This is accompanied by substantially higher levels of glutathione. When dexamethasone-treated hypoxic cells are irradiated in the presence of nitroxyl biradicals there is no effect on the slope ratio of the exponential portion of the survival curves. In the case of uncharged biradicals, Ro.03-6061 and RSU-4072, which have been shown to modify the shoulder region of the hypoxic cell survival curve, there is an increase in extrapolation number in dexamethasone-treated cells. When hypoxic cells are exposed to the charged biradical RSU-4073, which does not exhibit shoulder modification, there is no change in extrapolation number. Experiments to examine the effect of concentration of these compounds on radiosensitization show that lower concentrations of both RSU-4072 and RSU-4073 are required to mediate changes in the slope of the hypoxic cell survival curve than to mediate shoulder modification, in the case of RSU-4072. Quantitative ESR data comparing the uptake of RSU-4072 and RSU-4073 with the monoradical TMPN into cells suggest that the cell membrane may act as a barrier to the incorporation of biradicals, and that this is greater for charged than for uncharged compounds. Treatment of cells with dexamethasone does not affect the uptake of the compounds

  2. Influence the oxidant action of selenium in radiosensitivity induction and cell death in yeast Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Ionizing radiations are from both natural sources such as from anthropogenic sources. Recently, radiotherapy has emerged as one of the most common therapies against cancer. Co-60 irradiators (cobalt-60 linear accelerators) are used to treat of malignant tumors routinely in hospitals around the world. Exposure to ionizing radiation can induce changes in cellular macromolecules and affect its functions, because they cause radiolysis of the water molecule generating reactive oxygen species, which can cause damage to virtually all organelles and cell components known as oxidative damage that can culminate in oxidative stress. Oxidative stress is a situation in which the balance between oxidants and antioxidants is broken resulting in excessive production of reactive species, it is not accompanied by the increase in antioxidant capacity, making it impossible to neutralize them. Selenium is a micronutrient considered as antioxidant, antiinflammatory, which could prevent cancer. Selenium in biological system exists as seleno proteins. Nowadays, 25 human seleno proteins have been identified, including glutathione peroxidase, an antioxidant enzyme. Yeasts have the ability to incorporate various metals such as iron, cadmium, zinc and selenium, as well as all biological organisms. The yeast Saccharomyces cerevisiae, unlike mammalian cells is devoid of seleno proteins, being considered as a practical model for studies on the toxicity of selenium, without any interference from the metabolism of seleno proteins. Moreover, yeast cells proliferate through the fermentation, the microbial equivalent of aerobic glycolysis in mammals and the process is also used by tumors. Several reports show that the pro-oxidante effects and induced toxic selenium compounds occur at lower doses and in malignant cells compared with benign cells. Therefore selenium giving a great therapeutic potential in cancer treatment .Our objective was to determine whether selenium is capable to sensitize yeasts

  3. The p53 gene as a modifier of intrinsic radiosensitivity: implications for radiotherapy

    International Nuclear Information System (INIS)

    Background and purpose: Experimental studies have implicated the normal or 'wild type' p53 protein (i.e. WTp53) in the cellular response to ionizing radiation and other DNA damaging agents. Whether altered WTp53 protein function can lead to changes in cellular radiosensitivity and/or clinical radiocurability remains an area of ongoing study. In this review, we describe the potential implications of altered WTp53 protein function in normal and tumour cells as it relates to clinical radiotherapy, and describe novel treatment strategies designed to re-institute WTp53 protein function as a means of sensitizing cells to ionizing radiation. Methods and Materials: A number of experimental and clinical studies are critically reviewed with respect to the role of the p53 protein as a determinant of cellular oncogenesis, genomic stability, apoptosis, DNA repair and radioresponse in normal and transformed mammalian cells. Results: In normal fibroblasts, exposure to ionizing radiation leads to a G1 cell cycle delay (i.e. a 'G1 checkpoint') as a result of WTp53-mediated inhibition of G1-cyclin-kinase and retinoblastoma (pRb) protein function. The G1 checkpoint response is absent in tumour cells which express a mutant form of the p53 protein (i.e. MTp53), leading to acquired radioresistance in vitro. Depending on the cell type studied, this increase in cellular radiation survival can be mediated through decreased radiation-induced apoptosis, or altered kinetics of the radiation-induced G1 checkpoint. Recent biochemical studies support an indirect role for the p53 protein in both nucleotide excision and recombinational DNA repair pathways. However, based on clinicopathologic data, it remains unclear as to whether WTp53 protein function can predict for human tumour radiocurability and normal tissue radioresponse. Conclusions: Alterations in cell cycle control secondary to aberrant WTp53 protein function may be clinically significant if they lead to the acquisition of mutant

  4. Association between SNPs in defined functional pathways and risk of early or late toxicity as well as individual radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Reuther, Sebastian; Raabe, Annette; Borgmann, Kerstin; Dikomey, Ekkehard [University Medical Center Hamburg-Eppendorf, Laboratory of Radiobiology and Experimental Radiooncology, Department of Radiotherapy and Radiooncology, Hamburg (Germany); Szymczak, Silke [University at Luebeck, Institute of Medical Biometry and Statistics, University Medical Center Schleswig-Holstein (Germany); Christian-Albrechts-University Kiel, Institute of Clinical Molecular Biology, Kiel (Germany); Ziegler, Andreas [University at Luebeck, Institute of Medical Biometry and Statistics, University Medical Center Schleswig-Holstein (Germany); University of Luebeck, Center for Clinical Trials, Luebeck (Germany); Petersen, Cordula [University Medical Center Hamburg-Eppendorf, Clinic of Radiotherapy and Radiooncology, Hamburg (Germany); Hoeller, Ulrike [Charite Universitaetsmedizin Berlin, Department of Radiotherapy, Berlin (Germany)

    2014-08-26

    The aim of this study was to determine the impact of functional single nucleotide polymorphism (SNP) pathways involved in the ROS pathway, DNA repair, or TGFB1 signaling on acute or late normal toxicity as well as individual radiosensitivity. Patients receiving breast-conserving surgery and radiotherapy were examined either for erythema (n = 83), fibrosis (n = 123), or individual radiosensitivity (n = 123). The 17 SNPs analyzed are involved in the ROS pathway (GSTP1, SOD2, NQO1, NOS3, XDH), DNA repair (XRCC1, XRCC3, XRCC6, ERCC2, LIG4, ATM) or TGFB signaling (SKIL, EP300, APC, AXIN1, TGFB1). Associations with biological and clinical endpoints were studied for single SNPs but especially for combinations of SNPs assuming that a SNP is either beneficial or deleterious and needs to be weighted. With one exception, no significant association was seen between a single SNP and the three endpoints studied. No significant associations were also observed when applying a multi-SNP model assuming that each SNP was deleterious. In contrast, significant associations were obtained when SNPs were suggested to be either beneficial or deleterious. These associations increased, when each SNP was weighted individually. Detailed analysis revealed that both erythema and individual radiosensitivity especially depend on SNPs affecting DNA repair and TGFB1 signaling, while SNPs in ROS pathway were of minor importance. Functional pathways of SNPs may be used to form a risk score allowing to predict acute and late radiation-induced toxicity but also to unravel the underlying biological mechanisms. (orig.) [German] Fuer ein SNP-Netzwerk (''single nucleotide polymorphism'', Einzelnukleotidpolymorphismus), welches im ROS-Signalweg, an der DNA-Reparatur und im TGFB1-Signalweg involviert ist, sollen die Bedeutung fuer die akute und spaete Toxizitaet sowie die individuelle Strahlenempfindlichkeit bestimmt werden. Nach Strahlentherapie wurden Brustkrebspatientinnen entweder

  5. 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.)

  6. Heat shock transcription factor1gene silenced with RNAi to enhance radio-sensitivity of cervical carcinoma cell

    International Nuclear Information System (INIS)

    In order to suppress HSF1 gene expression using RNA interference technique and explore the changes of the radiation sensitivity of cervical carcinoma cells, HSF1-pSilencer2.1-U6neo for siRNA expression was transfected into cervical carcinoma cells by lipofectamine. HSF1mRNA expression was detected by real time poly- merase chain reaction and flow cytometry was employed to evaluate HSFlprotein expression. In addiction, the radiation sensitivity of cervical carcinoma cells was assessed by clone forming assay. The results show that HSF1mRNA expression of the cells transfected HSF1A-pSilencer2.1-U6neo descends obviously compared with control. Mean- while the radiation sensitivity of Hela cells increases with the descension of HSF1 gene expression. Experiment has been confirmed that siRNA plasmid expression vector HSF1A-pSilencer2.1-U6neo successfully suppresses HSF1gene expression. Plasmid expression vector of HSF1 gene siRNA can be use to enhance the radio-sensitivity of cervical carcinoma cells and may be used as a powerfully adjunct method for conventional radiotherapy. (authors)

  7. Radiosensitivity and capacity for radiation-induced sublethal damage repair of canine transitional cell carcinoma (TCC) cell lines.

    Science.gov (United States)

    Parfitt, S L; Milner, R J; Salute, M E; Hintenlang, D E; Farese, J P; Bacon, N J; Bova, F J; Rajon, D A; Lurie, D M

    2011-09-01

    Understanding the inherent radiosensitivity and repair capacity of canine transitional cell carcinoma (TCC) can aid in optimizing radiation protocols to treat this disease. The objective of this study was to evaluate the parameters surviving fraction at 2 Gy (SF(2) ), α/β ratio and capacity for sublethal damage repair (SLDR) in response to radiation. Dose-response and split-dose studies were performed using the clonogenic assay. The mean SF(2) for three established TCC cell lines was high at 0.61. All the three cell lines exhibited a low to moderate α/β ratio, with the mean being 3.27. Two cell lines exhibited statistically increased survival at 4 and 24 h in the dose-response assay. Overall, our results indicate that the cell lines are moderately radioresistant, have a high repair capacity and behave similarly to a late-responding normal tissue. These findings indicate that the radiation protocols utilizing higher doses with less fractionation may be more effective for treating TCC.

  8. WAF1 induction and infection by HPV E6 as a determinants of radiosensitivity in human cervical cancer

    Energy Technology Data Exchange (ETDEWEB)

    Harima, Yoko; Oka, Atsutoshi; Harima, Keizo; Tanaka, Yoshimasa [Kansai Medical Univ., Moriguchi, Osaka (Japan)

    1998-02-01

    To establish a new predictor of outcome for human cervical carcinoma treatment, the relationship between WAF1 mRNA levels during treatment, human papilloma virus (HPV) infection and tumor radiosensitivity were investigated. Forty patients with uterine cervical carcinoma were treated with definitive radiotherapy. Only those patients who beard wild-type p53 were included into present clinical trial. p53 status was investigated using SSCP analysis. HPV E6 was determined by PCR, WAF1 mRNA was estimated by RT-PCR. Twenty-one patients achieved complete response (CR), 11 patients achieved partial response (PR), and 8 patients had no change (NC). The increase in WAF1 mRNA after irradiation at 10.8 Gy positively correlated both with better treatment response and improved survival. Although the infection by HPV did not directly influence on the survival rate, it decreased the inducibility of WAF1. p53-dependent activation of WAF1 gene expression during treatment may be a strong determinant of the efficacy of cervical cancer radiotherapy. (author)

  9. Rad51C deficiency destabilizes XRCC3, impairs recombination and radiosensitizes S/G2-phase cells

    Energy Technology Data Exchange (ETDEWEB)

    Lio, Yi-Ching; Schild, David; Brenneman, Mark A.; Redpath, J. Leslie; Chen, David J.

    2004-05-01

    The highly conserved Rad51 protein plays an essential role in repairing DNA damage through homologous recombination. In vertebrates, five Rad51 paralogs (Rad51B, Rad51C, Rad51D, XRCC2, XRCC3) are expressed in mitotically growing cells, and are thought to play mediating roles in homologous recombination, though their precise functions remain unclear. Here we report the use of RNA interference to deplete expression of Rad51C protein in human HT1080 and HeLa cells. In HT1080 cells, depletion of Rad51C by small interfering RNA caused a significant reduction of frequency in homologous recombination. The level of XRCC3 protein was also sharply reduced in Rad51C-depleted HeLa cells, suggesting that XRCC3 is dependent for its stability upon heterodimerization with Rad51C. In addition, Rad51C-depleted HeLa cells showed hypersensitivity to the DNA cross-linking agent mitomycin C, and moderately increased sensitivity to ionizing radiation. Importantly, the radiosensitivity of Rad51C-deficient HeLa cells was evident in S and G{sub 2}/M phases of the cell cycle but not in G{sub 1} phase. Together, these results provide direct cellular evidence for the importance of human Rad51C in homologous recombinational repair.

  10. Downregulation of cell division cycle 25 homolog C reduces the radiosensitivity and proliferation activity of esophageal squamous cell carcinoma.

    Science.gov (United States)

    Yin, Yachao; Dou, Xiaoyan; Duan, Shimiao; Zhang, Lei; Xu, Quanjing; Li, Hongwei; Li, Duojie

    2016-09-30

    Radiation therapy is one of the most important methods of contemporary cancer treatment. Cells in the G2 and M phases are more sensitive to radiation therapy, and cell division cycle 25 homolog C (CDC25C) is essential in shifting the cell cycle between these two phases. In this study, the knockdown of CDC25C in human esophageal squamous carcinoma EC9706 cells was mediated by transfecting shRNA against human CDC25C-subcloning into pGV248. The levels of CDC25C mRNA and protein expression were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and western blotting, respectively. Moreover, cell proliferation and radiosensitivity were measured. Stable CDC25C-knockdown EC9706 cell lines were successfully established. Furthermore, the proliferation of both control and CDC25C-shRNA-EC9706 cells was inhibited after the cells were treated with increasing X-ray doses, and the proliferation of the control cells was affected more significantly (p<0.05). Moreover, cell colony formation assays allowed us to reach the same conclusion. Taken together, our experiments demonstrated that the knockdown of CDC25C can reduce both the radiotherapy sensitivity and the proliferation activity of EC9706 cells. Thus, CDC25C might be a potential biomarker for radiotherapy treatment. PMID:27188256

  11. In vivo tumor inhibitory and radiosensitizing effects of an Indian medicinal plant, Plumbago rosea on experimental mouse tumors

    International Nuclear Information System (INIS)

    Tumor growth inhibitory and radiosensitizing effects of the alcoholic root extract of P. rosea was studied on experimental mouse tumors, S-180 solid tumor and Ehrlich ascites carcinoma in vivo. Intraperitoneal injection of 50 mg/kg of plumbago extract (PE) for 10 days starting from 24 hr after intradermal inoculation of S-180 cells in BALB/c mice produced about 16% complete response (CR). The CR% increased with increase in drug dose, to 50% at 100 mg/kg for 10 days. As 100 mg/kg produced toxic side effects, lower doses were used with other treatment modalities, radiation (RT) and hyperthermia (HT). Treatment of 50 mm3 tumor with PE (75 mg/kg) for 10 days with local RT (10 Gy) and/or HT (43 degC, 30 min) subadditively increased the CR% and tumor free survival. The combination also significantly reduced the growth rates of uncured tumors. The PE significantly reduced the tumor glutathione content and this effect was markedly enhanced by the combination of the three modalities. PE alone was not very effective in preventing the growth of Ehrlich ascites carcinoma in Swiss mice, though it increased mean survival time and increase in life span (ILS%) of the mice. But with radiation it produced a synergistic effect in increasing the tumor inhibition and 120 day animal survival from 10% to 50%. The results demonstrate that though PE may have only a weak antitumor effect, it may be a good candidate for use with radiation to enhance the tumor killing effect. (author). 13 refs., 3 figs., 4 tabs

  12. Use of halogenated thymidine analogs as clinical radiosensitizers: rationale, current status, and future prospects: non-hypoxic cell sensitizers

    International Nuclear Information System (INIS)

    The halogenated pyrimidine analogs, bromodeoxyuridine (BUdR) and iododeoxyuridine (IUdR) have been recognized as potential clinical radiosensitizers for over two decades. In vivo and in vitro experimental studies document that radiosensitization is directly dependent on the amount of thymidine replacement in DNA by these analogs. Based on recent in vivo and clinical pharmacology studies on continuous intravenous infusions of these drugs, clinical trials are underway evaluating the potential of radiosensitization in high grade gliomass and other poorly radioresponsive tumors using the technically safer intravenous route of administration. In this paper, the authors review the basic strategy for the use of these analogs, the ongoing clinical trials and the potential areas for future experimental and clinical studies

  13. Silencing of microRNA-21 confers radio-sensitivity through inhibition of the PI3K/AKT pathway and enhancing autophagy in malignant glioma cell lines.

    Directory of Open Access Journals (Sweden)

    Ho-Shin Gwak

    Full Text Available Radiation is a core part of therapy for malignant glioma and is often provided following debulking surgery. However, resistance to radiation occurs in most patients, and the underlying molecular mechanisms of radio-resistance are not fully understood. Here, we demonstrated that microRNA 21 (miR-21, a well-known onco-microRNA in malignant glioma, is one of the major players in radio-resistance. Radio-resistance in different malignant glioma cell lines measured by cytotoxic cell survival assay was closely associated with miR-21 expression level. Blocking miR-21 with anti-miR-21 resulted in radio-sensitization of U373 and U87 cells, whereas overexpression of miR-21 lead to a decrease in radio-sensitivity of LN18 and LN428 cells. Anti-miR-21 sustained γ-H2AX DNA foci formation, which is an indicator of double-strand DNA damage, up to 24 hours and suppressed phospho-Akt (ser473 expression after exposure to γ-irradiation. In a cell cycle analysis, a significant increase in the G₂/M phase transition by anti-miR-21 was observed at 48 hours after irradiation. Interestingly, our results showed that anti-miR-21 increased factors associated with autophagosome formation and autophagy activity, which was measured by acid vesicular organelles, LC3 protein expression, and the percentage of GFP-LC3 positive cells. Furthermore, augmented autophagy by anti-miR-21 resulted in an increase in the apoptotic population after irradiation. Our results show that miR-21 is a pivotal molecule for circumventing radiation-induced cell death in malignant glioma cells through the regulation of autophagy and provide a novel phenomenon for the acquisition of radio-resistance.

  14. [Enhanced radiosensitivity of H22 ascitic tumor to 12C6+ ions radiation in ultra-filtration extract mixture from Astragalus mongholicus-treated mice].

    Science.gov (United States)

    Wang, Bin-bin; Wang, Xiao-hu; Liu, Kai; Sun, Shao-bo; Song, Peng; Li, Ying-dong

    2015-12-01

    This study was designed to investigate the impact of ultra-filtration extract mixture from Astragals mongholicus (UEMAM) o radiosensitivity of H22 ascitic tumor in mice to 12C6+ ions radiation. The H22 ascitic tumor model was established in mice by intraperitoneal injection of 0.2 mL H22 ascitic cells. The animals were subsequently divided into 4 groups randomly, treated with normal saline, UEMAM, heavy ion beam radiotherapy and UEMAM plus heavy ion beam radiotherapy, respectively. The body weights, abdomen circumference of the mice were measured and the mouse behavior was monitored every day; survival time was recorded to evaluate life extension effect; flow cytometry technique was used to detect H22 cell apoptosis and cell cycle; protein levels of p53, Bax, Bcl-2 and cleaved Caspase-3 were analyzed by Western blot; the single cell gel electrophoresis was used to detect the level of deoxyribonucleic acid damage (DNA damage). The results suggest that UEMAM significantly increased survival time, and decreased body weights and abdomen circumference over the saline control group. The treatment increased cell apoptosis, cycle arrest and DNA damage compared to the saline control group. UEMAM significantly enhanced the therapeutic effect of heavy ion beam radiation in survival time, and decreased body weights and abdomen circumference in the tumor-baring mice. The combination increased cell apoptosis, cycle arrest and DNA damage compared to the radiotherapy group. The results of Western blot suggest that the treatment significantly enhanced p53-induced apoptotic signals. The experiment discovered that UEMAM could improve radiosensitivity of H22 ascitic tumor through activation of p53-mediated apoptotic signal pathway. PMID:27169282

  15. Evaluation of different biomarkers to predict individual radiosensitivity in an inter-laboratory comparison--lessons for future studies.

    Directory of Open Access Journals (Sweden)

    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

  16. A novel approach to sensitize solid tumor to radiosurgery by using hypoxic and proliferating-cell radiosensitizers

    International Nuclear Information System (INIS)

    There are two types of radiosensitizers have been used for clinical trial. Namely, halogenated pyrimidine (e.g. 5-iododeoxyuridine (IUdR)), and hypoxic cell radiosensitizers (e.g. misonidazole (MISO), etanidazole, etc.). However, there is no report of simultaneous application of these two radiosensitizers in research and clinical radiotherapy. In recent years, single dose stereotatic radiosurgery has been used for controlling metastatic lesions in the brain. In these lesions are composing of aerated cycling and hypoxic resting tumor cells. We proposed to used the above two types of radiosensitizers to enhance tumor control probability of the stereotactic radiosurgery. In this study, drugs such as IUdR and MISO were selected and C3H/HeN mice bearing KHT sarcoma were used for evaluation of biodistribution and effectiveness of these two radiosensitizers. The biodistribution of these two drugs was studied using gamma counting and autoradiographic techniques. The optimal effectiveness of these two drugs combined with radiation was evaluated by in vivo - in vitro clonogenic assay system. The biodistribution data obtained from gamma counting was similar to that obtained from autoradiography. Although the clearance rates of [131I] IUdR and [18F] FMISO were very rapid, the incorporation of [131I] IUdR into DNA of KHT sarcoma cells was very stable from 0.5 to 24 hours. The biodistribution of [131I] IUdR and [18F] FMISO as shown by macroautoradiography appeared that they were incorporated/bound to the different areas of the tumor. At 2 hours after quartic injection of IUdR followed by a single injection of MISO appears to be the optimal time for the combination with radiation. The enhancement ratio for MISO, IUdR and MISO + IUdR combined with radiation were 1.2, 1.3 and 1.55 respectively. These results demonstrated for the first time that a maximum radiosensitization effect was occurred using the above method of combination

  17. α-Solanine Modulates the Radiosensitivity of Esophageal Cancer Cells by Inducing MicroRNA 138 Expression

    Directory of Open Access Journals (Sweden)

    Yuanyuan Wang

    2016-08-01

    Full Text Available Background: Esophageal cancer (EC is one of the most common malignant tumors in the world. Due to difficulties with performing the operation, most patients choose to have palliative treatment instead. Radiotherapy is one of the main palliative treatments of EC. However, the clinical efficacy of radiotherapy is not satisfactory α-Solanine is a bioactive component of steroidal glycoalkaloids which has been demonstrated to exhibit anti-metastasis activity in different cancers. In the present study, we determined the effect of α-solanine on the radiosensitivity of EC cells and priliminarily explored the underlying molecular mechanisms. Methods: Cell Counting Kit-8 (CCK-8 assay was conducted to found the cytotoxic effect of α-solanine on EC cells. CCK-8 assay and colony-forming survival assays were performed to explore the effect of α-solanine on cell viability and proliferation of EC cells after irradiation. Immunofluorescence and comet assays were used to detect the effect of α-solanine on DNA repair capacity of EC cells after irradiation. The flow cytometry (FCM and Hoechst/PI staining were conductd to study the effect of α-solanine on apoptosis of EC cells after irradiation. Results: The cytotoxic effect of α-solanine to EC cells was dose-dependent. The results of CCK-8, colony-forming survival assay, immunofluorescence, comet assay, FCM and Hoechst/PI staining showed that α-solanine could enhance the radiosensitivity of EC cells. α-Solanine could downregulate Survivin expression level by upregulating miR-138 expression in EC cells. Upregulation of miR-138 and knock down Survivin both enhanced the radiosensitivity of EC cells. Moreover, Survivin could restore the effect of α-solanine and miR-138 on radiosensitivity of EC cells. Conclusions: α-solanine could enhance the radiosensitivity of esophageal cancer cells by inducing microRNA-138 expression, and probably be an effective radiosensitizer in treating EC.

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

    International Nuclear Information System (INIS)

    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

  19. Influence of biological and ecological factors on the radio-sensitivity of laboratory animals

    International Nuclear Information System (INIS)

    The biological and ecological factors liable to induce a change in the radio-sensitivity of a species are undoubtedly responsible for the large fluctuations observed during radio-biological experiments. It is easy to limit or to suppress the effects of some of them (genetic or nutritional factors). Since the research worker cannot control the others it is necessary to take them into account. In this report the authors analyse the action of two factors chosen as examples: - the first concerns biological rhythms; - the second attempts to define the role of health conditions. Other factors will be dealt with in a later report. (authors)

  20. Radiosensitization of Escherichia coli and Salmonella typhi in presence of active compounds

    Science.gov (United States)

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

    2004-09-01

    The radiosensitization of Escherichia coli and Salmonella typhi in ground beef was evaluated in the presence of 18 active compounds. Medium fat ground beef (23% fat) was inoculated with E. coli or S. typhi and each active compound was added separately at various concentrations. For E. coli, the most efficient compounds were trans-cinnamaldehyde, thymol and thyme. For S. typhi, the most efficient compounds was trans-cinnamaldehyde, carvacrol and thymol. The addition of tetrasodium pyrophosphate, carvacrol and ascorbic acid had no effect on the irradiation sensitivity of E. coli. For S. typhi, only ascorbic acid had no effect.

  1. Radiosensitization of Escherichia coli and Salmonella typhi in presence of active compounds

    Energy Technology Data Exchange (ETDEWEB)

    Lacroix, M. E-mail: monique.lacroix@inrs-iaf.uquebec.ca; Chiasson, F.; Borsa, J.; Ouattara, B

    2004-10-01

    The radiosensitization of Escherichia coli and Salmonella typhi in ground beef was evaluated in the presence of 18 active compounds. Medium fat ground beef (23% fat) was inoculated with E. coli or S. typhi and each active compound was added separately at various concentrations. For E. coli, the most efficient compounds were trans-cinnamaldehyde, thymol and thyme. For S. typhi, the most efficient compounds was trans-cinnamaldehyde, carvacrol and thymol. The addition of tetrasodium pyrophosphate, carvacrol and ascorbic acid had no effect on the irradiation sensitivity of E. coli. For S. typhi, only ascorbic acid had no effect.

  2. EGFR-dependent Impact of Indol-3-Carbinol on Radiosensitivity 
of Lung Cancer Cells

    OpenAIRE

    Xiao, Xiao(Institute for Strings, Cosmology and Astroparticle Physics (ISCAP) and Physics Department, Columbia University, 538 West 120th Street, New York, NY, 10027 U.S.A.); Meng, Qinghui; Xu, Jiaying; Jiao, Yang; Rosen, Eliot M.; Fan, Saijun

    2012-01-01

    Background and objective Indole-3-carbinol (I3C) is a naturally occurring phytochemical found in cruciferous vegetables. The aim of the present study is to investigate the influence of I3C on radiosensitivity in epidermal growth factor receptor (EGFR)-positive and EGFR-negative lung cancer cell lines. Methods Human lung adenocarcinoma NIH-H1975 cells and human lung squamous carcinoma NIH-H226 and NIH-H520 cells were routinely cultured in RPMI-1640. MTT assay and clonogenic assay were used to ...

  3. Nano-diamond as a multimodal platform for drug delivery and radiosensitization of tumor cells

    International Nuclear Information System (INIS)

    Nano-diamonds (NDs) are often considered as inert platforms with high interests for biomedical applications. They are well adapted for drug delivery, and may display embedded fluorescence. We report here on a new way to consider these nano-carbon particles, by revealing therapeutic capacities coming from electronic properties of NDs. With an optimized surface chemistry, the generation of Reactive Oxygen Species (ROS) occurs when those hydrogen-terminated NDs are exposed to photon irradiation, thus opening up the field towards the radiosensitization of tumor cells. (authors)

  4. Evaluation of the single radiosensitivity in patients subjected to medical exposure that show severe skin reactions

    International Nuclear Information System (INIS)

    The Burnt Hospital of the Buenos Aires City Government (HQGCBA) it is a hospital of reference of the Net of Medical Responses in Radiological Emergencies of the Argentine Republic. In the mark of an agreement among the HQGCBA and the Authority Regulatory Nuclear (ARN), it is in execution a study protocol for the one boarding diagnoses and therapeutic of radioinduced cutaneous leisure. They exist individual variations that can condition the response to the ionizing radiations (IR), so much in accidental exposures as having programmed (radiotherapy, radiology interventionist). In this context, the individual radiosensitivity is evaluated in the patients signed up in this protocol that presented sharp or late cutaneous reactions, with grades of severity 3-4 (approaches EORTC/RTOG). The capacity of repair of the DNA was evaluated in outlying blood lymphocytes irradiated in vitro (2 Gy, gamma of Co-60) by means of the micronucleus techniques and comet essay in alkaline conditions. In this work two cases in those that is applied this study protocol, the therapeutic answer and its correlate with the discoveries of the radiosensitivity tests is presented. Case 1: patient of feminine sex, subjected to external radiotherapy by a breast infiltrating ductal carcinoma; developed sharp cutaneous radiotoxicity grade 3 (confluent humid epithelitis) that motivate the interruption of the treatment. Case 2: patient of masculine sex, subjected to a coronary angioplasty (interventionist radiology); developed late cutaneous radiotoxicity grade 4 (ulceration in dorsal region). Both patients were treated with topical trolamine associated to systemic administration of pentoxiphiline and antioxidants. The therapeutic answer is evaluated by means of clinical pursuit, photographic serial register and complementary exams (thermography and ultrasonography of high frequency). In the case 1 the answer was very favorable, with precocious local improvement and complete remission of symptoms and

  5. Radiosensitivity of marrow stromal cells and the effect of some radioprotective agents

    International Nuclear Information System (INIS)

    The results showed that marrow stromal cells include fibroblasts, reticular cells, macrophages and adipocytes. The capability of the adherent layer derived from marrow cells of 2 mouse femurs to support hematopoietic stem cells was stronger than those of layers derived from 0.5 or 1 mouse femurs. The radiosensitivity of bone marrow stromal cells was lower than that of hematopoietic stem cells. The radioprotective effect of AET and PLP (polysaccharide of Lobaria Pulmonaria Hoffm) on the bone marrow stromal cells and their capability to support hematopoietic stem cells was clearly demonstrated

  6. The radiosensitivity of alfalfa varieties and the fuzzy concentration analysis

    International Nuclear Information System (INIS)

    The dried alfalfa seeds (12.1% moisture) were exposed to 6'0Co γ radiation field with 0∼36.1 C/kg radiation doses (irradiation rate is 2.84 x 10-2 C/(kg·min)) to observe and measure some radio-bio-effectivity. In the range of irradiation doses, vitality index, root length, seedling survival rate, seedling height, plant height and grass yield decreased and pollen sterility, micro-nucleus rate, free radical relative content increased as the amount of radiation increased. The activity of peroxidase increased as the amount of radiation increased within certain range of dose and tended to decreased beyond that range. Vitality index and root length, which dosage effect curve is compatible with multiple targets-single hit model, and seedling survival rate, seedling height, plant height and grass yield, which dosage effect curve is compatible with linear regression model. There were strong co-relations between the seedling height, micro-nucleus cell rate and the free radical relative content (P<0.01). There were very significant difference (P<0.01) between the alfalfa species and varieties. With fuzzy concentration analysis method, the alfalfa sample were classified into five groups: higher sensitive, sensitive, intermediate, resistant, higher resistant. The suitable irradiation doses for the alfalfa species and varieties are between 12.9∼34.8 mCi/kg

  7. In vitro studies on radiosensitization effect of glucose capped gold nanoparticles in photon and ion irradiation of HeLa cells

    Science.gov (United States)

    Kaur, Harminder; Pujari, Geetanjali; Semwal, Manoj K.; Sarma, Asitikantha; Avasthi, Devesh Kumar

    2013-04-01

    Noble metal nanoparticles are of great interest due to their potential applications in diagnostics and therapeutics. In the present work, we synthesized glucose capped gold nanoparticle (Glu-AuNP) for internalization in the HeLa cell line (human cervix cancer cells). The capping of glucose on Au nanoparticle was confirmed by Raman spectroscopy. The Glu-AuNP did not show any toxicity to the HeLa cell. The γ-radiation and carbon ion irradiation of HeLa cell with and without Glu-AuNP were performed to evaluate radiosensitization effects. The study revealed a significant reduction in radiation dose for killing the HeLa cells with internalized Glu-AuNPs as compared to the HeLa cells without Glu-AuNP. The Glu-AuNP treatment resulted in enhancement of radiation effect as evident from increase in relative biological effectiveness (RBE) values for carbon ion irradiated HeLa cells.

  8. MicroRNA-148b enhances the radiosensitivity of non-Hodgkin's Lymphoma cells by promoting radiation-induced apoptosis

    OpenAIRE

    Wu, Y.; Liu, G.-L.; Liu, S.-H.; Wang, C.-X.; Xu, Y.-L.; Ying, Y; Mao, P.

    2012-01-01

    Growing evidence has demonstrated that microRNAs (miRNAs) play an important role in regulating cellular radiosensitivity. This study aimed to explore the role of miRNAs in non-Hodgkin's lymphoma (NHL) radiosensitivity. Microarray was employed to compare the miRNA expression profiles in B cell lymphoma cell line Raji before and after a 2-Gy dose of radiation. A total of 20 differentially expressed miRNAs were identified including 10 up-regulated and 10 down-regulated (defined as P 

  9. Cysteine but not glutathione modulates the radiosensitivity of human melanoma cells by affecting both survival and DNA damage.

    Science.gov (United States)

    Kinnaert, E; Duez, P; Morandini, R; Dubois, J; Van Houtte, P; Ghanem, G

    2004-06-01

    Glutathione (GSH) and its precursor cysteine (Cys) are both known to react within any cells with oxidative species and thus play an important role in cellular defense mechanisms against oxidative stress. In melanocytes, these are also important precursors of melanogenesis by reacting non-enzymatically with l-dopaquinone to form the sulfur-containing pheomelanin. Our aim was to assess pigment role in the cellular radioprotection mechanism using a human melanoma cell model of mixed-type melanin under GSH depletion to obtain a radiosensitizing effect. The latter has been achieved either by Cys deprivation or GSH specific depletion. We first compared cell survival of Cys-deprived and GSH-depleted cells vs. control cells. Cys deprivation was achieved by decreasing Cys concentration in the culture medium for 24 h. In this condition, no toxicity was observed, Cys and GSH levels decreased, melanogenesis switched to a higher eumelanin synthesis and cells were significantly more resistant to 10-Gy dose of ionizing radiations than untreated cells. Glutathione depletion was achieved with the gamma-glutamylcysteine synthetase inhibitor buthionine-S-sulfoximine (BSO) for 24 h at 50 microM, a concentration yielding no toxicity. In this condition, intracellular GSH level decreased but no change in pigmentation was observed and cells were slightly but significantly more sensitive to radiation than the control. We then compared DNA radio-induced damages by Comet assay in control cells, cells treated as above and cells with stimulated pigmentation by increasing Tyr concentration in the medium. Our results showed that, when intracellular eumelanin content increased, DNA damage decreased. By contrast, DNA damage increased in cells treated with BSO alone. It is concluded that increasing the intracellular eumelanin content by the melanin precursor Tyr or by favoring the Pheo- to Eumelanin switch, compensates for the loss of the two intracellular radioprotectors that are GSH and Cys. PMID

  10. 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.

  11. 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.)

  12. 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.

  13. 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

    2016-01-01

    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. PMID:27558808

  14. Metformin radiosensitization effect of low and high linear energy transfer radiation in HCC

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Ho; Jung, Won Gyun [Division of Heavy Ion Clinical Research, Korea University, Seoul (Korea, Republic of); Kim, Mi Sook; Cho, Chul Koo; Jeong, Youn Kyoung [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2014-04-15

    Metformin (1,1-dimethylbiguanide hydrochloride), the most widely used treatment for type 2 diabetes, provides a good tolerability profile and low cost and has recently sparked keen interest as a potential anticancer agent. Recent evidence has suggested Metformin provides a synergistic benefit with chemotherapy or radiotherapy against certain cancers in several clinical cohort studies.Treatment response rates are higher in patients treated with metformin in cohort studies of breast cancer treated with neoadjuvant chemotherapy in head and neck cancer treated with radiation and in esophageal cancer treated with chemoradiotherapy. As the sensitizing effect of Metformin in HCC has been characterized in vitro and in vivo, we investigated the radio-sensitizing effect of Metformin in HCC cells in combination with γ-ray (low LET) and neutron (high LET) radiation. The radiosensitizing effect of Metformin was much higher in neutron-irradiated than in γ -irradiated cell lines. Fortunately, Metformin had little effect on normal tissues. Our studies revealed no interaction between Metformin and radiation in normal hepatocytes. High LET radiation,including neutron and carbon ion, would produce more complicated and different cellular effects; indeed, the molecular biological mechanism of high LET radiation remains a topic of investigation.

  15. Size-dependent radiosensitization of PEG-coated gold nanoparticles for cancer radiation therapy

    CERN Document Server

    Zhang, Xiao-Dong; Shen, Xiu; Chen, Jie; Sun, Yuan-Ming; Liu, Pei-Xun; Liang, Xing-Jie

    2012-01-01

    Gold nanoparticles have been conceived as a radiosensitizer in cancer radiation therapy, but one of the important questions for primary drug screening is what size of gold nanoparticles can optimally enhance radiation effects. Herein, we perform in vitro and in vivo radiosensitization studies of 4.8, 12.1, 27.3, and 46.6 nm PEG-coated gold nanoparticles. In vitro results show that all sizes of the PEG-coated gold nanoparticles can cause a significant decrease in cancer cell survival after gamma radiation. 12.1 and 27.3 nm PEG-coated gold nanoparticles have dispersive distributions in the cells and have stronger sensitization effects than 4.8 and 46.6 nm particles by both cell apoptosis and necrosis. Further, in vivo results also show all sizes of the PEG-coated gold nanoparticles can decrease tumor volume and weight after 5 Gy radiations, and 12.1 and 27.3 nm PEG-coated gold nanoparticles have greater sensitization effects than 4.8 and 46.6 nm particles, which can lead to almost complete disappearance of the ...

  16. 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.)

  17. The radiosensitivities of 4 human tumor cell lines to p (35) Be neutron irradiation

    International Nuclear Information System (INIS)

    Objective: The difference of radiosensitivity of 4 human tumor cell lines to p(35)Be fast neutron and gamma ray was studied in order to provide basis for clinical therapy of tumors. Methods: The radiosensitivity of these cell lines after p(35)Be neutron or gamma ray irradiation was assayed with cell clonogenic survival assay. And the gamma ray-and p(35)Be neutron-induced DNA damage and its repair in human melanoma cells line WM9839 was studied by using the method of comet-electrophoresis assay. Results: The difference of D0(or SF2) after p(35)Be neutron irradiation between these 4 human tumor cell lines was smaller than that after gamma ray irradiation. The repair rate of DNA damage in WM9839 cells after 2 Gy fast-neutron irradiation was lower than that after 2 Gy γ-ray irradiation. The residual DNA damage at 180 min after neutron-irradiation was obviously severer than that after 2 Gy γ-ray irradiation. Conclusion: The fast neutron therapy may make up the defect of the low LET ray therapy, especially to those radioresistant tumor cells to low LET rays

  18. Radiosensitivity of toxigenic Aspergillus isolated from spices and destruction of aflatoxins by gamma-irradiation

    Science.gov (United States)

    Kume, Tamikazu; Ito, Hitoshi; Soedarman, Harsono; Ishigaki, Isao

    Radiosensitivities of Aspergillus flavus var columnaris isolated from spices were investigated. The D10 values and induction doses were 267-293 Gy and 75-165 Gy in wet conditions, respectively. In dry conditions, the survival curves were exponential and D10 values were 538-600 Gy. The survival curves of standard strain of A. parasiticus IFO 30179 were similar both in wet and dry conditions. The necessary dose of 8 kGy for the destruction of these toxigenic Aspergillus was calculated from these values. Two of 11 strains of A. flavus var columnaris produced aflatoxins and the content of B 1 was especially high. In the study of irradiation effect on aflatoxins produced on polished rice, aflatoxins G 1 and B 1 were more radiosensitive than G 2 and B 2. However, these aflatoxins were very stable to radiation and the dose required for destruction was found to be more than 500 kGy. It is therfore concluded that the decontamination of molds by irradiation is necessary prior to their production of aflatoxins.

  19. Cancer stem cells: The potential of carbon ion beam radiation and new radiosensitizers (Review).

    Science.gov (United States)

    Baek, Sung-Jae; Ishii, Hideshi; Tamari, Keisuke; Hayashi, Kazuhiko; Nishida, Naohiro; Konno, Masamitsu; Kawamoto, Koichi; Koseki, Jun; Fukusumi, Takahito; Hasegawa, Shinichiro; Ogawa, Hisataka; Hamabe, Atsushi; Miyo, Masaaki; Noguchi, Kozo; Seo, Yuji; Doki, Yuichiro; Mori, Masaki; Ogawa, Kazuhiko

    2015-11-01

    Cancer stem cells (CSCs) are a small population of cells in cancer with stem-like properties such as cell proliferation, multiple differentiation and tumor initiation capacities. CSCs are therapy-resistant and cause cancer metastasis and recurrence. One key issue in cancer therapy is how to target and eliminate CSCs, in order to cure cancer completely without relapse and metastasis. To target CSCs, many cell surface markers, DNAs and microRNAs are considered as CSC markers. To date, the majority of the reported markers are not very specific to CSCs and are also present in non-CSCs. However, the combination of several markers is quite valuable for identifying and targeting CSCs, although more specific identification methods are needed. While CSCs are considered as critical therapeutic targets, useful treatment methods remain to be established. Epigenetic gene regulators, microRNAs, are associated with tumor initiation and progression. MicroRNAs have been recently considered as promising therapeutic targets, which can alter the therapeutic resistance of CSCs through epigenetic modification. Moreover, carbon ion beam radiotherapy is a promising treatment for CSCs. Evidence indicates that the carbon ion beam is more effective against CSCs than the conventional X-ray beam. Combination therapies of radiosensitizing microRNAs and carbon ion beam radiotherapy may be a promising cancer strategy. This review focuses on the identification and treatment resistance of CSCs and the potential of microRNAs as new radiosensitizers and carbon ion beam radiotherapy as a promising therapeutic strategy against CSCs. PMID:26330103

  20. From bench to bedside: Experience of the glioblastoma model for the optimization of radiosensitization

    International Nuclear Information System (INIS)

    Despite significant progress in the treatment of glioblastoma, the prognosis of these radioresistant, invasive and hypoxic tumours remain dark. The constant relapse after treatment of this tumour is in part due to its intra-cellular but also micro-environmental radioresistance, largely controlled by growth factors and their receptors. The complexity of the biology of these tumours and the presence of numerous cross-talks between the pathways of these different growth factors can be in part responsible for the negative results obtained in clinical trials associating radiotherapy and targeted drugs designed without previous in vitro and in vivo studies validating the proof of concept of a specific target as key factor of radioresistance. In the aim to optimize the treatment of glioblastoma and to reduce the risks of failure of new trials, several laboratories and clinical departments are developing translational research in radiotherapy and radiobiology, validating in vitro and then in ortho-topic xenografts interesting targets, then studying the radiosensitizing effect of targeted drugs directed against these proteins, studying the mechanisms of action and resistance of these drugs, validating these proteins as predictive factors of response to radiotherapy in the patients, and then designing clinical trials, integrating metabolic or functional imaging and surrogate markers to better understand the mechanism of action of these associations. We describe in this article the main translational research axis developed for radiosensitizing glioblastoma, which our lab and department have pursued for several years. (author)

  1. The molecule HLA-G: radiosensitivity indicator of a human melanoma cell line

    International Nuclear Information System (INIS)

    The physiological and pathological relevance of the HLA-G molecule (non-classical Human Leukocyte Antigen) has been motif of important research studies. Its distribution is restricted to only few tissues. HLA-G takes part in the implantation after in vitro fecundation, in graft tolerance, in auto-immune diseases, and in tumoral immune escape. Its expression has been demonstrated in more than 30% of tumors of 15 different histological types. Gamma radiation modulates HLA-G expression at the cell surface. However, its involvement in tumoral radiosensitivity has not been demonstrated yet. The objective of this work was to demonstrate if the HLA-G molecule intervenes in the radiosensibility of human melanoma cells cultured in vitro. For this purpose we used the human melanoma cell line M8, which was transfected with the plasmid containing the HLA-G gene (M8 HLA-G+) or with the plasmid alone, without the HLA-G gene (M8 pc DNA). Both cell lines were irradiated with 0, 2, 5 y 10 Gy and in all cases survival frequency was determined with the clonogenic assay. We observed a significant reduction in M8 HLA-G+ survival with respect to M8 pc DNA for all irradiation doses and was independent of doses. These results, if confirmed in other histological types, could postulate the HLA-G molecule as a tumoral radiosensitivity marker. The specific mechanism involved in the radiosensibility modification exerted by HLA-G has not been elucidated yet. (authors)

  2. Icaritin synergistically enhances the radiosensitivity of 4T1 breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Jinsheng Hong

    Full Text Available Icaritin (ICT is a hydrolytic form of icariin isolated from plants of the genus Epimedium. This study was to investigate the radiosensitization effect of icaritin and its possible underlying mechanism using murine 4T1 breast cancer cells. The combination of Icaritin at 3 µM or 6 µM with 6 or 8 Gy of ionizing radiation (IR in the clonogenic assay yielded an ER (enhancement ratio of 1.18 or 1.28, CI (combination index of 0.38 or 0.19 and DRI (dose reducing index of 2.51 or 5.07, respectively. These strongly suggest that Icaritin exerted a synergistic killing (? effect with radiation on the tumor cells. This effect might relate with bioactivities of ICT: 1 exert an anti-proliferative effect in a dose- and time-dependent manner, which is different from IR killing effect but likely work together with the IR effect; 2 suppress the IR-induced activation of two survival paths, ERK1/2 and AKT; 3 induce the G2/M blockage, enhancing IR killing effect; and 4 synergize with IR to enhance cell apoptosis. In addition, ICT suppressed angiogenesis in chick embryo chorioallantoic membrane (CAM assay. Taken together, ICT is a new radiosensitizer and can enhance anti-cancer effect of IR or other therapies.

  3. Deficiency of DNA double-strand break repair and enhanced radiosensitivity in Tip60 silenced cells

    International Nuclear Information System (INIS)

    Objective: To investigate the effect of Tip60 on the cellular radiosensitivity,and to explore the related mechanism. Methods: siRNA and anacardic acid (AA, an inhibitor of Tip60 acetyltransferase) were used to inhibit Tip60 expression and its acetyltransferase activity, respectively. Radiosensitivity was analyzed by colony-forming ability assay. γ-H2AX foci were detected to analyze the DNA double-strand break (DSB). Immunoprecipitation was used to determine the interaction of proteins. Results: siRNA-mediated silencing of Tip60 led to enhanced sensitivity of U2OS cells at 1, 2 Gy after γ-ray irradiation, but had no significant effect at 4 Gy post-irradiation (t=3.364, 3.979, P<0.05).γ-H2AX foci detection indicated that Tip60 silencing resulted in a decreased capability of DNA double-strand break repair at 1, 4 and 8 h after irradiation (t=3.875, 3.183 and 3.175, respectively, P<0.05). The interaction of Tip60 and DNA-PKcs was prompted by ionizing radiation. Anacardic acid largely abrogated the phosphorylation of DNA-PKcs at T2609 site induced by irradiation. Conclusions: Tip60 plays a role in the cellular response to ionizing radiation-induced DNA damage through, at least in part, interacting with DNA-PKcs and regulating its phosphorylation. (authors)

  4. Radiosensitivity of skin fibroblasts from atomic bomb survivors with and without breast cancer

    International Nuclear Information System (INIS)

    Fibroblasts were established in vitro from skin biopsies obtained from 55 women and one man with or without breast cancer and with or without exposure to radiation from the atomic bomb explosion in Hiroshima. The radiosensitivity of these cells was evaluated by clonogenic assays after exposure to X rays or to fission neutrons from a 252Cf source. Data were fitted to a multitarget model, S/S0 = A[1-(1-ekD)N], for both X-ray and neutron dose-survival curves. A single-hit model, S/S0 = AekD, fits the neutron dose-survival responses as well. These was no difference in the means or variances of radiosensitivity between exposed and nonexposed groups, or between patients with or without breast cancer. Hence, although the sample is not large, it provides no support for the hypothesis that A-bomb radiation preferentially induces breast cancer in women whose cells in vitro are sensitive to cell killing by radiation. (author)

  5. LET-dependent radiosensitization effects of gold nanoparticles for proton irradiation

    Science.gov (United States)

    Li, Sha; Penninckx, Sébastien; Karmani, Linda; Heuskin, Anne-Catherine; Watillon, Kassandra; Marega, Riccardo; Zola, Jerome; Corvaglia, Valentina; Genard, Geraldine; Gallez, Bernard; Feron, Olivier; Martinive, Philippe; Bonifazi, Davide; Michiels, Carine; Lucas, Stéphane

    2016-11-01

    The development of new modalities and protocols is of major interest to improve the outcome of cancer treatment. Given the appealing physical properties of protons and the emerging evidence of biological relevance of the use of gold nanoparticles (GNPs), the radiosensitization effects of GNPs (5 or 10 nm) have been investigated in vitro in combination with a proton beam of different linear energy transfer (LET). After the incubation with GNPs for 24 h, nanoparticles were observed in the cytoplasm of A431 cells exposed to 10 nm GNPs, and in the cytoplasm as well as the nucleus of cells exposed to 5 nm GNPs. Cell uptake of 0.05 mg ml‑1 of GNPs led to 0.78 pg Au/cell and 0.30 pg Au/cell after 24 h incubation for 10 and 5 nm GNPs respectively. A marked radiosensitization effect of GNPs was observed with 25 keV μm‑1 protons, but not with 10 keV μm‑1 protons. This effect was more pronounced for 10 nm GNPs than for 5 nm GNPs. By using a radical scavenger, a major role of reactive oxygen species in the amplification of the death of irradiated cell was identified. All together, these results open up novel perspectives for using high-Z metallic NPs in protontherapy.

  6. Role of novel anticancer drug Roscovitine on enhancing radiosensitivity in carcinoma cell lines

    International Nuclear Information System (INIS)

    The present study was conducted to evaluate the radiosensitization effect of Roscovitine (cyclin dependent kinase inhibitor) in carcinoma cell lines. Three cell lines are used (HepG2 liver carcinoma cell line, U251 brain carcinoma cell line, H460 Lung carcinoma cell line) in this study .cells were treated with Roscovitine in different concentrations ranging from 0.1μM to 100 μM before exposure to radiation doses ranging from 0.5 Gy to 20 Gy according to each experiment. The cell viability by MTT assay, The cell cycle analysis by flow cytometry and DNA fragmentation repair mechanism by diphenylamine were measured after Roscovitine treatment with or without radiation to explore the sensitization effect of Roscovitine. The present study conclude that Roscovitine a good candidate as radiosensitizer for modifying the ionizing radiation (IR) response in cancer cells, beside its cyclin dependent kinase inhibitor function, roscovitine can generate DNA Double strand Breaks and cooperate to enhance IR induce DNA damages . Roscovitine is currently in clinical trials, although our findings suggest that the combination of Roscovitine with IR appears to be a very promising especially for liver, brain and lung cancer treatment, further investigation is needed to evaluate the therapeutic index before tested in clinical trial

  7. Modulation of radiosensitivity of biological systems by medicinal herbs

    International Nuclear Information System (INIS)

    The global environmental pollution is responsible for the exposure of living beings to the influence of various technogenic factors, including ionizing radiation. Exposure to such radiation represents a genuine, increasing threat to mankind and our environment. The steadily increasing applications of radiation in clinical practice, industrial and agricultural activities, residual radio-activity resulting from nuclear test explosions, have a measurable impact contributing to significant radiation hazards in humans. Further, the proliferation of terrorism and asymmetric warfare in the 21st century has rendered the modern world a dangerous place to live and work. With the realization of deleterious effects of ionizing radiation, a need was felt to protect human beings against these harmful effects by using physical and/or chemical means. Many chemical compounds have been tested for radio protective action but their practical applicability remained limited owing to their inherent toxicity at the optimum dose level. Various plants have been used for various ailments in humans since time immemorial, and herbal preparations have usually been considered safe and less toxic than the synthetic compounds. Therefore, screening of natural products present a major avenue for the discovery of new radio protective drugs and such products have drawn the attention of investigators during the last two decades. The Indian system of medicine employs a large number of plants and some of these herbals viz. The extracts of certain medicinal plant like Amla (Emblica officinalis), Rosemary (Rosemary officinalis), Methi (Trigonella foenum graecum) sapthaparna (Alstonia scholaris), Bael (Aegle inarmelos), Bhumi amla (Phyllanthus niruri), Jamun (Syzgium cumini), Gloe (Tinospora cordifolia) have been trialed in this laboratory for their radio protective action in various biological systems of mammals. The extracts of various parts of such plants have appreciable DRF on the basis of survival

  8. Radiosensitivity of dissociated male germ cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, J. (Utsunomiya Univ. (Japan). Faculty of Education)

    1980-12-01

    The meiotic and redifferentiating activities of dissociated testicular cells were used as the criteria for the injurious effect of /sup 3/H-TdR on spermatogenic cells in vivo. /sup 3/H-TdR was given intraperitoneally to 10-day-old dd mice at dose of 100 ..mu..Ci/10 g for 30 min to 24 hr. The testes from normal and /sup 3/H-TdR-treated mice were mechanically dissected and tripsinized in calcium- and magnesium-free balanced salt solution. After several times of washing, the cells were collected and cultured in the plastic dishes. About 4 x 10/sup 6/ dissociated cells were seeded in each dish. Two to 6 days after the cultivation, the cells in the static state were stained with Giemsa, and those in the floating state were stained with aceto-dahlia. Some of the testicular cells in the static state formed the aggregates consisting mainly of spermatogoneal cells. The aggregate formation observed 1 day after the culture began to decrease sharply with the increase in the dose of /sup 3/H-TdR used, but that observed later (3rd and 6th day) decreased gradually. It is considered that this was due to the recovery from injury during the prolonged culture. The frequency of meiotic cells in the floating cells was 0.5 to 1.0% in the control during the first 24 hr. The dose response curve for meiosis determined 1, 5 and 7 days after the incubation following the treatment with 100 ..mu..Ci/10 g /sup 3/H-TdR for 3 - 24 hr, consists of dose-sensitive and -insensitive phases. In the control, about 2% of the spermatocytic cells in the floating cells in vitro were polynucleic cells, the number increasing after /sup 3/H-TdR treatment. These results suggest that the effect of /sup 3/H-TdR on cell division differs from that on cell differentiation.

  9. Effects of dexamethasone on C6 astrocytoma radiosensitivity

    International Nuclear Information System (INIS)

    Brain-tumor patients often undergo radiation therapy while receiving corticosteroids for the treatment of cerebral edema. Studies have demonstrated that dexamethasone is radioprotective in a number of cell lines. The C6 astrocytoma cell line is well established in vitro and is modulated by dexamethasone treatment. It has therefore been hypothesized that dexamethasone-treated C6 astrocytoma cells would be more resistant to radiation-induced damage. The present study was carried out to assess this hypothesis using both the in vitro C6 astrocytoma monolayer and three-dimensional multicellular spheroid models. Dexamethasone was inhibitory to the C6 astrocytoma cells in the monolayer preparation, increasing their doubling time by 13%. In the spheroid cultures, dexamethasone treatment decreased the number of cells per spheroid by 46%. Dexamethasone did not affect the plating efficiency of either the cells from the monolayer experiment or those dissociated from spheroids, however, suggesting that the inhibitory effect was not tumoricidal. At a clinical concentration (1.94 x 10(-5) M), dexamethasone did not significantly influence plating efficiency of irradiated C6 astrocytoma cells in monolayer or three-dimensional spheroid cultures

  10. 5-Azacytidine enhances the radiosensitivity of CNE2 and SUNE1 cells in vitro and in vivo possibly by altering DNA methylation.

    Science.gov (United States)

    Jiang, Wei; Li, Ying-Qin; Liu, Na; Sun, Ying; He, Qing-Mei; Jiang, Ning; Xu, Ya-Fei; Chen, Lei; Ma, Jun

    2014-01-01

    The radioresistance of tumor cells remains a major cause of treatment failure in nasopharyngeal carcinoma (NPC). Recently, several reports have highlighted the importance of epigenetic changes in radiation-induced responses. Here, we investigated whether the demethylating agent 5-azacytidine (5-azaC) enhances the radiosensitivity of NPC cells. The NPC cell lines CNE2 and SUNE1 were treated with 1 μmol/L 5-azaC for 24 h before irradiation (IR); clonogenic survival was then assessed. Tumor growth was investigated in a mouse xenograft model in vivo. The apoptosis, cell cycle progression and DNA damage repair were examined using flow cytometry, immunofluorescent staining and western blotting. Promoter methylation and the expression of four genes epigenetically silenced during the development of NPC were evaluated by pyrosequencing and real-time PCR. We found that pretreatment with 5-azaC significantly decreased clonogenic survival after IR compared to IR alone; the sensitivity-enhancement ratio of 5-azaC was 1.4 and 1.2 for CNE2 and SUNE1 cells, respectively. The combined administration of 5-azaC and IR significantly inhibited tumor growth in the mouse xenograft model, and enhanced radiation-induced apoptosis in vitro compared to 5-azaC alone or IR alone. 5-AzaC also decreased promoter methylation and upregulated the expression of genes which are epigenetically silenced both in vitro and in vivo in NPC. Thus, 5-azaC enhance the radiosensitivity of both the CNE2 and SUNE1 cell lines, possibly by altering DNA methylation levels and increasing the ability of irradiated cells to undergo apoptosis. The use of 5-azaC combined with IR maybe represent an attractive strategy for the treatment of NPC. PMID:24691157

  11. 5-Azacytidine Enhances the Radiosensitivity of CNE2 and SUNE1 Cells In Vitro and In Vivo Possibly by Altering DNA Methylation

    Science.gov (United States)

    Sun, Ying; He, Qing-Mei; Jiang, Ning; Xu, Ya-Fei; Chen, Lei; Ma, Jun

    2014-01-01

    The radioresistance of tumor cells remains a major cause of treatment failure in nasopharyngeal carcinoma (NPC). Recently, several reports have highlighted the importance of epigenetic changes in radiation-induced responses. Here, we investigated whether the demethylating agent 5-azacytidine (5-azaC) enhances the radiosensitivity of NPC cells. The NPC cell lines CNE2 and SUNE1 were treated with 1 μmol/L 5-azaC for 24 h before irradiation (IR); clonogenic survival was then assessed. Tumor growth was investigated in a mouse xenograft model in vivo. The apoptosis, cell cycle progression and DNA damage repair were examined using flow cytometry, immunofluorescent staining and western blotting. Promoter methylation and the expression of four genes epigenetically silenced during the development of NPC were evaluated by pyrosequencing and real-time PCR. We found that pretreatment with 5-azaC significantly decreased clonogenic survival after IR compared to IR alone; the sensitivity-enhancement ratio of 5-azaC was 1.4 and 1.2 for CNE2 and SUNE1 cells, respectively. The combined administration of 5-azaC and IR significantly inhibited tumor growth in the mouse xenograft model, and enhanced radiation-induced apoptosis in vitro compared to 5-azaC alone or IR alone. 5-AzaC also decreased promoter methylation and upregulated the expression of genes which are epigenetically silenced both in vitro and in vivo in NPC. Thus, 5-azaC enhance the radiosensitivity of both the CNE2 and SUNE1 cell lines, possibly by altering DNA methylation levels and increasing the ability of irradiated cells to undergo apoptosis. The use of 5-azaC combined with IR maybe represent an attractive strategy for the treatment of NPC. PMID:24691157

  12. 5-Azacytidine enhances the radiosensitivity of CNE2 and SUNE1 cells in vitro and in vivo possibly by altering DNA methylation.

    Directory of Open Access Journals (Sweden)

    Wei Jiang

    Full Text Available The radioresistance of tumor cells remains a major cause of treatment failure in nasopharyngeal carcinoma (NPC. Recently, several reports have highlighted the importance of epigenetic changes in radiation-induced responses. Here, we investigated whether the demethylating agent 5-azacytidine (5-azaC enhances the radiosensitivity of NPC cells. The NPC cell lines CNE2 and SUNE1 were treated with 1 μmol/L 5-azaC for 24 h before irradiation (IR; clonogenic survival was then assessed. Tumor growth was investigated in a mouse xenograft model in vivo. The apoptosis, cell cycle progression and DNA damage repair were examined using flow cytometry, immunofluorescent staining and western blotting. Promoter methylation and the expression of four genes epigenetically silenced during the development of NPC were evaluated by pyrosequencing and real-time PCR. We found that pretreatment with 5-azaC significantly decreased clonogenic survival after IR compared to IR alone; the sensitivity-enhancement ratio of 5-azaC was 1.4 and 1.2 for CNE2 and SUNE1 cells, respectively. The combined administration of 5-azaC and IR significantly inhibited tumor growth in the mouse xenograft model, and enhanced radiation-induced apoptosis in vitro compared to 5-azaC alone or IR alone. 5-AzaC also decreased promoter methylation and upregulated the expression of genes which are epigenetically silenced both in vitro and in vivo in NPC. Thus, 5-azaC enhance the radiosensitivity of both the CNE2 and SUNE1 cell lines, possibly by altering DNA methylation levels and increasing the ability of irradiated cells to undergo apoptosis. The use of 5-azaC combined with IR maybe represent an attractive strategy for the treatment of NPC.

  13. PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways.