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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. Increased chromosome radiosensitivity during pregnancy

    International Nuclear Information System (INIS)

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

  3. 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.

  4. 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...

  5. Increased radiosensitivity of microorganisms by vacuum treatment

    International Nuclear Information System (INIS)

    The influence of dehydration by vacuum (down to 10-7 to r) on radiobiological processes was studied on stationary phase cells of Escherichia coli B/r and Bacillus subtilis 168, and on spores of the latter strain. X-rays of 145 kV with a dose-rate of 1 krad/min and ultraviolet irradiation of 254 nm wavelength were applied. When the microorganisms were irradiated during vacuum exposure, their radiation sensitivity had increased, compared with the wet controls, irradiated at 760 torr. For the inactivation of E. coli cells by X-rays, the slope of the dose effect curve was increased by a factor of approximately 4. This supersensitivity to X-rays was not observed in cells which were exposed in multicellular layers or in the presence of salts (PO4-buffer), 5% glucose or nutrient broth. Likewise, the sensitivity to UV-irradiation of vegetative cells and spores was increased when irradiation was applied in vacuo. It was found that specific photoproducts of the DNA, such as DNA-protein, cross-links, 5-thyminyl-5,6-dihydrothyminine-, and trans-syn thymine dimer were formed under vacuum treatment. Since these lesions are not - or only less - repairable by cell-owned enzymatic repair processes, at least one of them may be responsible for the increased UV-sensitivity in vacuo. The formation of trans-syn thymine by UV requires an at least partially denatured DNA. Therefore, it is suggested that vacuum treatment of microorganisms could induce structural changes in their DNA, such as partial denaturation of the polymer. This effect might also be responsible for the increased sensitivity of microorganisms to ionizing radiation. (author)

  6. Increased Radiosensitivity of Microorganisms by Vacuum Treatment

    International Nuclear Information System (INIS)

    The influence of dehydration by vacuum (down to 10-7 torr) on radiobiological processes was studied on stationary phase cells of Escherichia coli B/r and Bacillus subtilis 168, and on spores of the latter strain. X-rays of 145 kV with a dose-rate of 1 krad/min and ultraviolet irradiation of 254 nm wavelength were applied. When the microorganisms were irradiated, during vacuum exposure, their radiation sensitivity had increased, compared with the wet controls, irradiated at 760 torr. For the inactivation of E. coli cells by X-rays, the slope of the dose effect curve was increased by a factor of approximately 4. This super sensitivity to X-rays was not observed in cells which were exposed in multicellular layers or in the presence of salts (Po4-buffer), 5% glucose or nutrient broth. Likewise, the sensitivity to UV-irradiation of vegetative cells and spores was increased when irradiation was applied in vacuo. It was found that specific photoproducts of the DNA, such as DNA-protein, cross-links, 5-thyminyl-, 5,6-dihydrothyminme-, and trans-syn thymine dimer were formed under vacuum treatment. Since these lesions are not - or only less - repairable by cell-owned enzymatic repair processes, at least one of them may be responsible for the increased UV-sensitivity in vacuo. The formation of trans-syn thymine dimer by UV requires an at least partially denatured DNA. Therefore, it is suggested that vacuum treatment of microorganisms could induce structural changes in their DNA, such as partial denaturation of the polymer. This effect might also be responsible for the increased sensitivity of microorganisms to ionizing radiation. (author)

  7. 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)

  8. Increase in radiosensitivity with increase in age of Populus tremuloides seed

    International Nuclear Information System (INIS)

    Populus tremuloides seeds from one tree were irradiated with a 260-Ci 137 Cs gamma source to exposures of 0.47, 0.94, 1.4, 1.8, 3.7, 7.5, 15, 22, 30, 45, and 60 kr at increasing time intervals after seed collection. Two methods of seed storage were used prior to irradiation, refrigerator storage at 50C and freezer storage at -190C with vacuum desiccation. Gamma radiation had no effect upon germination percentage. However, marked decreases in the LD/sub 50-30/ of Populus tremuloides seedlings, grown from seed that was gamma irradiated at increasing time intervals after seed collection, indicated that the seed radiosensitivity increases with increasing age of the seed. Seed storage under vacuum desiccation in a freezer at -190C prolonged the viable storage life of the seed over refrigerator storage

  9. 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

  10. Increased betulinic acid induced cytotoxicity and radiosensitivity in glioma cells under hypoxic conditions

    Directory of Open Access Journals (Sweden)

    Paschke Reinhard

    2011-09-01

    Full Text Available Abstract Background Betulinic acid (BA is a novel antineoplastic agent under evaluation for tumor therapy. Because of the selective cytotoxic effects of BA in tumor cells (including gliomas, the combination of this agent with conservative therapies (such as radiotherapy and chemotherapy may be useful. Previously, the combination of BA with irradiation under hypoxic conditions had never been studied. Methods In this study, the effects of 3 to 30 μM BA on cytotoxicity, migration, the protein expression of PARP, survivin and HIF-1α, as well as radiosensitivity under normoxic and hypoxic conditions were analyzed in the human malignant glioma cell lines U251MG and U343MG. Cytotoxicity and radiosensitivity were analyzed with clonogenic survival assays, migration was analyzed with Boyden chamber assays (or scratch assays and protein expression was examined with Western blot analyses. Results Under normoxic conditions, a half maximal inhibitory concentration (IC50 of 23 μM was observed in U251MG cells and 24 μM was observed in U343MG cells. Under hypoxic conditions, 10 μM or 15 μM of BA showed a significantly increased cytotoxicity in U251MG cells (p = 0.004 and p = 0.01, respectively and U343MG cells (p Conclusion Our results suggest that BA is capable of improving the effects of tumor therapy in human malignant glioma cells, particularly under hypoxic conditions. Further investigations are necessary to characterize its potential as a radiosensitizer.

  11. 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

  12. Significant increase in residual DNA damage as a possible mechanism of radiosensitization by gemcitabine

    International Nuclear Information System (INIS)

    Purpose: To investigate the effect of gemcitabine (dFdC), a promising radiosensitizing nucleoside analog, on the induction and repair of DNA double-strand breaks (dsbs) after ionizing radiation (RT) in a pancreatic tumor cell line. Material and Methods: BxPC3 pancreatic tumor cells were treated using different concentrations of gemcitabine with and without subsequent irradiation. DNA dsbs were detected by constant-field gel electrophoresis under neutral conditions. Results: With the addition of gemcitabine (0.5-1,000 μmol/l for 2 h prior to RT) to RT (0-75 Gy), a considerable and dose-dependent increase of remaining DNA damage after 24 h (5.4-fold for 0.5 μmol/l dFdC, 12.2-fold for 1,000 μmol/l dFdC at 25 Gy) was noted. Enhancement factors were inversely correlated with increasing X-ray dose (7.8-fold for 0.5 μmol/l dFdC at 1 Gy decreasing to 1.6-fold at 75 Gy). Conversely, the induction of DNA dsbs was not affected. Gemcitabine alone lead to a slight increase of initial DNA dsbs and only a modest elevation of residual DNA damage. Conclusion: These findings strengthen the hypothesis of DNA repair inhibition as a major mechanism of radiosensitization by gemcitabine. (orig.)

  13. 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

  14. 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

  15. 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.

  16. Mutations in Succinate Dehydrogenase Subunit C Increase Radiosensitivity and Bystander Responses

    Science.gov (United States)

    Zhou, Hongning; Hei, Tom K.

    Although radiation-induced bystander effect is well studied in the past decade, the precise mech-anisms are still unclear. It is likely that a combination of pathways involving both primary and secondary signaling processes is involved in producing a bystander effect. There is recent evidence that mitochondria play a critical role in bystander responses. Recently studies found that a mutation in succinate dehydrogenese subunit C (SDHC), an integral membrane protein in complex II of the electron transport chain, resulted in increased superoxide, oxidative stress, apoptosis, tumorigenesis, and genomic instability, indicating that SDHC play a critical role in maintaining mitochondrial function. In the present study, using Chinese hamster fibroblasts (B1 cells) and the mutants (B9 cells) containing a single base substitution that produced a premature stop codon resulting in a 33-amino acid COOH-terminal truncation of the SDHC protein, we found that B9 cells had an increase in intracellular superoxide content, nitric oxide species, and mitochondrial membrane potential when compared with wild type cells. After irradiated with a grade of doses of gamma rays, B9 cells show an increased radiosensitivity, especially at high doses. The HPRT- mutant yield after gamma-ray irradiation in B9 cells was significantly higher than that of B1 cells. A single, 3Gy dose of gamma-rays increased the background mutant level by more than 4 fold. In contrast, the mutant induction was less than 2 fold in B1 cells. In addition, B9 cells produced a higher bystander mutagenesis after alpha particle irradiation than the B1 cells. Furthermore, pretreated with carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), a nitric oxide scavenger, significantly decreased the bystander effect. Our findings demonstrate that a mutation in SDHC increases radiosensitivity in both directly irradiated cells and in neighboring bystander cells, and mito-chondrial function play an essential role in

  17. Increased betulinic acid induced cytotoxicity and radiosensitivity in glioma cells under hypoxic conditions

    International Nuclear Information System (INIS)

    Betulinic acid (BA) is a novel antineoplastic agent under evaluation for tumor therapy. Because of the selective cytotoxic effects of BA in tumor cells (including gliomas), the combination of this agent with conservative therapies (such as radiotherapy and chemotherapy) may be useful. Previously, the combination of BA with irradiation under hypoxic conditions had never been studied. In this study, the effects of 3 to 30 μM BA on cytotoxicity, migration, the protein expression of PARP, survivin and HIF-1α, as well as radiosensitivity under normoxic and hypoxic conditions were analyzed in the human malignant glioma cell lines U251MG and U343MG. Cytotoxicity and radiosensitivity were analyzed with clonogenic survival assays, migration was analyzed with Boyden chamber assays (or scratch assays) and protein expression was examined with Western blot analyses. Under normoxic conditions, a half maximal inhibitory concentration (IC50) of 23 μM was observed in U251MG cells and 24 μM was observed in U343MG cells. Under hypoxic conditions, 10 μM or 15 μM of BA showed a significantly increased cytotoxicity in U251MG cells (p = 0.004 and p = 0.01, respectively) and U343MG cells (p < 0.05 and p = 0.01, respectively). The combination of BA with radiotherapy resulted in an additive effect in the U343MG cell line under normoxic and hypoxic conditions. Weak radiation enhancement was observed in U251MG cell line after treatment with BA under normoxic conditions. Furthermore, under hypoxic conditions, the incubation with BA resulted in increased radiation enhancement. The enhancement factor, at an irradiation dose of 15 Gy after treatment with 10 or 15 μM BA, was 2.20 (p = 0.02) and 4.50 (p = 0.03), respectively. Incubation with BA led to decreased cell migration, cleavage of PARP and decreased expression levels of survivin in both cell lines. Additionally, BA treatment resulted in a reduction of HIF-1α protein under hypoxic conditions. Our results suggest that BA is capable of

  18. 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

  19. Adenovirus-mediated p53 gene transfer increases radiosensitivity of human gastric carcinoma cells

    International Nuclear Information System (INIS)

    Objective: To evaluate the effect of adenovirus-mediated p53 gene (Adp53) on apoptosis and radiosensitivity of human gastric carcinoma cell lines. Methods: Recombinant adenovirus carrying 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 and Western blot assay. Cell survival was assessed using a clonogenic assay. TUNEL assay was used in determination of apoptosis. The four human gastric carcinoma cell line infected with Adp53 were irradiated with 4 Gy, and cell cycle distribution and apoptotic rate were assayed by flow cytometry. Nude mice xenograft models of W and M cell were intratumorally injected with Adp53 and 48 h later were irradiated with 6 Gy. Relative volume in growth curve of tumor was used to observe tumor regression. Results: G2/M arrest, apoptosis and inhibition of tumor cell proliferation were induced by infection with Adp53 at 100 MOI, which caused high transfer rate of wild-type p53 and strong expression of P53 protein in the four human gastric carcinoma cell line cells. When evaluating radio-biologic efficacy by apoptotic rate, the apoptotic enhancement ratio of Adp53 at 4 Gy was 3.0 for W cell, 3.6 for M cell, 2.2 for neo cell and 2.5 for 823 cell respectively, in vitro. The antitumor enhancement ratio of Adp53 at 6 Gy was 1.41 for cell-implanted tumor and 1.91 for M cell-implanted tumor in vivo. Conclusion: This study demonstrated that Adp53 transfer increased cellular apoptosis and radiosensitivity of human gastric carcinoma

  20. N-acetylphytosphingosine enhances the radiosensitivity of tumor cells by increasing apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Han, Y.; Kim, Y.; Yun, Y.; Jeon, S.; Kim, K.; Song, J. [Lab. of Immunology, Korea Inst. of Radiological and Medical Sciences, KAERI, Seoul (Korea); Hong, S.H. [Lab. of Experimental therapeutics, Korea Inst. of Radiological and Medical Sciences, KAERI, Seoul (Korea); Park, C. [Doosan Biotech BU, Yongin-City, Kyonggi-Do (Korea)

    2005-07-01

    Ceramides are well-known second messengers which mediate apoptosis, proliferation, differentiation in mammalian cells, but the physiological roles of phytosphingosines are poorly understood. We hypothesized that one of the phytosphingosine derivatives, N-acetylphytosphingosine (NAPS) can induce apoptosis in human leukemia Jurkat cell line and increase apoptosis in irradiated MDA-MB-231 cells. We first examined the effect of NAPS on apoptosis of Jurkat cells. NAPS had a more rapid and stronger apoptotic effect than C{sub 2}-ceramide in Jurkat cells and significant increase of apoptosis was observed at 3 h after treatment. In contrast, the apoptosis induced by C2-ceramide was observed only after 16 h of treatment. NAPS induced apoptosis was mediated by caspase 3 and 8 activation and inhibited by z-VAD-fmk. Ceramide plays a pivotal role in radiation induced apoptosis. We postulated that exogenous treatment of NAPS sensitizes tumor cells to ionizing radiation, since NAPS might be used as a more effective alternative to C2-ceramide. As expected, NAPS decreased clonogenic survival of irradiated MDA-MB-231 cells dose dependently, and apoptosis of irradiated cells in the presence of NAPS was increased through the caspase activation. Taken together, NAPS is an effective apoptosis-inducing agent, which can be readily synthesized from yeast sources, and is a potent alternative to ceramide for the further study of ceramide associated signaling and the development of radiosensitizing agent. (orig.)

  1. 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

  2. antiEGFR conjugated gold nanoparticles for increasing radiosensitivity in lung cancer cells

    International Nuclear Information System (INIS)

    One of the set back that lies in lung cancer treatment is the over expression of Epidermal Growth Factor Receptor (EGFR). EGFR is a transmembrane receptor that is highly expressed in lung cancer that leads to cell survival, proliferation and spread of the disease. Over the years, EGFR inhibitors, monoclonal antibodies, are being used in combination with radiotherapy in lung cancer patients so as to achieve better results. In the recent time, application of Au nanoparticles (AuNPs) in diagnosis and treatment of cancer has been extensively used in biomedical research. Among various applications, there is considerable use of AuNPs seen on the dose enhancement effect (radiosensitization) in radiation therapy of cancer. The conjugation of AuNP with monoclonal antibody antiEGFR (antiEGFR-AuNP) may provide excellent agent to sensitize the cells to heavy ion radiation. We synthesized AuNPs by citrate reduction method. Most of AuNPs were in the size range of 6-8 nm as studies by Transmission Electron Microscope (TEM). These AuNPs were found to be non toxic in A549 cells and thus biocompatible. Further, we conjugated AuNPs with antiEGFR (antiEGFR-AuNP). The conjugation was confirmed by UV-Vis spectroscopy. A549 cells were treated with antiEGFR-AuNP. TEM was carried out of ultrathin cross sections of antiEGFR-AuNP treated A549 cells to check the attachment internalization of AuNPs. We observed that the AuNPs are attached on the cell membrane as well as internalized in cytoplasm. Upon exposure of antiEGFR-AuNP treated cells to heavy ion 12C beam, showed increase in radiosensitization as studied by survival assay and MTT assay. We will also explain the EGFR expression and cell cycle proliferation in A549 cells upon heavy ion beam irradiation of these. The study aims to overcome the current limitations of cancer-targeted therapies and improve the treatment modality of lung cancer. (author)

  3. 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.

  4. 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)

  5. Knockdown of checkpoint kinase 1 is associated with the increased radiosensitivity of glioblastoma stem-like cells

    International Nuclear Information System (INIS)

    Glioblastoma multiforme is an aggressive brain tumor with a poor prognosis. The glioblastoma stem-like cells (GSCs) represent a rare fraction of human glioblastoma cells with the capacity for multi-lineage differentiation, self-renewal and exact recapitulation of the original tumor. Interestingly, GSCs are more radioresistant compared with other tumor cells. In addition, the remarkable radioresistance of GSCs has been known to promote radiotherapy failure and therefore is associated with a significantly higher risk of a local tumor recurrence. Moreover, the hyperactive cell cycle checkpoint kinase (Chk) 1 and 2 play a pivotal role in the DNA damage response including radiation and chemical therapy. Based on aforementioned, we hypothesized that knockdown of Chk1 or Chk2 might confer radiosensitivity on GSCs and thereby increases the efficiency of radiotherapy. In this study, we knocked down the expression of Chk1 or Chk2 in human GSCs using lentivirus-delivered short hairpin RNA (shRNA) to examine its effect on the radiosensitivity. After radiation, the apoptosis rate and the cell cycle of GSCs were measured with Flow Cytometry. Compared with control GSCs (apoptosis, 7.82±0.38%; G2/M arrest, 60.20±1.28%), Chk1 knockdown in GSCs increased the apoptosis rate (37.87±0.32%) and decreased the degree of the G2/M arrest (22.37±2.01%). In contrast, the radiosensitivity was not enhanced by Chk2 knockdown in GSCs. These results suggest that depletion of Chk1 may improve the radio-sensitivity of GSCs via inducing cell apoptosis. In summary, the therapy targeting Chk1 gene in the GSCs may be a novel way to treat glioblastoma. (author)

  6. 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

  7. 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)

  8. 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)

  9. 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

  10. 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.

  11. 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.

  12. 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)

  13. 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.

  14. Simultaneous perturbation of the MAPK and the PI3K/mTOR pathways does not lead to increased radiosensitization

    International Nuclear Information System (INIS)

    The mitogen-activated protein kinases (MAPK) and the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways are intertwined on various levels and simultaneous inhibition reduces tumorsize and prolonges survival synergistically. Furthermore, inhibiting these pathways radiosensitized cancer cells in various studies. To assess, if phenotypic changes after perturbations of this signaling network depend on the genetic background, we integrated a time series of the signaling data with phenotypic data after simultaneous MAPK/ERK kinase (MEK) and PI3K/mTOR inhibition and ionizing radiation (IR). The MEK inhibitor AZD6244 and the dual PI3K/mTOR inhibitor NVP-BEZ235 were tested in glioblastoma and lung carcinoma cells, which differ in their mutational status in the MAPK and the PI3K/mTOR pathways. Effects of AZD6244 and NVP-BEZ235 on the proliferation were assessed using an ATP assay. Drug treatment and IR effects on the signaling network were analyzed in a time-dependent manner along with measurements of phenotypic changes in the colony forming ability, apoptosis, autophagy or cell cycle. Both inhibitors reduced the tumor cell proliferation in a dose-dependent manner, with NVP-BEZ235 revealing the higher anti-proliferative potential. Our Western blot data indicated that AZD6244 and NVP-BEZ235 perturbed the MAPK and PI3K/mTOR signaling cascades, respectively. Additionally, we confirmed crosstalks and feedback loops in the pathways. As shown by colony forming assay, the AZD6244 moderately radiosensitized cancer cells, whereas NVP-BEZ235 caused a stronger radiosensitization. Combining both drugs did not enhance the NVP-BEZ235-mediated radiosensitization. Both inhibitors caused a cell cycle arrest in the G1-phase, whereas concomitant IR and treatment with the inhibitors resulted in cell line- and drug-specific cell cycle alterations. Furthermore, combining both inhibitors synergistically enhanced a G1-phase arrest in sham-irradiated glioblastoma

  15. 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.

  16. Radiosensitivity - a genotype dependent mechanism

    International Nuclear Information System (INIS)

    For determining relative radiosensitivity, bulbs of 3 different sizes of Allium cepa L. having same cell size, chromosome number, ICV, INV and DNA content were exposed to different doses of gamma-rays. Gamma ray induced chromosomal aberrations as the end point of radiosensitivity was studied in root meristem and it was found that the aberration percentage increased with increase in doses in all cases. The medium size was found to be much sensitive indicating genotype dependent mechanism for radiosensitivity. (author). 34 refs., 3 tabs

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

    International Nuclear Information System (INIS)

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

  18. Radiosensitive severe combined immunodeficiency disease.

    Science.gov (United States)

    Dvorak, Christopher C; Cowan, Morton J

    2010-02-01

    Inherited defects in components of the nonhomologous end-joining DNA repair mechanism produce a T-B-NK+ severe combined immunodeficiency disease (SCID) characterized by heightened sensitivity to ionizing radiation. Patients with the radiosensitive form of SCID may also have increased short- and long-term sensitivity to the alkylator-based chemotherapy regimens that are traditionally used for conditioning before allogeneic hematopoietic cell transplantation (HCT). Known causes of radiosensitive SCID include deficiencies of Artemis, DNA ligase IV, DNA-dependent protein kinase catalytic subunit, and Cernunnos-XLF, all of which have been treated with HCT. Because of these patients' sensitivity to certain forms of chemotherapy, the approach to donor selection and the type of conditioning regimen used for a patient with radiosensitive SCID requires careful consideration. Significantly more research needs to be done to determine the long-term outcomes of patients with radiosensitive SCID after HCT and to discover novel nontoxic approaches to HCT that might benefit those patients with intrinsic radiosensitivity and chemosensitivity as well as potentially all patients undergoing an HCT. PMID:20113890

  19. 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

  20. 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.

  1. 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

  2. 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.

  3. Deregulation of cap-dependent mRNA translation increases tumour radiosensitivity through reduction of the hypoxic fraction

    International Nuclear Information System (INIS)

    Background and purpose: Tumour hypoxia is an important limiting factor in the successful treatment of cancer. Adaptation to hypoxia includes inhibition of mTOR, causing scavenging of eukaryotic initiation factor 4E (eIF4E), the rate-limiting factor for cap-dependent translation. The aim of this study was to determine the effect of preventing mTOR-dependent translation inhibition on hypoxic cell survival and tumour sensitivity towards irradiation. Material and methods: The effect of eIF4E-overexpression on cell proliferation, hypoxia-tolerance, and radiation sensitivity was assessed using isogenic, inducible U373 and HCT116 cells. Results: We found that eIF4E-overexpression significantly enhanced proliferation of cells under normal conditions, but not during hypoxia, caused by increased cell death during hypoxia. Furthermore, eIF4E-overexpression stimulated overall rates of tumour growth, but resulted in selective loss of hypoxic cells in established tumours and increased levels of necrosis. This markedly increased overall tumour sensitivity to irradiation. Conclusions: Our results demonstrate that hypoxia induced inhibition of translational control through regulation of eIF4E is an important mediator of hypoxia tolerance and radioresistance of tumours. These data also demonstrate that deregulation of metabolic pathways such as mTOR can influence the proliferation and survival of tumour cells experiencing metabolic stress in opposite ways of nutrient replete cells.

  4. 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)

  5. 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.

  6. Radiosensitization by nickel lapachol

    International Nuclear Information System (INIS)

    The properties of interest in the radiosensitization of a metal complex, nickel lapachol, are compared with those of the 2-nitroimidazole, misonidazole. These very different compounds were found to be surprisingly similar in terms of their reduction potential (-370 mV), enhancement ratios for killing of hypoxic Chinese hamster ovary cells by X-irradiation, and enhancement of DNA breaks in hypoxia. For nitroimidazoles, the sensitization depends on 'electron affinity', reduction of the nitro group; for nickel lapachol it is the metal which is necessary for reduction, yet the sensitization efficiencies are remarkably close. However, the metal complex has additional activities (some sensitization in aerobic cells; increased sensitization with preincubation) which are as yet unexplained but are assumed to be related to the nature of the naphthoquinone ligand, rather than to the reduction of the metal. (Author)

  7. 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

  8. 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.)

  9. Radiosensitivity of garlic air bulbs

    International Nuclear Information System (INIS)

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

  10. 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

  11. 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

  12. 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)

  13. 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...

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

    International Nuclear Information System (INIS)

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

  15. Pharmacokinetics of hypoxic cell radiosensitizers: a review

    International Nuclear Information System (INIS)

    The comparative pharmacokinetics of various nitroimidazole radiosensitizers in different species are reviewed. Radiosensitization is dependent upon the tumor concentration at the time of radiotherapy, whereas host toxicity, including peripheral neuropathy, appears to be related to the tissue exposure or area under the curve (AUC). Nitroimidazoles penetrate lipoid membranes by passive diffusion, the rate increasing with lipophilicity. Derivatives more hydrophilic than misonidazole penetrate nervous tissues comparatively slowly. They are eliminated mainly by renal clearance. Most plasma data for intravenous radiosensitizers can be described by a two-compartment open model. But in the mouse, the kinetics of misonidazole are dose dependent with increasing apparent t1/2 and AUC at higher doses due to saturable Michaelis-Menten kinetics for metabolism

  16. 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)

  17. 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.

  18. 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)

  19. 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)

  20. 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

  1. 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.

  2. Radiosensitivity of amphibia

    International Nuclear Information System (INIS)

    Radiosensitivity (semi-lethal dose) and the damages of radiation in the amphibia were studied by 3H-TdR from the standpoint of cellular kinetics. The cell mitosis cycle of the amphibia required a long time. The functional cell regeneration and the physiological function of the cell were slower than in mice. The reason for the low radiosensitivity of the amphibia was discussed relative to the environmental factor of temperature. Because the amphibia change body temperature according to environmental temperature, the danger of radiation damage, the actual lethal dose and the period of survival were influenced by the environmental temperature. Acute radiation danger to amphibia was essentially the same as the danger to mammalia, both young and old. LD50 irradiation effects varied among the species. The cell regeneration, turn over, and the mitosis in the amphibia, were affected by environmental temperature, however, the courses proceeded slower than those of the mammalia. Therefore, the question remains, whether the comparison of the radiosensitivities of amphibia with other classes of animal by LDsub(50/30) irradiation was appropriate. (Serizawa, K.)

  3. 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.

  4. Lymphocyte radiosensitivity in multiple sclerosis patients

    International Nuclear Information System (INIS)

    from MS patients had similar sensitivity to those from controls. In addition, a decrease of radiosensitivity with increasing illness duration was observed in the CD4+ cells. In conclusion one stresses: Secondary progressive multiple sclerosis patients have higher spontaneous induction of MN. We presume that the increased spontaneous micronucleus formation might be the result of oxidative damage to which cells have often been exposed throughout the disease evolution. Under 2 Gy 60 Co irradiation, the lymphocytes of SPMS patients seem to be less sensitive, and the observed radioresistance was due to the subset of CD4+ lymphocytes. This enhanced radioresistance could be accounted for by an adaptive response triggered by oxidative stress or by abnormalities in cytokine signaling which characterizes MS pathology. (authors)

  5. Radiosensitivity and the clinician

    International Nuclear Information System (INIS)

    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. (U.K.)

  6. 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.

  7. 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)

  8. Hypoxic cell radiosensitizer

    International Nuclear Information System (INIS)

    Since an unsuccessful clinical trial of Misonidazole, many investigations were carried out to find out the useful hypoxic cell radio-sensitizers all over the world. In the USA., Dr. M. Brown synthesized and tested SR-2508 and this drug is now on the phase II-III clinical trials. In the U.K., Dr. J. Adams proposed Ro-08-8799. In Japan, partly supported by the Ministry of Education, Science and Culture, a research group was formed and got an agreement to use the same screening system to evaluate newly synthesized drugs. Through this screening system, thousand of drugs were tested. Among these drugs, KU-2285, RK-28, RP-170 and KIH-801(2) showed remarkable sensitizing effects or minor toxicity. Right now, these drugs are on either phase I clinical trial or pre-clinical evaluations. (author)

  9. Hypoxic cell radiosensitizers

    International Nuclear Information System (INIS)

    Hyperbaric oxygen results have demonstrated that there is a problem of hypoxid cells in some types of tumour, and that even small daily fractions with HBO can give improved results. Reasons are given for expecting radiosensitizing drugs to penetrate better than HBO to the hypoxic cells, which exist in tumours exceeding 1 or 2 mm diameter. Preliminary clinical studies have demonstrated significant effects on human tumours of misonidazole and metronidazole. Concentrations of misonidazole have been measured in human tumours which were 40-110% of those in plasma, usually 70-90%. A number of clinical trials are being initiated using misonidazole. Future clinical results of hypoxic cell radiosentizers will clarify further the role of hypoxic cells in causing resistance to radiotherapy. (orig./MG) 891 MG/orig.- 892 RDG

  10. Radiosensitivities of sensitized lymphocytes

    International Nuclear Information System (INIS)

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

  11. 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.

  12. 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

  13. Azomycin riboside: a new radiosensitizer

    International Nuclear Information System (INIS)

    Azomycin riboside (2-nitro-1-β-D-ribofuranosylimidazole) (AR), a nucleoside analogue with the base component replaced by a 2-nitroimidazole was studied to determine its potential as a radiosensitizer. In vitro evidence showed that AR is as good as or slightly better than misonidazole (MISO) as a hypoxic cell radiosensitizer. AR was also found to kill hypoxic cells directly and this cytotoxicity was at least as great as MISO cytotoxicity. However, when tumor regrowth delay was used to assess in vivo radiosensitization, AR was found to be inferior to MISO while the LD50 host toxicity assay indicated that AR might be nearly as toxic as MISO. Unless AR proves to be less toxic than MISO or can be selectively distributed with nucleoside transport inhibitors, these preliminary observations have not shown any advantage of AR over MISO as a potential clinically useful radiosensitizer

  14. Effect of salt solutions on the radiosensitivity of mammalian cells

    International Nuclear Information System (INIS)

    The effects of a wide concentration range of NaCl solutions containing either ouabain, ethanol, para-nitroacetophenone (PNAP), N-ethylmaleimide (NEM), cysteamine or dimethyl sulphoxide (DMSO) on cellular radiosensitivity have been examined. Ouabain and NEM treatment increased the radiosensitivity of V79 Chinese hamster cells, but the action of these chemicals did not depend on the concentration of NaCl. PNAP increased cellular radiosensitivity with increasing NaCl concentration reaching a maximum effect at 0.6 to 0.7 M NaCl. The radioprotective properties of cysteamine, DMSO and ethanol were all strongly dependent on the NaCl concentration in a complex but qualitatively similar manner. DMSO (2.0 M) increased survival of cells after a 1380 rad dose by a factor of about 104 when present in 0.075 NaCl and by a factor of 8.7 when present in 1.2 M NaCl. (author)

  15. 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

  16. Clinical importance of predicting radiosensitivity

    International Nuclear Information System (INIS)

    Full text: The optimal use of radiation therapy in cancer treatment is hampered by the application of normal tissue tolerance limits that are derived from population averages. Such limits do not reflect the considerable differences in susceptibility to radiation injury that exist among individuals. Development of assays that accurately predicted normal tissue tolerance in individual patients would permit real application of the concept of treatment to tolerance. By adjusting doses upwards or downwards to achieve a uniform probability of complication in each patient, the therapeutic ratio, i e., the probability of an uncomplicated cure, would be increased for the population as a whole. Although the pathogenesis of radiation injury is highly complex, clinical studies have demonstrated a significant correlation between the in vitro radiosensitivity of patients' fibroblasts and their risk of developing late connective tissue type complications of radiotherapy. While such assays lack the precision and practicality to be used clinically, they do establish the principle of prediction of normal tissue tolerance. Newer assays using surrogate endpoints for cell survival and incorporating insights into the effects of radiation on cellular growth, differentiation, senescence and cytokine production are being developed. Such assays may, in the future, be complemented or replaced by molecular and/or cytogenetic probes to derive robust estimates of individual tolerance. The goal of accurate prediction of individual tolerance for clinical use, while not imminent, does seem achievable

  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. Radiosensitizers, radioprotectors, and radiation mitigators

    Directory of Open Access Journals (Sweden)

    Jayam Raviraj

    2014-01-01

    Full Text Available Radiotherapy is regarded as one of the most important therapeutic modality for the treatment of malignant lesions. This field is undergoing rapid advancements in the recent times. With the use of radiosensitizers and radioprotective agents, the course of radiotherapy has improved the sensitization of tumor cells and protection of normal cells, respectively. The aim of this paper was to critically review and analyze the available compounds used as radiosensitizers, radioprotectors, and radiation mitigators. For reviewing, the author used the electronic search for the keywords ′Radiosensitizers′, ′Radioprotectors′, ′Radiation mitigators′ on PubMed for inclusion of previously published articles and further search of reference papers on individual radiosensitizing and radioprotecting agents was done. Radiosensitizers are agents that sensitize the tumor cells to radiation. These compounds apparently promote fixation of the free radicals produced by radiation damage at the molecular level. The mechanism of action is similar to the oxygen effect, in which biochemical reactions in the damaged molecules prevent repair of the cellular radiation damage. Free radicals such as OH + are captured by the electron affinity of the radiosensitizers, rendering the molecules incapable of repair. Radioprotectors are compounds that are designed to reduce the damage in normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness. Other agents, termed mitigators, may be used to minimize toxicity even after radiation has been delivered. This article tries to discuss the various aspects of radiosensitizers, radioprotectors, and radiation mitigators including the newer agents.

  1. Effect of hydrocortisone on radiosensitivity of hemopoietic stem cells

    International Nuclear Information System (INIS)

    Differentiation and radiosensitivity of colony-forming units (CFU) of the bone marrow and spleen were studied in the course of one month after a single injection of hydrocortisone to mice (5 mg/mouse). The direction of differentiation of CFU from different organs was found to change drastically. CFU of the bone marrow stimulated erythropoiesis and of spleen, myelopoiesis which is different from what we have in normal mice. Study of the radiosensitivity of CFU from various organs by the ''splenic colony'' test did not show any variations in the values of D0 and the extrapolation number, whereas the ''bone marrow colony'' test exhibited considerable atleration of the CFU radiosensitivity. Radioresistance of CFU from bone marrow decreased while that of splenic CFU increased compared with controls. The phenomena described are probably due to redistribution of T-lymphocytes in response to the hydrocortisone administration

  2. Radiosensitivity of carcinoma of esophagus

    International Nuclear Information System (INIS)

    With a detailed graphic reconstruction of radiation effects shown in 11 operation materials of carcinoma of esophagus with preoperative irradiation, histologic analysis of the radiosensitivity was made. Residual cancer lesions in 11 operation specimens contained adenocarcinoma elements. Carcinoma of esophagus belonged to mixed carcinoma (syn. metaplastic cancer). Radioresistant nature resulted from the remnant adenocarcinoma elements. Protruded type (3 cases) showed about 60 % of residual cancer after preoperative irradiation of 40 Gy (Lineac or 60Co.). The residual cancer nests histologically revealed well-differentiated squamous cell carcinoma with a few signet-ring cells, compatible with mucoepidermoid carcinoma. In protruded type, the mixed carcinoma was composed of segmental, disproportioned zonal squamous metaplasia. As its histogenetic origin, a main duct of esophageal gland was suggested. In 9 autopsy cases of esophageal cancer, recurrent lesion within the field of irradiation failed to respond to radiotherapy. In recurrent residual lesions, a higher proportion of adenocarcinoma elements was noticed. Therefore, the cancer part formed by a high rate of metaplasia was markedly responsive to irradiation, whereas increased residue of adenocarcinoma elements was enhanced the radioresistant property. In a middle thoracic esophagus (Im) corresponding to the commonest site of esophageal cancer, the distribution of esohageal glands was in a high density with a constant ratio of density in each age group particularly in male. In age groups with higher incidence of carcinoma of esophagus, esophageal glands markedly increased especially in male, in contrast with the indefinite number and density ratio in female cases. A high density of esophageal glands was noticed in the upper (Iu) and lower (Im) parts of the 2nd physiologic constriction, in proportion to the commonest site of carcinoma of esophagus. (J.P.N.)

  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. 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...

  5. Iododeoxyuridine radiosensitization by low- and high-energy photons for brachytherapy dose rates

    International Nuclear Information System (INIS)

    The dependence of iododeoxyuridine (IUdR) radiosensitization on photon energy and dose rate in the range of interest to brachytherapy was investigated by irradiating Chinese hamster cells in vitro under aerobic conditions. The radiosensitization produced by 10(-5) and 10(-4) M IUdR for 28-keV (average) photons from 125I, 60-keV photons from 241Am, and 830-keV (average) photons from 226Ra was measured at nominal dose rates of 0.17, 0.30, 0.57, and 0.73 Gy/h. Radiosensitization factors for IUdR were essentially independent of dose rate from 0.30 to 0.73 Gy/h for all cases except for 10(-4) M IUdR plus 241Am, in which case the radiosensitization factor increased from 2.5 +/- 0.2 to 3.0 +/- 0.1. In all cases, the radiosensitization factor decreased significantly as the dose rate was lowered from 0.30 to 0.17 Gy/h e.g., the radiosensitization factor for 241Am dropped to 1.9 +/- 0.2 at a dose rate of 0.17 Gy/h. Moreover, at 0.17 Gy/h the radiosensitization factors were essentially the same for all three photon energies. As the dose rate increased from 0.17 to 0.73 Gy/h, the difference between the radiosensitization factors for the three photon energies became larger; radiosensitization factors for 241Am were higher than those for 226Ra and 125I. In temporary brachytherapy the tumor is irradiated at the higher dose rate of about 0.50-0.70 Gy/h, while the normal tissues are irradiated at lower dose rates; the dose rate dependence of the radiosensitization factor may therefore lead to an improvement in the therapeutic ratio for brachytherapy in combination with IUdR

  6. 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)

  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. 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.

  10. 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)

  11. Enhancement of misonidazole radiosensitization by an inhibitor of glutathione biosynthesis

    International Nuclear Information System (INIS)

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

  12. Anoxic-cell radiosensitization induced by heterocyclic compounds

    International Nuclear Information System (INIS)

    The anoxic cell compartment of in vivo solid tumors limits to some extent the effects of therapeutic radiation. The development of anoxic-cell radiosensitizers, as represented by the imidazole derivatives, has been given considerable attention. Hyperbaric oxygen was also considered for this purpose, Misonidazole, one of the imidazole derivatives, has a radiosensitization effect on anoxic cell killing. However, clinical application was not feasible because the drug proved to be toxic to the central nervous system. The extent of neurotoxicity of the imidazole derivatives correlates with the lipophilicity of the drugs. If the hydrophilicity of the drug could be increased to the extent that the toxicity to the central nervous system would be diminished, then the effect of anoxic-cell radiosensitization of the drug in unit drug amount/body weight or body surface could be maintained. The authors assayed a series of compounds, o-, m-, and p-nitrophenyl-tatrazoles, for their possible anoxic-cell radiosensitization effects. The differential effects were observed among the three isomers by cell survival assays in colony formations of Chinese hamster V-79 strain of cells, in vitro

  13. Radiosensitizing effect of RHOB protein in melanoma cells

    International Nuclear Information System (INIS)

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

  14. Radiosensitizing and cytotoxic effects of hyperthermia on various biological systems

    International Nuclear Information System (INIS)

    When mouse leukosis cell suspensions were subjected to heating the survival rate of animals decreased exponentially with increasing time of heating. It is shown that the increase of temperature for 1 deg C in range 40-45 deg C us equivalent to a decrease in the heating time by a factor of approximately 2. The hyperthermia-induced increase in the radiosensitivity of leukosis cells was dependent upon a medium in which heating was performed

  15. Heat inactivation of Ku autoantigen: possible role in hyperthermic radiosensitization.

    Science.gov (United States)

    Burgman, P; Ouyang, H; Peterson, S; Chen, D J; Li, G C

    1997-07-15

    Heat shock prior, during, or immediately after ionizing radiation synergistically increases cell killing, a phenomenon termed hyperthermic radiosensitization. Recently, we have shown a constitutive DNA-binding factor in rodent cells that is inactivated by heat shock to be identical to Ku autoantigen. Ku, consisting of an Mr 70,000 (Ku70) and an Mr 86,000 (Ku80) subunit, is a heterodimeric nuclear protein and is the DNA-binding regulatory component of the mammalian DNA-dependent protein kinase DNA-PK. Recent genetic and biochemical studies indicate the involvement of Ku and DNA-PK in DNA double-strand break repair and V(D)J recombination. On the basis of these findings, we propose that heat-induced loss of the DNA-binding activity of Ku may lead to hyperthermic radiosensitization. To test this hypothesis, we examined and compared the DNA-binding activity of Ku, the DNA-PK kinase activity, and hyperthermic radiosensitization in rodent cells immediately after heat shock and during post-heat shock recovery at 37 degrees C. Our results show that the heat-induced loss of Ku-DNA binding activity correlates well with an increased radiosensitivity of the heat-shocked cells, and furthermore, the loss of synergistic interaction between heat and radiation parallels the recovery of the DNA-binding activity of Ku. On the other hand, the heat-induced decrease of DNA-PK activity did not correlate with hyperthermic radiosensitization. Our data, for the first time, provide evidence for a role of Ku protein in modulating the cellular response to combined treatments of heat shock and ionizing radiation. PMID:9230187

  16. 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

  17. 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

  18. 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

  19. 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

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

    International Nuclear Information System (INIS)

    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

  1. 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.

  2. 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.)

  3. 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).

  4. Radiosensitization of DNA in presence of Pt(II)-based compounds

    International Nuclear Information System (INIS)

    X-ray irradiation of plasmid DNA in presence of platinum (II)-based compounds was carried out in order to assess the radiosensitization capabilities of these drugs. In present investigations pBR322 plasmid DNA was used to monitor the effectiveness of chosen compounds in inducing strand breaks. Samples were incubated in the presence of potential radiosensitizers: platinum (II) bromide and cis-diammine-dibromo-platinum (II). The results were examined against a common cancer chemotherapy drug cis-diamminedichloroplatinum (II). It was found that platinum (II) bromide can greatly increase the levels of single- and double-strand break formation observed in the irradiated samples with respect to the samples containing platinum as a radiosensitizer only, possessing very little chemotherapeutic activity. The suggested drugs exhibit much higher level of radiosensitivity than widely used cisplatin and thus may be good candidates for cancer treatment. (authors)

  5. 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)

  6. Radiosensitivity of soft tissue sarcomas

    Energy Technology Data Exchange (ETDEWEB)

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

    1989-05-01

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

  7. The role of glutathione in the radiosensitive effect induced by treating HeLa cells with sanazole

    International Nuclear Information System (INIS)

    Objective: To investigate radiosensitive effect of sanazole on HeLa cells and its relationship with glutathione (GSH). Methods: The anoxia model was made by inflow of nitrogen gas. The survival rate of HeLa cells was observed with method of colony formation after treatment with sanazole and 60Co γ irradiation. Radiosensitive effect was evaluated through measurement of sensitizing enhancement ratio (SER) resulted from single-target multi-hit model. The GSH content in these HeLa cells was determined by the tetra-oxypyrimidine UV-spectrophotometer method to explore the mechanism of radiosensitive effect. Results: SER was more than 1.4. The concentration of GSH decreased significantly with increasing concentration of sensitizer and dose of radiation, especially under anoxia condition. Conclusions: Sanazole has significant radiosensitive effect and decrease in GSH content resulted from combination with 60Co γ irradiation may be one of its radiosensitive mechanisms

  8. Radiosensitivity of synchronized Yoshida sarcoma cells

    International Nuclear Information System (INIS)

    Yoshida sarcoma cells were synchronized in vitro, and the cultures were irradiated with the Stabilipan pendulum unit under deep X-ray therapy conditions. Cellular proliferation after irradiation was measured in the cell culture and, after i.p. injection of the cells, in mice. The growth of unsynchronized cultures was inhibited by irradiation, depending on the radiation dose; the LD50 was 380 rad in vivo and 480 rad in vitro. In further investigations, the cultures were irradiated with 150, 300 and 450 rad, and the mitotic behaviour, the rates of proliferation, the incorporation of 3H-thymidine into DNA and of 14C-leucine into cell protein were measured. The mitotic index of unsynchronized cells decreases as a function of the radiation dose, starting 2 h after irradiation and with a peak after periods of different length. Incorporation into DNA of 3H-thymidine is inhibited by 20 to 40%, depending on the radiation dose. Incorporation into the cell proteins of 3H thymidine is inhibited by 10 to 30%, depending on the radiation dose. Synchronized cells were irradiated in the G1/S, S, G2 and G1 phases. As regards incorporation of 3H-thymidine and 14C-lencine and the mitotic index, there was no difference between synchronized cells and unsynchronized control cultures. However, in cultures irradiated in the G2 phase, growth was significantly inhibited in vivo 48 h later. This distinction between cells irradiated in the G2 phase and cells irradiated in other phases was blurred when the cells were cultivated for more than 72 h after irradiation. The higher radiosensitivity of G2 cells can be explained as being due to delayed cell division and does not suggest increased radiosensitivity of this phase. (orig./MG)

  9. 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)

  10. [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

  11. 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

  12. Induction during G1 of heat radiosensitization in Chinese hamster ovary cells following single and fractionated heat doses

    International Nuclear Information System (INIS)

    When G1 Chinese hamster ovary cells were heated at 42.2 degrees C and X-irradiated, heat radiosensitization increased slightly with cell killing. However, when thermo-tolerance was allowed to develop by continuous heating for periods longer than 4 hours, which reduces survival to 0.18, heat radiosensitization no longer increased with continued heating or cell killing. When cells were heated with single doses at 45.5 degrees C, heat radiosensitization increased as a function of heat killing. However, if acute heat doses at 45.5 degrees C were fractionated and cells incubated for 10 hours at 37 degrees C between fractions, significant tolerance to heat radiosensitization was observed. For example, heating cells at 45.5 degrees C for 15 minutes reduced survival to 0.40 and decreased the D0 to 0.45 gray, whereas 2 fractionated 15-minute doses at 45.5 degrees C, separated by 10 hours at 37 degrees C, resulted in a D0 of 0.65 gray. Thus if heat killing increased without the development of thermotolerance, heat radiosensitization also increased continually, whereas when thermotolerance developed after continuous or fractionated heating without cell progression, some tolerance to continued heat radiosensitization also was observed. This tolerance to both heat killing and heat radiosensitization indicates that both involve similar target(s)

  13. 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.)

  14. Radiogenomics: predicting clinical normal tissue radiosensitivity

    DEFF Research Database (Denmark)

    Alsner, Jan

    2006-01-01

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

  15. 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...

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

    International Nuclear Information System (INIS)

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

  17. 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

  18. 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.

  19. 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

  20. A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown

    DEFF Research Database (Denmark)

    Higgins, Geoff S; Prevo, Remko; Lee, Yin-Fai;

    2010-01-01

    radiosensitivity are largely unknown. We have conducted a small interfering RNA (siRNA) screen of 200 genes involved in DNA damage repair aimed at identifying genes whose knockdown increased tumor radiosensitivity. Parallel siRNA screens were conducted in irradiated and unirradiated tumor cells (SQ20B) and...... irradiated normal tissue cells (MRC5). Using gammaH2AX foci at 24 hours after IR, we identified several genes, such as BRCA2, Lig IV, and XRCC5, whose knockdown is known to cause increased cell radiosensitivity, thereby validating the primary screening end point. In addition, we identified POLQ (DNA...

  1. 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

  2. Dependence of Gold Nanoparticle Radiosensitization on Functionalizing Layer Thickness.

    Science.gov (United States)

    Spaas, Cedric; Dok, Rüveyda; Deschaume, Olivier; De Roo, Bert; Vervaele, Mattias; Seo, Jin Won; Bartic, Carmen; Hoet, Peter; Van den Heuvel, Frank; Nuyts, Sandra; Locquet, Jean-Pierre

    2016-04-01

    Gold nanoparticles functionalized with polyethylene glycol of different chain lengths are used to determine the influence of the capping layer thickness on the radiosensitizing effect of the particles. The size variations in organic coating, built up with polyethylene glycol polymers of molecular weight 1-20 kDa, allow an evaluation of the decrease in dose enhancement percentages caused by the gold nanoparticles at different radial distances from their surface. With localized eradication of malignant cells as a primary focus, radiosensitization is most effective after internalization in the nucleus. For this reason, we performed controlled radiation experiments, with doses up to 20 Gy and particle diameters in a range of 5-30 nm, and studied the relaxation pattern of supercoiled DNA. Subsequent gel electrophoresis of the suspensions was performed to evaluate the molecular damage and consecutively quantify the gold nanoparticle sensitization. In conclusion, on average up to 58.4% of the radiosensitizing efficiency was lost when the radial dimensions of the functionalizing layer were increased from 4.1 to 15.3 nm. These results serve as an experimental supplement for biophysical simulations and demonstrate the influence of an important parameter in the development of nanomaterials for targeted therapies in cancer radiotherapy. PMID:26950059

  3. On the role of ploidy in cell radiosensitivity

    International Nuclear Information System (INIS)

    Sensitivity of experimentally obtained diploid cells of naturally occuring haplonts Pichia pinus and Pichia quilliermondii to gamma-quanta and α-particles has been shown to be twice as high as that of haploid cells and, therefore, independent of the ploidy, as calculated per one set of chromosomes. In this respect, the haplonts under study are similar to diplonts Saccharomyces cerevisiae, carrying rad 51 mutation, and drastically different from Saccharomyces cerevisiae of ''wild type'' whose haploid cells are much more radiosensitive than diploids. It has also been found that relative biological effectiveness (RBE) of α-particles for yeasts of the strains under study decreases, with increasing radiosensitivity, varying from 4.6 to 1.0. It is concluded that: (1) similar lesions lay the basis of radiation damage to both haploid and diploid yeast cells; the probability of formation of these lesions is conditioned by the dimensions of the ''target'' (DNA content) and the effectiveness of the repair systems, (2) the presence in the cell of at least two sets of chromosomes is necessary for productive work of the repair systems, (3) a higher radioresistance of diploid cells as compared to haploids in diplonts is mainly due to the effective work of the repair systems, (4) a higher radiosensitivity of diploid cells as compared to haploids in haplonts is perhaps due to a deficiency of these yeasts in repair systems, (5) an important role is ascribed to repair processes in the estimation of RBE of radiations possessing different LET

  4. Comparative study of repurinase (incertase) activity in tissues of radioresistant (Raphanus sativus) and radiosensitive (vicia faba) plants

    International Nuclear Information System (INIS)

    Experimental evidence is obtained that the repair enzyme, repurinase (increase), involving adenine in apurinic DNA, is present is seedlings of radioresistant plants (Raphanus sativus) and absent, as was shown by the method used, in seedlings of radiosensitive plants (Vicia faba)

  5. Radiosensitization of mouse L cells by an electron affinic radiosensitizer, Ro-07-0582 under an extremely hypoxic condition

    International Nuclear Information System (INIS)

    The present investigation was undertaken with the hope for elucidating the effect of a radiosensitizer on mouse L cells in culture following x-irradiation. Under the aerobic condition, a survival curve of irradiated cells showed a shoulder region with the extrapolation number of 6.4 and mean lethal dose (D0 value) of 126 rad. On the other hand, under the extremely hypoxic condition prepared with nitrogen gas using a stainless steel apparatus, a survival curve was found to show no shoulder region, having extrapolation number of 1.1 and D0 value of 629 rad. Thus, the oxygen enhancement ratio (o. e. r.) was calculated as a factor 5. An electron affinic radiosensitizer, Ro-07-0582 revealed a pronounced sensitizing effect under the extremely hypoxic condition by an enhancement ratio 3.9 at a concentration of 10 mM. The sensitizer reduced D0 value with increasing concentration of the drug. The evidence obtained suggests that Ro-07-0582 acts as oxygen-mimic, although the drug shows no radiosensitizing effect at low concentration and low irradiation doses. (author)

  6. 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.

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

    International Nuclear Information System (INIS)

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

  8. 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

  9. 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.

  10. Cisplatin-mediated radiosensitization of non-small cell lung cancer cells is stimulated by ATM inhibition

    International Nuclear Information System (INIS)

    Background and purpose: Cisplatin activates ataxia-telangiectasia-mutated (ATM), a protein with roles in DNA repair, cell cycle progression and autophagy. We investigated the radiosensitizing effect of cisplatin with respect to its effect on ATM pathway activation. Material and methods: Non-small cell lung cancer cells (NSCLC) cell lines (A549, H460) and human fibroblast (ATM-deficient AT5, ATM-proficient 1BR3) cells were used. The effects of cisplatin combined with irradiation on ATM pathway activity, clonogenicity, DNA double-strand break (DNA-DSB) repair and cell cycle progression were analyzed with Western blotting, colony formation and γ-H2AX foci assays as well as FACS analysis, respectively. Results: Cisplatin radiosensitized H460 cells, but not A549 cells. Radiosensitization of H460 cells was not due to impaired DNA-DSB repair, increased apoptosis or cell cycle dysregulation. The lack of radiosensitization demonstrated for A549 cells was associated with cisplatin-mediated stimulation of ATM (S1981) and AMPKα (T172) phosphorylation and autophagy. However, in both cell lines inhibition of ATM and autophagy by KU-55933 and chloroquine diphosphate (CQ) respectively resulted in a significant radiosensitization. Combined treatment with the AMPK inhibitor compound-C led to radiosensitization of A549 but not of H460 cells. As compared to the treatment with KU-55933 alone, radiosensitivity of A549 cells was markedly stimulated by the combination of KU-55933 and cisplatin. However, the combination of CQ and cisplatin did not modulate the pattern of radiation sensitivity of A549 or H460 cells. In accordance with the results that cisplatin via stimulation of ATM activity can abrogate its radiosensitizing effect, ATM deficient cells were significantly sensitized to ionizing radiation by cisplatin. Conclusion: The results obtained indicate that ATM targeting can potentiate cisplatin-induced radiosensitization

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

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    F Seif

    2008-04-01

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

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

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    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)

  13. Radiosensitivity, radio-curability and DNA repair

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    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)

  14. Lanthanum fluoride nanoparticles for radiosensitization of tumors

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    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.

  15. Radiosensitizers in cervical cancer. Cisplatin and beyond

    International Nuclear Information System (INIS)

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

  16. 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

  17. Silencing survivin gene enhances radio-sensitivity of human hepatoma SMMC-7721

    International Nuclear Information System (INIS)

    In order to investigate the effect of RNA interference silencing survivin gene on radio-sensitivity of human hepatoma SMMC-7721 cells, mRNA and protein expression of survivin gene in SMMC-7721 cells after transfection with pGenesil-survivin-HIF mediated by liposome were detected by RT-PCR and western blot respectively. Cell viability was detected by MTT assay. Cell cycle distribution and apoptosis of SMMC-7721 cells were detected by FCM assay. Radio-sensitivity of SMMC-7721 cells was determined by clonogenic assay. The results showed that mRNA and protein expression of survivin gene in SMMC-7721 cells was significantly lower than that of control and negative interference group 48 h after transfection with pGenesil-survivin (p2/M phase of cell cycle (p0 of SMMC-7721 cells after transfection with pGenesil-survivin decreased and its radio-sensitivity increased. The radio-sensitization ratio was determined to be 1.24. These results can be suggested that silencing survivin gene enhances radio-sensitivity of human hepatoma SMMC-7721 cells. (authors)

  18. Study of intratumoral administration of hypoxic radiosensitizer

    International Nuclear Information System (INIS)

    Relations between the radiosensitizing effect of the hypoxic radiosensitizer, RP-170, and its intratumoral concentration when injected intratumoral-intratumorally or intraperitoneally, was studied in Lewis lung carcinoma. Intratumoral injection of 400 mg/kg of RP-170 5 min before irradiation had a greater radiosensitizing effect on subcutaneous tumors than intraperitoneal injection 30 min before irradiation. In intramuscular tumors, the effect of the drug injected intraperitoneally 30 min before irradiation was larger than that injected intratumorally 5 min before irradiation, and the same as that of RP-170 injected intratumorally 30 min before irradiation. Intratumoral concentration of the drug injected intratumorally had higher mean values with larger deviation than that injected intraperitoneally. The drug concentration in tumors was only 0.5% of the dose administered 10 min after intratumoral injection and the concentrations 10 min and 30 min after injection were not different. The sensitizing effect on post-irradiated tumors was not so much different from that on non-irradiated tumors for either route of administration, even though the drug concentrations in the tumors were much different. Although epinephrine reduced the radiation effect when injected intratumorally, it inhibited the efflux of intratumorally injected sensitizer from the tumors, so the sensitizing effect with epinephrine was the same as that without. Thus, between its radiosensitizing effect and intratumoral concentration were poorly correlated. This indicates that other factors, such as blood supply, presence of hypoxic cells, and diffusion of the drug in tumors, are related to the radiosensitizing effect. Limited diffusion and easy efflux of drugs injected intratumorally are discussed. We conclude that intratumoral injection of hypoxic radiosensitizer is useful for some tumors, especially tumors with low blood flow. (author)

  19. Radiosensitivities of immune organs' stromal progenitors

    International Nuclear Information System (INIS)

    By using the technique of culture of immuno-stromal progenitors in vitro, we studied their radiosensitivities after irradiation in various doses. The values of D0 and n of thymus, spleen and lymph node were 2.3 Gy and 1.5, 2.8 Gy and 1.2, 2.7 Gy and 1.4 respectively. The radiosensitivity of the CFU-F subgroups which formed dense colonies was significantly higher than that of loose colonies, when cultured in vitro

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

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    Xiaomeng Zhang

    2011-02-01

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

  1. The effects of acetaminophen combine with radiation on the radiosensitivity of filial generation from irradiated human glioma cell line

    International Nuclear Information System (INIS)

    Objective: To study the effects of acetaminophen (ACE) combined with radiation on the filial generation from irradiated human glioma cell line SHG-44 in vitro and to investigate if ACE may prove to be a useful therapeutic agent and be radiosensitive in the treatment of recurrent human glioma. Methods: The SHG-44 cells were irradiated with 6MV X ray and the progeny of the cells were cultured (SHG-44-10 cell line). The population doubling time (PDT) was detected pre-and post-irradiation. The culture of the progeny of irradiated human glioma cell line SHG-44 was treated with ACE to do the radiosensitive experiment. ACE's radiosensitivity was measured by clone forming assay. The cell cycle distribution was analyzed by flow cytometry (FCM). Results: Comparing with SHG-44 cells it was found that growth delay and declined radiosensitivity were confirmed in SHG-44-10 cell after irradiation, but if they were treated with ACE, the radiosensitivity increased. To SHG-44-10 cell, after 12 h irradiation, the percentages of the G2/M phase cells were significantly increased, and then decreased rapidly after treatment ACE for 24 h. While the percentage in the group in which SHG-44 cells were treated with ACE still maintained in high level. Conclusion: (1) In the present study, growth delay and declined radiosensitivity are confirmed in the progeny of irradiated SHG-44 cells. (2)Subtoxic dose of ACE increased the radiosensitivity of the progeny of irradiated human glioma cell line SHG-44. The mechanism may be that the SHG-44 cells were blocked in the G2/M phase of the cell cycle and induce cells apoptosis. (3) ACE may be an useful radiosensitivity in the treatment of recrudescent human malignant glioma. (authors)

  2. Effects of siRNA-silenced CHD6 on radiosensitivity in A549

    International Nuclear Information System (INIS)

    Objective To observe the effects of siRNA-silenced chromatin reconstitution protein CHD6 on the proliferation and radiosensitivity in A549 cells. Methods: CHD6-silenced cellular model was constructed by plasmid mediated siRNA technique. RT-PCR was used to detect the expression of mRNA. Growth curve, flow cytometry and fluorescent staining method were used to measure changes of cell proliferation, cell cycle and apoptosis, respectively. The radiosensitivity of A549 cells was determined with cell cloning efficiency test. Results siRNA-asilence CHD6 increased the growth of A549 cells and enhanced the radiation resistance of A549 cells when gamma irradiation dose was lesser than two grays, whereas it had no significant effect on apoptosis in cells being irradiated with larger doses. Conclusion: Inhibition of CHD6 could enhance cell proliferation and cell radiosensitivity. (authors)

  3. Radiosensitization of DNA in presence of Pt(II)-based compounds

    Science.gov (United States)

    Śmiałek, Małgorzata A.; Ptasińska, Sylwia; Gow, Jason; Pieve, Chiara Da; Mason, Nigel J.

    2014-04-01

    X-ray irradiation of plasmid DNA in presence of platinum (II)-based compounds was carried out in order to assess the radiosensitization capabilities of these drugs. In present investigations pBR322 plasmid DNA was used to monitor the effectiveness of chosen compounds in inducing strand breaks. Samples were incubated in the presence of potential radiosensitisers: platinum (II) bromide and cis-diamminedibromoplatinum (II). The results were examined against a common cancer chemotherapy drug cis-diamminedichloroplatinum (II). It was found that platinum (II) bromide can greatly increase the levels of single- and double-strand break formation observed in the irradiated samples with respect to the samples containing platinum as a radiosensitizer only, possessing very little chemotherapeutic activity. The suggested drugs exhibit much higher level of radiosensitivity than widely used cisplatin and thus may be good candidates for cancer treatment.

  4. Evaluation of radiosensitivity of nasopharyngeal cancer cells by in situ nick translation

    International Nuclear Information System (INIS)

    The radiosensitivity of two nasopharyngeal cell lines was evaluated, which had been treated with γ-rays by in situ nick translation (ISNT). The results indicated that the incorporation rate of dNTP of the two cell lines increased with the radiation dose. Good correlations were found between the radiosensitivity determined by the in situ nick translation assay and confirmed by the colony-forming assay in CNE and CNE-2Z cell lines. Although this report deals with cultured cells, the described technique of detecting DNA nick in situ without destruction of morphology seems to be applicable to tissue section. It may be possible to use it as a tool for predicting radiosensitivity of cancerous tissues treated with γ-rays

  5. 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)

  6. Histamine as a Radiosensitizer of Malignant Cell Lines

    International Nuclear Information System (INIS)

    It has been established that the treatment with Histamine (Hi) produces a significant growth inhibition of different cell lines derived from human neoplasia. In a model of Knockout mice completely depleted of endogenous Hi, it was observed a significant delay in bone marroe repopulation after whole body irradiation. These results are in agreement with the hypothesis that histamine has a role in the regulation of haematopoiesis as well as an inhibitory effect on apoptosis. The objective of this paper was to study the possible effect of Hi as protector of normal cells and radiosensitizer of malignant ones. To study the effect of Hi on small-intestine and bone marrow, thirty made mice were randomly separeted into two groups: Control irradiated (C), and irradiated receiving Histamine (HI-group). All animals received a single dose of 10 Gy on whole-body employing a ''137Cs source of 189 TBq (Dose rate: 7.7 Gy/min) calibrated with TLD 700 dosimeter. Hi-group recieved a daily se injection (0.1 mg/kg) starting 20 hs before irradiation. Mice were sacrificed 5 days after irradiation. Histopathological analysis indicated that intestinal mucosae of C group showed important injury, whist mucosae of Hi-treated mice showed mild mucosal atrophy with conservation of villous projections and absence of vascular congestive changes. In order to investigate the effect of Hi on radiosensitivity of transformed cells, MDA-MB-231 (human breast carcinoma cells) were irradiated in vitro with doses ranging from 0 to 10 Gy. Results of radiobiological parameters indicate a significant increase on radiosensitivity of malignant cells. Employing specific fluorescent dyes and flow cytometric analysis we determined that the intracellular levels of hydrogen peroxide (H2O2) are significant increased by Hi 10 μM in control and also in irradiated MDA-MB-231 cells, while the levels of superoxide (SO2) were not significantly modified by Hi-treatment. (Author) 9 refs

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

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    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.

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

    International Nuclear Information System (INIS)

    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. Growth and radiosensitivity of embryonic fowl femurs in vivo and in vitro

    International Nuclear Information System (INIS)

    Cultured embryonic chicken femurs revealed a higher radioresistance than femurs grown in the ovum. After irradiation in vitro and in ovo, resp., growth-promoting as well as growth-retarding ranges of radiation could be distinguished. The in ovo growth curves showed between the 9th and the 11th day of development a step of differentiation concerning the ossification. Accordingly femurs of 9 and 11 day old chicken embryos revealed a different growth in tissue culture following explantation. As to the radiosensitivity there were age differences of the cultured femurs according to decreasing radiosensitivity with increasing differentiation

  10. 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.

  11. Radiosensitivity of quince seeds (Cydonia oblonga Mill.)

    International Nuclear Information System (INIS)

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

  12. Radiosensitivity testing of primary cervical carcinoma

    International Nuclear Information System (INIS)

    Biopsies from 89 patients with cervical carcinoma were studied using a clonogenic assay to obtain values for the surviving fraction at 2 Gy (SF2). Heterogeneity in intrinsic radiosensitivity was investigated by independently processing multiple biopsies from 18 tumors. No significant differences between intratumour SF2 values were demonstrated (p = 0.30). The results have shown that intra-tumour heterogeneity is not a limitation to radiosensitivity testing using the Courteney-Mills assay. A wide range of values (0.13-0.97) for SF2 was obtained with a mean value of 0.47 ± 0.18 (± 1 S.D., CV = 38%) for 52 squamous cell carcinomas and 0.59 ± 0.27 for four adenocarcinomas. There were statistically significant differences between the individual tumours (P 2 results it appears to be the surviving fractions below about 0.40 and those above about 0.7 which show significant differences in radiosensitivity between pairs of tumours (p = 0.05). Also 36% of the values of SF2 show significant differences from the mean SF2 of all tumours. The storage of tumour cell suspensions in liquid nitrogen improved the colony-forming efficiency (CFE) but it did not alter the radiosensitivity. (author). 26 refs.; 5 figs.; 1 tab

  13. Radiosensitization by the novel DNA intercalating agent vosaroxin

    International Nuclear Information System (INIS)

    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. 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. 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 = 0.042), or radiation alone (p = 0.039) after

  14. In situ tumour radiosensitization induced by clofibrate administration

    International Nuclear Information System (INIS)

    It is generally accepted that hypoxia is a common occurrence in many experimental and human tumors and that it is a major cause of local failure after radiotherapy. Many attempts have been made over the last years to eliminate this problem. One of the manoeuvres to improve tumour oxygenation is to manipulate the binding affinity of oxygen (O2) and haemoglobin (Hb). Previous studies have shown that some antilipidaemic drugs (clofibrate and its analogues) can reduce the Hb/O2 binding affinity and sensitize various animal tumors to radiation. The present study evaluated the ability of clofibrate to sensitize in situ a mouse carcinoma (CaNT) to radiation. Clofibrate at 1.5 mmol/kg increased the tumor radiosensitivity, when it was administered per os 2-6 h before a single radiation dose or 2-4 h before each of 10 fractions in 5 days. In both the single dose and fractionated regimens, the radiosensitizing effect was drug dose-dependent, but was only statistically significant at doses from 1.0 to 2.0 mmol/kg. These results suggest that clofibrate may be an effective sensitizer at radiation doses that are clinically relevant. Further experiments need to be carried out to evaluate clofibrate analogues for their radiosensitizing properties. Clofibrate tolerable doses in man have to be determined first in order to know if clofibrate and analogues could play a role in the clinical management of tumors where hypoxia may limit the outcome of radiotherapy. (author). 25 refs.; 3 figs.; 1 tab

  15. Radiosensitivity of CD3-CD8+CD56+ NK cells

    Energy Technology Data Exchange (ETDEWEB)

    Vokurkova, Doris [Charles University in Prague, Faculty of Medicine in Hradec Kralove, Department of Medical Biochemistry, Simkova 870, 50038 Hradec Kralove 1 (Czech Republic); Vavrova, Jirina [University of Defence, Faculty of Military Health Sciences, Department of Radiobiology, Hradec Kralove (Czech Republic); Sinkora, Jiri [Becton Dickinson (Czech Republic); Stoklasova, Alena [Charles University in Prague, Faculty of Medicine in Hradec Kralove, Department of Medical Biochemistry, Simkova 870, 50038 Hradec Kralove 1 (Czech Republic); Blaha, Vaclav [University of Defence, Faculty of Military Health Sciences, Department of Radiobiology, Hradec Kralove (Czech Republic); Rezacova, Martina, E-mail: rezacovam@lfhk.cuni.c [Charles University in Prague, Faculty of Medicine in Hradec Kralove, Department of Medical Biochemistry, Simkova 870, 50038 Hradec Kralove 1 (Czech Republic)

    2010-10-15

    The effect of lower doses (0.5-3.0 Gy) of gamma radiation on radiosensitivity of CD3-/CD8+ NK cells subpopulation isolated from the peripheral blood of healthy volunteers was studied 48 h after the irradiation. Only a subtle increase in terms of induction of apoptosis (A+ cells), was observed in Annexin positive CD3-/CD8+ NK cells. The assessment of the relative presence of CD3{sup -}/CD8{sup +} NK cells in Annexin negative populations of lymphocytes considerably contributes to the elimination of individual variability and could be useful in biodosimetry. Living CD3-/CD8+; Annexin negative NK cells were analyzed using five-color flow cytometry 16 h after irradiation by the doses of 1-10 Gy. The study was carried out on NK cells subsets CD3-/CD8- CD16+, CD56 (dim) and CD56 (bright). NK cells characterized with their low-density expression of CD56 (dim) are more cytotoxic and express CD16. Those with high-density expression of CD56 (bright) are known for their capacity to produce cytokines following activation of monocytes but their natural cytotoxicity is low; they are classified as CD16- or CD16 (dim). A dose-depending decrease in the relative presence of CD3-/CD8+ NK cells was observed 16 h after ionizing radiation (1-10 Gy). The decrease was highly pronounced in CD56 (bright) subset of NK cells and this subpopulation was considered as the most radiosensitive one. Unfortunately, the most radiosensitive subpopulation of NK cells - CD56bright cannot be used as a biodosimetric marker due to its insufficient amount in peripheral blood.

  16. Radiosensitizing and cytotoxic effects of hyperthermia on various biological systems. Radiosensitizing and cytotoxic effect of hyperthermia on mouse leukosis La cells

    Energy Technology Data Exchange (ETDEWEB)

    Shtejn, L.V.; Konoplyannikov, A.G. (Akademiya Meditsinskikh Nauk SSSR, Obninsk. Nauchno-Issledovatel' skij Inst. Meditsinskoj Radiologii)

    When mouse leukosis cell suspensions were subjected to heating the survival rate of animals decreased exponentially with increasing time of heating. It is shown that the increase of temperature for 1 deg C in range 40-45 deg C was equivalent to a decrease in the heating time by a factor of approximately 2. The hyperthermia-induced increase in the radiosensitivity of leukosis cells was dependent upon a medium in which heating was performed.

  17. Lung cancer radiosensitization by CMNa in vitro and in vivo

    International Nuclear Information System (INIS)

    Objective: To probe into the radiosensitization effect of CMNa on lung tumor cell lines after γ-irradiation combined with γ-knife to treat patients suffering from lung cancer. Methods: 1. Cells of small cell lung cancer cell line NCI-H446 and non-small cell lung cancer cell line NCI-H596 irradiated with 60Co γ-rays combined with or without CMNa were counted using trypan blue exclusion methods, and cell survival rate curves were depicted. 2. Patients suffering from lung cancer at different clinical stages were treated using γ-knife combined with or without CMNa, and the curative effect was evaluated 6 weeks after one cycle of treatment. Results: CMNa could significantly increase the sensitivity of lung cancer cell lines to γ-irradiation. Curative effect increased significantly by γ-knife treatment combined with CMNa i. e., the CR+PR rates for these two groups were 47.22% and 37.67% separately (P0.05). Conclusion: CMNa could significantly increase the radiation sensitivity of lung cancer cell line cells in vitro and tumors in vivo, therefore, it could be used as a radiosensitization agent in clinical treatment of lung cancer. (authors)

  18. 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

  19. 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)

  20. Pentoxifylline enhances tumor oxygenation and radiosensitivity in rat rhabdomyosarcomas during continuous hyperfractionated irradiation

    International Nuclear Information System (INIS)

    Purpose: to examine the influence of the hemorrheologic agent pentoxifylline (PTX) on tumor oxygenation and radiosensitivity. Material and methods: tumor oxygenation in rat rhabdomyosarcomas R1H after PTX administration (50 mg/kg body weight) was measured using interstitial pO2 probes (licox CMP system and eppendorf pO2-histograph). Tumors were irradiated with 60Co γ-irradiation using single doses (15 and 30 Gy), conventional fractionation (60 Gy/30 fractions/6 weeks), and continuous hyperfractionation (54 Gy/36 fractions/18 days) in combination with PTX or an equivalent volume of physiological saline. Radiation effects were determined by tumor growth delay (2Vo), and by partial and complete tumor remission. Results: PTX increased tumor oxygenation for up to 45 min after administration of the drug. Single doses of 15 and 30 Gy of irradiation, when combined with PTX, produced little radiosensitization of the R1H tumors as indicated by dose-modifying factors (DMFs) of 1.11 and 1.04, respectively. In conventional fractionated irradiation with PTX, a DMF of 1.10 was obtained only. However, in continuous hyperfractionated irradiation with 18 x 50 mg/kg of PTX, the DMF with respect to tumor growth delay was found to be 1.37. Local tumor control was not influenced by PTX. In vitro studies identified R1H cells as p53 wildtype and showed a G1 arrest in response to irradiation. When 2 mM PTX was given prior to irradiation, it did not improve radiosensitivity of R1H cells as measured by clonogenic survival assays. Conclusion: PTX effectively enhances tumor oxygenation and radiosensitivity of R1H rhabdomyosarcomas, especially during continuous hyperfractionated irradiation. Given to rats as an adjuvant to fractionated irradiation, PTX does not enhance acute or late skin reactions or tumor metastasis. No radiosensitization was observed in vitro, when oxygen was not limiting. The observed radiosensitization by PTX is caused mainly by improved tumor oxygenation. (orig.)

  1. 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

  2. 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)

  3. 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)

  4. New 2-nitroimidazoles: Enhanced radiosensitizing efficiency by the introduction of groups that deplete nonprotein thiols (NPSH)

    International Nuclear Information System (INIS)

    During the past few years structural analogues of misonidazole have been synthesized either to improve the pharmacokinetics or alter the electron affinity to develop a superior radiosensitizing agent. A series of reports have also suggested that the depletion of cellular NPSH results in increased radiosensitization. The authors therefore, report a new class of 2-nitroimidazoles that have been substituted at 1-position by α,β-unsaturated ester or amides, the groups capable of depleting cellular NPSH. These agents were synthesized to enhance radiosensitization not only by increased electron affinity but also by their rapid reaction with endogenous NPSH. Ethyl β[1-(2-nitroimidazolyl)]acrylate (ENA) was one of the most active agent, producing an enhancement ratio of 2.2 at 25μM against Chinese hamster (V-79) cells in vitro. Doses >50 μM were selectively more toxic to hypoxic cells even at a 2 hr exposure time. Hypoxic toxicity increased as a function of time. ENA (0.1 mM) in 30 min caused an 80% depletion of NPSH under aerobic conditions and 100% depletion under hypoxic conditions. ENA thus represents a new class of 2-nitroimidazole derivatives possessing superior radiosensitizing activity

  5. Arsenic trioxide enhances radiosensitivity of nasopharyngeal carcinoma in vitro

    International Nuclear Information System (INIS)

    Objective: To evaluate the ability of arsenic trioxide to sensitize nasopharyngeal carcinoma (NPC) to radiation in vitro. Methods: CNE-1 human nasopharyngeal cancer cell line was treated with arsenic trioxide. Cell survival was determined by clonogenic assay. Cell cycle distribution after As2O3 treatment was analyzed by using flow cytometry. Immunochemistry was used to determine bax, p53 and bcl-2 expressions. Results: As2O3 definitely enhanced radiosensitivity of CEN-1 cells. Cell survival experiments showed sensitivity-enhancement ratio (SER) of 1.33 and 1.57 for 1.0 μmol/L and 1.5 μmol/L of As2O3, respectively. DNA flow cytometric analysis indicated that As2O3 (0.5-2.0 μmol/L) induced efficiently G2/M phase arrest in this cell line following 48 hours of exposure. Meanwhile ,the expression of p53 and bax/bcl-2 increased after As2O3 treatment. Conclusion: As2O3 might be a potential radiosensitizer for NPC. (authors)

  6. Radiosensitivity of antibody responses and radioresistant secondary tetanus antitoxin responses

    International Nuclear Information System (INIS)

    Primary tetanus antitoxin responses were increasingly repressed in mice when gamma radiation doses of 100 to 400 rads were delivered by whole-body exposure prior to immunization with fluid tetanus toxoid (FTT). Nearly normal secondary antitoxin responses were obtained in mice exposed to 600 rads of gamma radiation 4 days after secondary antigenic stimulation with FTT. A rapid transition from radiosensitivity of the antibody-forming system on days 1 to 3 was followed by relative radioresistance on day 4 after the booster injection of toxoid. Studies on lymphoid cellular kinetics in popliteal lymph nodes after injection of 3H--thymidine (3H--TdR) and incorporation of 3H--L-histidine into circulating antitoxin were carried out. Analysis of tritium radioactivity in antigen--antibody precipitates of serums 2 hr after injection of the labeled amino acid revealed maximum incorporation into antibody around day 7 after the booster in nonirradiated controls and about day 12, i.e., 8 days after irradiation, in experimental mice. The shift from radiosensitivity to relative radioresistance was attributed to a marked peak of plasma-cell proliferation in the medulla of lymph nodes on day 3. Many medullary plasma cells survived and continued to proliferate after exposure to radiation. Germinal centers were destroyed by radiation within 1 day. Since antibody formation continued after exposure to radiation and after the loss of germinal centers, this supports the view that germinal-center cells were involved more in the generation of memory cells than in antibody synthesis

  7. In vivo investigation of the radiosensitization of metastases by nitroimidazoles

    International Nuclear Information System (INIS)

    After the surgical removal of a primary Lewis lung tumor transplant from the flank of C57 B1 mice, the metastases occurring in the lung were later used to investigate the action of nitroimidazole compounds as possible radiosensitizers. This system resembles the commonest clinical problem, the presence of potentially lethal metastases after excision of the primary. The left mouse lung was x-irradiated: the right lung acted as a reference. The response measured was the ratio of the summed diameters of metastases per gram lung wt, left/right. This parameter had an approximately log. normal distribution and a satisfactory coefficient of variation in control series of mice. Using 1200 to 2400 rad of x irradiation, misonidazole (Ro-07-0582), a 2-nitroimidazole compound was found to have a radiosensitizing effect on metastases. The difference in the response of the left lung to x irradiation in the absence or presence of the drug was highly statistically significant and showed that a dose of 1.0 mg/g-body wt of the drug increased the effective dose of irradiation by approximately 50%. Metronidazole (Flagyl) a 5-nitro-imidazole compound, used as a single dose, did not enhance the action of 1200 or 2400 rad. Either drug used alone as a single dose was without effect on the size of the metastases. Reasons for the efficacy of Ro-07-0582 compared to Flagyl are discussed and the higher electron-affinity of the 2-nitroimidazole compound is stressed

  8. 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.

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

    International Nuclear Information System (INIS)

    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

  10. RRx-001, A novel dinitroazetidine radiosensitizer.

    Science.gov (United States)

    Oronsky, Bryan; Scicinski, Jan; Ning, Shoucheng; Peehl, Donna; Oronsky, Arnold; Cabrales, Pedro; Bednarski, Mark; Knox, Susan

    2016-06-01

    The 'holy grail' in radiation oncology is to improve the outcome of radiation therapy (RT) with a radiosensitizer-a systemic chemical/biochemical agent that additively or synergistically sensitizes tumor cells to radiation in the absence of significant toxicity. Similar to the oxygen effect, in which DNA bases modified by reactive oxygen species prevent repair of the cellular radiation damage, these compounds in general magnify free radical formation, leading to the permanent "fixation" of the resultant chemical change in the DNA structure. The purpose of this review is to present the origin story of the radiosensitizer, RRx-001, which emerged from the aerospace industry. The 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. PMID:26841903

  11. 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.

  12. Radiosensitivity study of salmonella enteritidis in chickens

    International Nuclear Information System (INIS)

    One of the applications of ionizing radiations in food is the inactivation of vegetative phatogenic bacteria (radicidation) such as Salmonella, Shigella, Campylobacter, Vibro and Listeria. These bacteria are associated with the diseases transmitted by food (ETA). Fresh and frozen farmyard fowls can be contaminated with pathogenic microorganisms, between them Salmonella. In Argentine, between years 1987-1990, Salmonella enteritidis was the main cause of salmonellosis. In food irradiation, with the aim of improving and assuring its hygienic quality, it is important to know the radiosensitivity of microorganisms to be inactivated. Inactivation of a determined microorganism shall depend, between others factors, of the species, strain, number and of the irradiation conditions (temperature, media, etc.). D10 value is a very useful data in order to compare radiosensitivities between the microorganisms and the influence of different factors in their sensitivities. In this paper, it was determined the sensitivity to the gamma radiation of Salmonella enteritidis in fresh and frozen chickens

  13. 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.)

  14. Cultures of cancer patient's skin tissue fibroblast and radiosensitivity assay

    International Nuclear Information System (INIS)

    In order to test the radiosensitivity of normal skin tissue, the authors cultured cancer patient's skin tissue fibroblast, surviving fraction experiment was employed to provide data for understanding of the different radiosensitivity among the cancer patients, Method: cancer patient's skin tissue fibroblast were cultured in vitro by the way of tar's attachment, cells were irradiated by graded doses of γ-ray , cell dose response experiment was used to test the radiosensitivity of cell. Result: Cancer patient's skin fibroblast could be propagated and passaged by the method of culture in vitro. Radiosensitivity are different among the various cancer patient's skin tissue fibroblasts

  15. 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

  16. Evaluation of nitroimidazole hypoxic cell radiosensitizers in a human tumor cell line high in intracellular glutathione

    International Nuclear Information System (INIS)

    Five nitroimidazole hypoxic cell radiosensitizers were evaluated in a human lung adenocarcinoma cell line (A549) whose GSH level was 8-fold higher than Chinese hamster V79 cells. One millimolar concentrations of Misonidazole (MISO), SR-2508, RSU-1164, RSU-1172, and Ro-03-8799 sensitized hypoxic A549 cells to radiation, with Ro-03-8799 giving the highest sensitizer enhancement ration (SER) (2.3). However, MISO, SR-2508 and Ro-03-8799 were less effective in this cell line than in V79 cells, presumably due to higher GSH content of the A549 cells. Increased hypoxic radiosensitization was seen with 0.1 mM Ro-03-8799 after GSH depletion by BSO as compared to 0.1 mM Ro-03-8799 alone (SER-1.8 vs 1.3). The combination of GSH depletion and 0.1 mM Ro-03-8799 was considerably more toxic than 0.1 mM or 1.0 mM Ro-03-8799 alone. This sensitivity was much greater than has been observed for SR-2508. These data show that Ro-03-8799 was the most efficient hypoxic cell radiosensitizer in a human tumor cell line considerably higher in GSH than the rodent cell lines often used in hypoxic radiosensitization studies. Thus, Ro-03-8799 may be a more effective hypoxic cell sensitizer in human tumors that are high in GSH

  17. The chemopreventive flavonoid apigenin confers radiosensitizing effect in human tumor cells grown as monolayers and spheroids

    International Nuclear Information System (INIS)

    Apigenin, a common dietary flavonoid present in many fruits and vegetables, is a nonmutagenic chemopreventive agent. In the present study, we investigated the effect of apigenin on the radiosensitivity of SQ-5 cells, which are derived from a human lung carcinoma. Actively growing cells were incubated for 16 h at 37 deg C in medium containing 40 μM apigenin. The cells were then irradiated with X-rays and incubated with apigenin for a further 8 h. Radiosensitivity was assessed using a clonogenic assay. Apoptosis and necrosis were assessed using acridine orange/ethidium bromide double staining. Cells incubated with apigenin exhibited significantly greater radiosensitivity and apoptosis levels than cells not incubated with apigenin. Protein levels were measured by Western blotting. Incubation with apigenin increased protein expression of WAF1/p21 and decreased protein expression of Bcl-2. Furthermore, apigenin sensitized SQ-5 spheroids (cell aggregates growing in a three-dimensional structure that simulate the growth and microenvironmental conditions of in vivo tumors) to radiation. Thus, apigenin appears to be a promising radiosensitizing agent for use against human carcinomas. (author)

  18. Radiosensitizing and cytotoxic properties of ortho-substituted 4- and 5-nitroimidazoles: role of NPSH reactivity

    International Nuclear Information System (INIS)

    Chinese hamster (V79) cells were used to investigate the radiosensitizing efficiency and chemical reactivity with non-protein sulfhydryl (NPSH) compounds such as glutathione, for a series of sigma-substituted 4 and 5 nitroimidazoles. When added to cells 5 minutes prior to irradiation, MJL-1-191-VII (1-methyl-5-sulfonamide-4-nitroimidazole) sensitizes hypoxic cells commensurate with its electron affinity, while not affecting the radiosensitivity of aerated cells. If the drug is incubated with the cells for a period of time at 370C prior to irradiation, both aerated and hypoxic cells show an increase in radiosensitivity. Under these conditions the radiosensitizing effectiveness towards hypoxic cells appears to be particularly anomalous, inasmuch as enhancement ratios similar to misonidazole can be obtained at concentrations 50 to 100 times lower. The isomer SK-21981 (1-methyl-4-sulfonamide-5-nitroimidazole) does not behave in this anomalous way, but sensitizes to an extent predictable from its electron affinity. These compounds differ in the rate at which they react spontaneously and intracellularly with NPSH compounds such as glutathione. It is suggested that MJL sensitizes by two mechanisms; the first a function of its electron affinity and the second a function of its rapid reaction with endogenous radioprotective and chemotherapeutic compounds in the cell

  19. Differential Radiosensitizing Effect of Valproic Acid in Differentiation Versus Self-Renewal Promoting Culture Conditions

    International Nuclear Information System (INIS)

    Purpose: It has been shown that valproic acid (VA) enhances the proliferation and self-renewal of normal hematopoietic stem cells and that breast cancer stem/progenitor cells can be resistant to radiation. From these data, we hypothesized that VA would fail to radiosensitize breast cancer stem/progenitor cells grown to three-dimensional (3D) mammospheres. Methods and Materials: We used the MCF7 breast cancer cell line grown under stem cell-promoting culture conditions (3D mammosphere) and standard nonstem cell monolayer culture conditions (two-dimensional) to examine the effect of pretreatment with VA on radiation sensitivity in clonogenic survival assays and on the expression of embryonic stem cell transcription factors. Results: 3D-cultured MCF-7 cells expressed higher levels of Oct4, Nanog, and Sox2. The 3D passage enriched self-renewal and increased radioresistance in the 3D mammosphere formation assays. VA radiosensitized adherent cells but radioprotected 3D cells in single-fraction clonogenic assays. Moreover, fractionated radiation sensitized VA-treated adherent MCF7 cells but did not have a significant effect on VA-treated single cells grown to mammospheres. Conclusion: We have concluded that VA might preferentially radiosensitize differentiated cells compared with those expressing stem cell surrogates and that stem cell-promoting culture is a useful tool for in vitro evaluation of novel cancer therapeutic agents and radiosensitizers.

  20. Radiosensitivity of Human Melanoma Cell Lines

    Energy Technology Data Exchange (ETDEWEB)

    Bergoc, R. M.; Medina, V.; Cricco, G.; Mohamed, N.; Martin, G.; Nunez, M.; Croci, M.; Crescenti, E. J.; Rivera, E. S.

    2004-07-01

    Cutaneous melanoma is a skin cancer resulting from the malign transformation of skin-pigment cells, the melanocytes. The radiotherapy, alone or in combination with other treatment, is an important therapy for this disease. the objective of this paper was to determine in vitro the radiosensitivity of two human melanoma cell lines with different metastatic capability: WM35 and MI/15, and to study the effect of drugs on radiobiological parameters. The Survival Curves were adjusted to the mathematical Linear-quadratic model using GrapsPad Prism software. Cells were seeded in RPMI medium (3000-3500 cells/flask), in triplicate and irradiated 24 h later. The irradiation was performed using an IBL 437C H Type equipment (189 TBq, 7.7 Gy/min) calibrated with a TLD 700 dosimeter. The range of Doses covered from 0 to 10 Gy and the colonies formed were counted at day 7th post-irradiation. Results obtained were: for WM35, {alpha}=0.37{+-}0.07 Gy''-1 and {beta}=0.06{+-}0.02 Gy''-2, for M1/15m {alpha}=0.47{+-}0.03 Gy''-1 and {beta}=0.06{+-}0.01 Gy''-2. The {alpha}/{beta} values WM35: {alpha}/{beta} values WM35: {alpha}/{beta}=6.07 Gy and M1/15: {alpha}/{beta}{sub 7}.33 Gy were similar, independently of their metastatic capabillity and indicate that both lines exhibit high radioresistance. Microscopic observation of irradiated cells showed multinuclear cells with few morphologic changes non-compatible with apoptosis. By means of specific fluorescent dyes and flow cytometry analysis we determined the intracellular levels of the radicals superoxide and hydrogen peroxide and their modulation in response to ionizing radiation. The results showed a marked decreased in H{sub 2}O{sub 2} intracellular levels with a simultaneous increase in superoxide that will be part of a mechanism responsible for induction of cell radioresistance. This response triggered by irradiated cells could not be abrogated by different treatments like histamine or the

  1. Mechanisms of modification of radiosensitivity of lymphoid organs of animals adapted to high altitudes

    International Nuclear Information System (INIS)

    It was established, according to DNA metabolism indices, that postradiation destruction of lymphoid organs increases at the early period of adaptation to high-altitude hypoxia and markedly decreases during long-term stay at high altitudes. The radiation effect is ehhanced against the background of inhibited DNA and protein syntheses. With increasing time of adaptation, radiosensitivity diminishes irrespective of the protein and DNA metabolism condition. It was demonstrated that the protein SH-group content of spleen increases concurrently with growing radioresistance

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

    International Nuclear Information System (INIS)

    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 G2/M arrest, and increased the G2 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 G2 checkpoint. We propose that this combination strategy may be useful in clinical applications of UCN-01 for radiotherapy of cancer patients.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  4. Development of an inverse optimization package to plan nonuniform dose distributions based on spatially inhomogeneous radiosensitivity extracted from biological images

    International Nuclear Information System (INIS)

    An inverse optimization package which is capable of generating nonuniform dose distribution with subregional dose escalation is developed to achieve maximum equivalent uniform dose (EUD) for target while keeping the critical structure doses as low as possible. Relative cerebral blood volume (rCBV) maps obtained with a dynamic susceptibility contrast-enhanced MRI technique were used to delineate spatial radiosensitivity distributions. The voxel rCBV was converted to voxel radiosensitivity parameters (e.g., α and α/β) based on previously reported correlations between rCBV, tumor grade, and radiosensitivity. A software package, DOSEPAINT, developed using MATLAB, optimizes the beamlet weights to achieve maximum EUD for target while limiting doses to critical structures. Using DOSEPAINT, we have generated nonuniform 3D-dose distributions for selected patient cases. Depending on the variation of the pixel radiosensitivity, the subregional dose escalation can be as high as 35% of the uniform dose as planned conventionally. The target dose escalation comes from both the inhomogeneous radiosensitivities and the elimination of integral target dose constraint. The target EUDs are found to be higher than those for the uniform dose planned ignoring the spatial inhomogeneous radiosensitivity. The EUDs for organs at risk are found to be approximately equal to or lower than those for the uniform dose plans. In conclusion, we have developed a package that is capable of generating nonuniform dose distributions optimized for spatially inhomogeneous radiosensitivity. Subregional dose escalation may lead to increased treatment effectiveness as indicated by higher EUDs. The current development will impact biological image guided radiotherapy

  5. 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.

  6. Chromosomal radiosensitivity in secondary-progressive multiple sclerosis patients

    International Nuclear Information System (INIS)

    Full text: In the present work we investigate chromosomal radiosensitivity of secondary progressive (SP) phase multiple sclerosis (MS) in comparison to a group of healthy individuals. Chromosomal radiosensitivity was assessed in vitro with the G2 assay and the G0 micronucleus (MN) assay. For the G2 assay PHA stimulated blood cultures were irradiated with a dose of 0.4 Gy 60Co γ rays in the G2 phase of the cell cycle. For the MN assay unstimulated blood cultures were exposed to 3.5 Gy 60Co γ rays delivered at a high dose - rate (HDR = 1 Gy / min) or low dose-rate (LDR = 4 mGy / min). This study shows that concerning the spontaneous formation of chromatid breaks there is no difference between MS patients and healthy individuals. On the contrary, the mean spontaneous micronucleus yield is higher in MS patients compared to healthy individuals. This observation was further sustained by the finding of an increased frequency of cells with multiple-micronuclei in MS patients. In our study the most prominent results were obtained with the LDR MN assay. The mean MN value as well as the frequency of multi-micronucleated cells was significantly lower in MS patients, pointing to an increased radioresistance in MS patients compared to healthy controls. This increased radioresistance could not be demonstrated with HDR MN assay or with the G2 assay. With the HDR MN assay no difference was observed between MS patients and healthy controls. With the G2 assay a higher mean radiation induced G2-index of 1.21 was obtained in MS compared to healthy control group (1.09) but this difference is not statistically significant (p=0.11). The distribution of individuals responses concerning the G2 index is also rather similar in the group of SPMS and the healthy controls. The radioresistance observed at LDR irradiation in the lymphocytes of SPMS patients may be due to an adaptive like response induced by the in vivo protracted oxidative stress exposure of lymphocytes associated with the AP

  7. 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

  8. Histamine as a Radiosensitizer of Malignant Cell Lines

    Energy Technology Data Exchange (ETDEWEB)

    Rivera, E. S.; Medina, V.; Cricco, G.; Mohamed, N.; Croci, M.; Martin, G.; Nunez, M.; Bergoc, R. M.

    2004-07-01

    It has been established that the treatment with Histamine (Hi) produces a significant growth inhibition of different cell lines derived from human neoplasia. In a model of Knockout mice completely depleted of endogenous Hi, it was observed a significant delay in bone marroe repopulation after whole body irradiation. These results are in agreement with the hypothesis that histamine has a role in the regulation of haematopoiesis as well as an inhibitory effect on apoptosis. The objective of this paper was to study the possible effect of Hi as protector of normal cells and radiosensitizer of malignant ones. To study the effect of Hi on small-intestine and bone marrow, thirty made mice were randomly separeted into two groups: Control irradiated (C), and irradiated receiving Histamine (HI-group). All animals received a single dose of 10 Gy on whole-body employing a ''137Cs source of 189 TB{sub q} (Dose rate: 7.7 Gy/min) calibrated with TLD 700 dosimeter. Hi-group recieved a daily se injection (0.1 mg/kg) starting 20 hs before irradiation. Mice were sacrificed 5 days after irradiation. Histopathological analysis indicated that intestinal mucosae of C group showed important injury, whist mucosae of Hi-treated mice showed mild mucosal atrophy with conservation of villous projections and absence of vascular congestive changes. In order to investigate the effect of Hi on radiosensitivity of transformed cells, MDA-MB-231 (human breast carcinoma cells) were irradiated in vitro with doses ranging from 0 to 10 Gy. Results of radiobiological parameters indicate a significant increase on radiosensitivity of malignant cells. Employing specific fluorescent dyes and flow cytometric analysis we determined that the intracellular levels of hydrogen peroxide (H{sub 2}O{sub 2}) are significant increased by Hi 10 {mu}M in control and also in irradiated MDA-MB-231 cells, while the levels of superoxide (SO{sub 2}) were not significantly modified by Hi-treatment. (Author) 9 refs.

  9. 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

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

    International Nuclear Information System (INIS)

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

  11. Physico-chemical basis of radiosensitization by iodine compounds

    International Nuclear Information System (INIS)

    This paper reviews the physico-chemical basis of radiosensitization by iodine compounds and discusses the likely mechanisms involved. Experiments on the radio-sensitization of bacteria by iodoacetate, iodoacetamide and potassium iodide are performed. A brief historical outline of the development of current ideas is given. (UK)

  12. Modern concepts for basic radiobiological factors characterizing tumor tissue radiosensitivity

    International Nuclear Information System (INIS)

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

  13. Taxonomic and developmental aspects of radiosensitivity

    International Nuclear Information System (INIS)

    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

  14. 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

  15. 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.

  16. 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

  17. Individual variability of seeds radiosensitivity in two species of Betula

    International Nuclear Information System (INIS)

    Interspecific variability of the seed radiosensitivity of common birch (Betula verrucosa) and of while birch (Betula pubescens) have been studied experimentally. Seeds from different trees of both birch species differ considerably in sowing properties and in the response to γ radiation. Level of variability of seed germination and of seedlings ability to survive in the variant without radiation effect is lower for the common birch (Betula verrucosa). Presowing irradiation of seeds in dose of 40 krad causes the increase of the level of seed germination of commmon birch (Betula verrucosa) in 6 times and of white birch (Betula pubescens) in 2 times. No differences are found in dose dependence between two series of different-ploid birch according to averaged values of seed germination for each excerpt

  18. 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)

  19. Radiosensitivity of chromosomes in two successive mitotic cycles of human lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Luchnik, N.V.; Poryadkova, N.A.

    1988-11-01

    A culture of human lymphocytes was irradiated with /gamma/-quanta in a dose of 0.5 Gy with different ratios of cells in first (M1) and second (M2) mitotic cycle and the frequency of aberrations induced at stage G2 was analyzed. With increase in interval of time between the start of culturing and irradiation, total yield of aberrations increased in a regular way. However, if the M1:M2 ratio is considered, then it turns out that in M2 chromosomes are /approximately/1.5 times more sensitive than in M1: within the limits of each cycle, radiosensitivity is constant and does not depend on its duration. It was established in accordance with data of other authors that 5-bromodeoxyuridine (5-BdU) increases radiosensitivity materially.

  20. 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.

  1. Combined radiation-protective and radiation-sensitizing agents. II. Radiosensitivity of hypoxic or aerobic Chinese hamster fibroblasts in the presence of cysteamine and misonidazole: implications for the oxygen effect with Appendix on calculation of dose-modifying factors

    International Nuclear Information System (INIS)

    Experiments have been done to test whether a hypoxic cell radiosensitizing agent (misonidazole) can be combined with a radioprotecting agent (cysteamine) to equalize partially the radiation response of hypoxic and aerobic mammalian cells in tissue culture. The results indicate that cysteamine will protect against the radiosensitization of a hypoxic cell sensitizing drug (2.5 mM misonidazole) at much lower concentration than it will protect against the radiosensitization of oxygen (350 μM). Thus the addition of a radiation-protective drug tends to cancel the drug benefit of the radiosensitizer and therefore increases the differential response of hypoxic and aerobic cells rather than equalizing this response. The data suggest that even in situations where tumor tissue absorbs far less radioprotective drug than normal tissue (e.g., WR 2721), one might expect difficulties with the simultaneous administration of radiosensitizing and radioprotecting drugs

  2. Radiosensitization by Inhibiting STAT1 in Renal Cell Carcinoma

    International Nuclear Information System (INIS)

    Purpose: Renal cell carcinoma (RCC) has been historically regarded as a radioresistant malignancy, but the molecular mechanism underlying its radioresistance is not understood. This study investigated the role of signal transducer and activator of transcription 1 (STAT1), a transcription factor downstream of the interferon-signaling pathway, in radioresistant RCC. Methods and Materials: The expressions of STAT1 and STAT3 in 164 human clear cell RCC samples, 47 papillary RCC samples, and 15 normal kidney tissue samples were examined by microarray expression profiling and immunohistochemistry. Western blotting was performed to evaluate the total and phosphorylated STAT1 expression in CRL-1932 (786-O) (human clear cell RCC), SKRC-39 (human papillary RCC), CCL-116 (human fibroblast), and CRL-1441 (G-401) (human Wilms tumor). STAT1 was reduced or inhibited by fludarabine and siRNA, respectively, and the effects on radiation-induced cell death were investigated using clonogenic assays. Results: STAT1 expression, but not STAT3 expression, was significantly greater in human RCC samples (p = 1.5 x 10-8 for clear cell; and p = 3.6 x 10-4 for papillary). Similarly, the expression of STAT1 was relatively greater in the two RCC cell lines. STAT1 expression was reduced by both fludarabine and siRNA, significantly increasing the radiosensitivity in both RCC cell lines. Conclusion: This is the first study reporting the overexpression of STAT1 in human clear cell and papillary RCC tissues. Radiosensitization in RCC cell lines was observed by a reduction or inhibition of STAT1 signaling, using fludarabine or siRNA. Our data suggest that STAT1 may play a key role in RCC radioresistance and manipulation of this pathway may enhance the efficacy of radiotherapy

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

    International Nuclear Information System (INIS)

    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 γH2AX 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 IC50 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 γH2AX 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.)

  4. 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.)

  5. Modification of bone marrow radiosensitivity by medicinal plant extracts

    International Nuclear Information System (INIS)

    Withaferin A (WA), a steroidal lactone, and Plumbagin (Pi), a naphthoquinone, from the roots of Withania somnifera and Plumbage rosea, respectively, have been shows to possess growth inhibitory and radiosensitizing effects on experimental mouse tumours. An aqueous extract of the leaves of Ocimum sanctum (OE) was found to protect mice against radiation lethality. Therefore, the radiomodifying effects of the above plant products on the bone marrow of the adult Swiss mouse was studied. Single doses of WA (30 mg kg-1) or P1 (5 mg kg-1) were injected intraperitoneally tip) and OE (10 mg kg-1) was injected ip once daily for five consecutive days. Administration of extracts was followed by 2 Gy whole body gamma irradiation. Bone marrow stem cell survival was studied by an exogenous spleen colony unit (CFU-S) assay. The effects of WA and P1 were compared with that of cyclophosphamide (CP) and radioprotection by OE was compared with that of WR-2721 (WR). Radiation reduced the CFU-S to less than 50% of normal. WA, CP and P1 significantly enhanced this effect and reduced the CFU-S to almost the same extent (to <20% of normal), although individually WA and P1 were less cytotoxic than CP. These results indicate that radiosensitization by WE and P1 is not tumour specific. OE significantly increased CFU-S compared with radiotherapy (RT) alone. OE + RT gave a higher stem cell survival (p < 0.05) than that produced by WR + RT. While WR alone had a toxic effect, OE treatment showed no such effect, suggesting that the latter may have an advantage over WR in clinical application. (author)

  6. Radiosensitivity and thermosensitization of thermotolerant Chinese hamster cells and RIF-1 tumors

    International Nuclear Information System (INIS)

    CHO cells subline HA-1 were made thermotolerant by a priming heat treatment(430C, 30 min). Later, 4, 16, or 24 hr, they were either irradiated or heated (430C, 30 min) and irradiated. Thermotolerance had no effect on the radiation sensitivity of the cells as measured by the D0 value of the clonogenic survival curve. However the N value of the curve (width of shoulder) showed a significant increase at 24 hr, indicating an increased capacity to accumulate sublethal damage. The same priming treatment was given to RIF-1 tumors growing in C3H mice. Later, 24 hr, when the tumors were either irradiated or heated (430C, 30 min) and irradiated, it was found that thermotolerance had no effect on the radiosensitivity of the cells as measured by in vitro assay. However, thermal radiosensitization was not apparent 24 hr after the priming treatment

  7. 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)

  8. 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

  9. 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...

  10. 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

  11. Serial cytological assay of micronucleus induction: a new tool to predict human cancer radiosensitivity

    International Nuclear Information System (INIS)

    Background and purpose: The micronucleus test, generally done in cultured tumour cells irradiated in vitro, has not gained wide acceptance in predicting human cancer radiosensitivity. The purpose of this study was to see if micronucleus assay by serial scrape smear cytology can predict oral cancer radiosensitivity. Materials and methods: Forty nine oral cancer patients given radiotherapy (60 Gy/25 fractions/5 weeks) form the study population. Serial scrape smears were taken from their tumours before treatment and after delivery of 2, 5, 8 and 12 fractions, stained by Giemsa and the number of micronucleated cells (MNC) noted. The patients were grouped to those who developed tumour recurrence ('Resistant') and those who did not ('Sensitive'), and the pattern of micronucleus induction compared. Results: Both groups of tumours had MNC even before treatment, with statistically significant dose-related increase with radiotherapy. The sensitive group had a higher mean increase in MNC count than the resistant group (6.1 times and 3.6 times the pre-treatment value, respectively) and better correlation with dose (r=0.54 vs. 0.43). The increase in MNC count occurred earlier in the resistant group than in the sensitive, the TMNC (time for the pre-treatment value to double) being 3.3 days and 7.6 days, respectively. Also, the resistant group showed a plateauing of the MNC count which the sensitive group lacked. Conclusion: The higher MNC induction in the sensitive tumours suggests the usefulness of the assay as a test of radiosensitivity. The differing patterns of MNC increase suggest that differences in proliferation rate is an important cause of tumour failure. Serial cytological assay of micronucleus induction can identify both radiosensitivity and proliferation characteristics of tumours, and thus may turn out to be a useful test of radiocurability

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

    OpenAIRE

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

    2012-01-01

    The anti-cancer effects of metformin, the most widely used drug for type 2 diabetes, alone or in combination with ionizing radiation were studied with MCF-7 human breast cancer cells and FSaII mouse fibrosarcoma cells. Clinically achievable concentrations of metformin caused significant clonogenic death in cancer cells. Importantly, metformin was preferentially cytotoxic to cancer stem cells relative to non-cancer stem cells. Metformin increased the radiosensitivity of cancer cells in vitro, ...

  13. A comparison of the intracellular uptake and radiosensitization efficiency in different media of uncharged 2-nitroimidazoles of varying lipophilicity

    International Nuclear Information System (INIS)

    The effect of varying octanol: water partition coefficients, P, (range 0.026-260) on the uptake of uncharged 2-nitroimidazoles into Chinese hamster V79 379A cells has been studied. The radio of intracellular concentration of radiosensitizer to extracellular concentration (Csub(i)/Csub(e)) for misonidazole (P = 0.43) was 0.85 for the oil and 0.68 for the aqueous method. When P was less than about 0.05, uptake was initially very slow and Csub(i) always less than Csub(e). When P > = 0.1 uptake was rapid and remained unchanged for up to 3 h; for P > = 10, Csub(i)/Csub(e) increased rapidly as P increased. Ro 31-1405 (P = 260) concentrated by a factor of 7 inside the cell. Although uptake was identical for cells suspended in full growth medium and PBS, radiosensitization was greater for cells in PBS: 1 mmol dm-3 misonidazole gave an enhancement ratio of 1.6 in full growth medium and 1.9 in PBS. This increase in radiosensitization could not be accounted for by protein binding. Measurements on cellular non-protein sulphydryl (NPSH) demonstrated levels reduced to about 60% for cells in PBS. Similar reductions in NPSH levels have previously been shown not to increase control cells radiosensitivity but to increase greatly the effectiveness of nitroimidazoles. (author)

  14. 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

  15. Prediction of radiosensitivity of oral cancers by serial cytological assay of nuclear changes

    International Nuclear Information System (INIS)

    Background and purpose: To identify the relationship between the radiosensitivity of oral cancers and the induction of micronucleation, nuclear budding and multinucleation (polynucleation) evaluated by serial cytology during fractionated radiotherapy. Materials and methods: Forty-four patients with epidermoid cancer of the oral cavity receiving radiotherapy (60 Gy in 25 fractions over 5 weeks) were studied. Serial scrape smears were taken from the tumour before and during radiotherapy and stained by Giemsa and the frequency of micronucleated cells (MNC), nuclear budded cells (NBC) and multinucleated cells (PNC) was evaluated by light microscopy. After a minimum follow-up period of 30 months the patients were classified as having resistant or sensitive tumours, depending on whether the primary tumour had recurred or not within that time. Within-group and between-group analysis on the induction of the above individual parameters and two combined parameters, the micro- or multinucleated cell (MPC) count and the abnormally nucleated cell (ANC) count, was done. The counts were expressed per 1000 uni-nucleated cells. Results: In both groups each parameter showed a statistically significant increase with dose, the increase being higher in the sensitive group. The ANC count showed the greatest increase, the mean counts before treatment and after 28.8 Gy being 24.3 and 157.8 (P<0.0005), respectively, in the sensitive group and 21.0 and 65.2 (P<0.0005), respectively, in the resistant group. After 28.8 Gy the sensitive tumours had significantly higher ANC (P=0.01), MPC (P<0.05) and PNC (P<0.05) counts. Conclusion: The study shows that serial cytological assay of nuclear changes (SCANCing) during radiotherapy is a potentially useful test to predict radiosensitivity. The fact that multinucleation showed the greatest relation with radiosensitivity suggests that injury to the cytokinetic apparatus is important in determining tumour radiosensitivity. (Copyright (c) 1998 Elsevier

  16. 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.

  17. 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

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

    International Nuclear Information System (INIS)

    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

  19. Constitutive NF-κB activity influences basal apoptosis and radiosensitivity of head-and-neck carcinoma cell lines

    International Nuclear Information System (INIS)

    Purpose: Nuclear factor-κB (NF-κB) has been implicated in anti-apoptotic gene transactivation, according to its transcriptional activity. The present study was designed to investigate whether constitutive NF-κB activity could modulate basal apoptosis and intrinsic radiosensitivity of KB head-and-neck carcinoma cell line and KB3 subline. The KB3 subline was more radiosensitive (SF2=0.48, α=0.064) than the radioresistant KB parental cell line (SF2=0.80, α=0.114). Methods and Materials: Constitutive NF-κB DNA-binding activity was determined using electrophoretic mobility shift assay. Modulation of NF-κB activity was performed by exposing both cell lines to tumor necrosis factor α or dexamethasone. Apoptotic cell population was analyzed using flow cytometry (annexin V/propidium iodide). Radiosensitivity was assessed from determination of the surviving fraction at 2 Gy (SF2), and α and β parameters were determined using the linear-quadratic model. Results: Constitutive NF-κB activity was found to be significantly lower in KB3 than in KB. KB cell line exposure to dexamethasone significantly decreased NF-κB DNA-binding activity and, consequently, enhanced baseline apoptosis and radiosensitivity (α values: 0.114 vs. 0.052). Conversely, exposure of KB3 cells to tumor necrosis factor α increased NF-κB DNA-binding activity and resulted in a significant decrease (50%) in rate of apoptosis and in radiosensitivity (SF2 values: 0.48 vs. 0.63). Conclusions: Modulation of NF-κB DNA-binding activity influences baseline apoptosis and intrinsic radiosensitivity

  20. Alterations in growth phenotype and radiosensitivity after fractionated irradiation of breast carcinoma cells from a single patient

    International Nuclear Information System (INIS)

    The purpose was to investigate growth regulation and radiosensitivity in surviving clonogens after fractionated irradiation. Four breast carcinoma cell lines isolated from the primary tumor (21NT, 21PT) and metastases (21MT-1, 21MT-2) of a single patient were exposed to cumulative radiation doses of 30 Gy yielding cell lines designated -IR with respect to their parent. The irradiated lines were then compared to their parent for serum- and growth factor-requirements under defined media conditions, ability to proliferate in soft agar, concentration of TGF-alpha in conditioned medium, and radiosensitivity. The irradiated lines showed no change in proliferative doubling times under serum- and growth factor-supplemented media conditions. A single line, 21MT-1-IR, acquired a limited ability to proliferate in serum- and growth factor-deplete medium with a day 2-4 doubling time of 44.5 hr. Three lines, 21MT-1-IR, 21MT-2-IR, and 21NT-IR, formed colonies in soft agar in contrast to none of the unirradiated parent lines. There were significant 6-8 fold increases in conditioned media TGF-alpha concentrations for 21MT-2-IR and 21NT-IR cells. The 21MT-1-IR and 21NT-IR cells were significantly less radiosensitive than their respective parent lines. This decrease in radiosensitivity appeared to be at least partially mediated by a released factor as the radiosensitivity of 21MT-1 cells was significantly decreased by pre-incubation with conditioned medium from 21MT-1-IR cells. Radiation-induced changes in growth phenotype vary with respect to clonal origin of the cell line and may influence the radiosensitivity of surviving clonogens after fractionated treatment. 18 refs., 4 figs., 3 tabs

  1. 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

  2. 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

  3. Pentoxifylline enhances tumor oxygenation and radiosensitivity in rat rhabdomyosarcomas during continuous hyperfractionated irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Zywietz, F. [Inst. for Biophysics and Radiobiology, Univ. Hospital Hamburg-Eppendorf, Hamburg (Germany); Boehm, L. [Dept. of Pharmacology, Univ. of Stellenbosch, Tygerberg (South Africa); Sagowski, C.; Kehrl, W. [Dept. of Oto-Rhino-Laryngology, Univ. Hospital Hamburg-Eppendorf, Hamburg (Germany)

    2004-05-01

    Purpose: to examine the influence of the hemorrheologic agent pentoxifylline (PTX) on tumor oxygenation and radiosensitivity. Material and methods: tumor oxygenation in rat rhabdomyosarcomas R1H after PTX administration (50 mg/kg body weight) was measured using interstitial pO{sub 2} probes (licox CMP system and eppendorf pO{sub 2}-histograph). Tumors were irradiated with {sup 60}Co {gamma}-irradiation using single doses (15 and 30 Gy), conventional fractionation (60 Gy/30 fractions/6 weeks), and continuous hyperfractionation (54 Gy/36 fractions/18 days) in combination with PTX or an equivalent volume of physiological saline. Radiation effects were determined by tumor growth delay (2V{sub o}), and by partial and complete tumor remission. Results: PTX increased tumor oxygenation for up to 45 min after administration of the drug. Single doses of 15 and 30 Gy of irradiation, when combined with PTX, produced little radiosensitization of the R1H tumors as indicated by dose-modifying factors (DMFs) of 1.11 and 1.04, respectively. In conventional fractionated irradiation with PTX, a DMF of 1.10 was obtained only. However, in continuous hyperfractionated irradiation with 18 x 50 mg/kg of PTX, the DMF with respect to tumor growth delay was found to be 1.37. Local tumor control was not influenced by PTX. In vitro studies identified R1H cells as p53 wildtype and showed a G1 arrest in response to irradiation. When 2 mM PTX was given prior to irradiation, it did not improve radiosensitivity of R1H cells as measured by clonogenic survival assays. Conclusion: PTX effectively enhances tumor oxygenation and radiosensitivity of R1H rhabdomyosarcomas, especially during continuous hyperfractionated irradiation. Given to rats as an adjuvant to fractionated irradiation, PTX does not enhance acute or late skin reactions or tumor metastasis. No radiosensitization was observed in vitro, when oxygen was not limiting. The observed radiosensitization by PTX is caused mainly by improved tumor

  4. 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.

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

    DEFF Research Database (Denmark)

    Serakinci, Nedime; Christensen, Rikke; Graakjaer, Jesper;

    2007-01-01

    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 r...... high telomerase activity have the advantage of re-establishing the telomeric caps...

  6. 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)

  7. 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).

  8. 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

  9. 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.

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

    International Nuclear Information System (INIS)

    Retinoblastoma is the most common intraocular malignant tumor in children. Previous investigations have reported that buthionine sulfoximine (BSO) can deplete intracellular glutathione (GSH) by the specific inhibition and increase cellular radiosensitivity. The toxic effects, GSH depletion and radiosensitivity of BSO on retinoblastoma were reported. GSH content of retinoblastoma cell lines Y-79, So-Rb50 and retinoblastoma xenograft is (2.7 +- 1.3) x 10-12 mmol/cell, (1.4 +- 0.2) x 10-12 mmol/cell, and 2.8 +- 1.2 μmol/g respectively. The ID50 of BSO on Y-79 and So-Rb50 in air for 3h exposure is 2.5 mM and 0.2 mM respectively. GSH depletion by 0.1 mM BSO for 24h on Y-79 cells and 0.01 mM BSO for 24 h on So-Rb50 cells is 16.35%, and 4.7% of control. GSH depletion in tumor and other organ tissues in retinoblastoma bearing nude mice after BSO administration is differential. BSH depletion after BSO exposure in Y-79 cells in vitro decrease the D0 value of retinoblastoma cells. The SER of 0.01 mM and 0.05 mM BSO for 24 h under the hypoxic condition is 1.21 and 1.36 respectively. Based on these observations, the authors conclude that BSO toxicity on retinoblastoma cells depends on the characteristics of cell line and BSO can increase hypoxic retinoblastoma cells radiosensitivity in vitro. Further study of BSO radiosensitization on retinoblastoma in vivo using nude mouse xenograft is needed

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

    International Nuclear Information System (INIS)

    Retinoblastoma is the most common intraocular malignant tumor in children. Previous investigations have reported that buthionine sulfoximine (BSO) can deplete intracellular glutathione (GSH) by specific inhibition and increase cellular radiosensitivity. The toxic effects, GSH depletion and radiosensitivity effects of BSO on retinoblastoma cells are reported in this paper. GSH content of retinoblastoma cell lines Y-79, So-Rb50 and retinoblastoma xenograft is 2.7 ± 1.3 X 1.0-12 mmol/cell, 1.4 ± 0.2 X 1.0-12 mmol/cell, and 2.8 ± 1.2 μmol/g, respectively. The ID50 of BSO on Y-79 and So-Rb50 in air for 3 h exposure is 2.5 mM and 0.2 mM, respectively. GSH depletion by 0.1 mM BSO for 24 h on Y-79 cells and 0.01 mM BSO for 24 h on So-Rb50 cells is 16.35%, and 4.7% of control. GSH depletion in tumor and other organ tissues in retinoblastoma-bearing nude mice after BSO administration is differential. GSH depletion after BSO exposure in Y-79 cells in vitro decreases the Do value of retinoblastoma cells. The SER of 0.01 mM and 0.05 mM BSO for 24 h under hypoxic conditions is 1.21 and 1.36, respectively. Based on these observations, the authors conclude that BSO toxicity on retinoblastoma cells depends on the characteristics of the cell line and that BSO can increase hypoxic retinoblastoma cells' radiosensitivity in vitro. Further study of BSO radiosensitization on retinoblastoma in vivo using nude mouse xenografts is needed. 25 refs., 3 figs., 3 tabs

  12. 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)

  13. 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.

  14. 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

  15. 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)

  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. 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

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

    International Nuclear Information System (INIS)

    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. Inhibition of DNA synthesis and radiosensitization effects of thalidomide on esophageal carcinoma TE1 cells

    International Nuclear Information System (INIS)

    Objective: To explore the radiosensitization effect of thalidomide combined with X-ray on esophageal carcinoma TE1 cells. Methods: Cell scratch assay was used to detect the inhibition ability of different concentration of Thalidomide on cell invasion and metastasis. H3-TdR incorporation assay was used to investigate the inhibition of DNA synthesis in TE1 cells by treated with Thalidomide singly or combination with X-rays. The colony formation assay was used to analyze the radiosensitization of Thalidomide effect on TE1 cells. Results: Thalidomide had obvious inhibition effect on TE1 cell metastasis, DNA synthesis and colony formation, which were correlated with drug concentration. The values D0, Dq and SF2 in TE1 cells were gradually decreased with thalidomide concentration increased. When the concentration of thalidomide was 100μg/ml, the SERD0 and SERD0 and SERDq were (1.4±0.2) and (1.5±0.1), respectively, While the concentration of thalidomide was 150 μg/ml, the SERD0 and SERDq were (1.5±0.2) and (1.8±0.2), respectively. Conclusions: Thalidomide could inhibit TE1 cell invasion, metastasis, DNA synthesis, and significantly enhance the radiosensitizing effect on esophageal carcinoma TE1 cells. (authors)

  20. Potential radiosensitizing agents. 6. 2-Nitroimidazole nucleosides: arabinofuranosyl and hexopyranosyl analogues

    International Nuclear Information System (INIS)

    New 2-nitroimidazole nucleosides have been synthesized as radiosensitizers of hypoxic mammalian cells in an attempt to reduce the neurotoxicity and to increase the therapeutic efficacy of this class of agents. The trimethylsilyl derivative of 2-nitroimidazole was condensed with 1-bromo-2,3,5-tri-O-benzoylarabinofuranose in the presence of mercuric cyanide to yield anomeric isomers of arabinofuranosides, which were separated by preparative thin-layer chromatography. Reaction of 2-deoxy-1,3,4,6-tetra-O-acetyl-D-glucose or 3,4,6-tri-O-acetyl-D-glucal with 2-nitroimidazole in the presence of an acid catalyst produced alpha and beta isomers of 2',3'-dideoxy-D-erythro-hex-2'-enopyranosides and an isomeric 3-substituted 1,2,3-trideoxy-D-erythro-hex-1-enopyranose. Hydrolysis of the esters was accomplished with sodium methoxide in methanol at 0 degrees C. The radiosensitizing efficacy of these agents was determined against Chinese hamster (V-79) cells in vitro. The 1-(2',3'-dideoxy-alpha-D-erythro-hex-2'-enopyranosyl)-2-nitroimidazole was the most active agent of this series and was found to be superior to misonidazole as a radiosensitizer

  1. [Radioresistance parameters in head and neck cancers and methods to radiosensitize].

    Science.gov (United States)

    Biau, J; Chautard, E; Miroir, J; Lapeyre, M

    2015-08-01

    Head and neck cancers have been widely studied concerning their sensitivity to radiation therapy. Several parameters affect tumour response to radiation therapy. Some parameters are linked to the tumour. Large or invasive tumours, localization, such as oral cavity or adenopathy, are factors of radioresistance. Others parameters are linked to the patients themselves. Tobacco intoxication during radiotherapy and a low hemoglobin level contribute to radioresistance. More recently, a positive human papilloma virus (HPV) status has been reported to positively affect radiosensitivity. Finally, other parameters are related to tumour biology. Hypoxia, intrinsic radiosensitivity of tumour cells, tumour differentiation and repopulation (provided by Ki-67 index or EGFR level) are components of radiosensitivity. Currently, concurrent chemoradiotherapy is one of the gold standard treatments to overcome clinical outcome of locally advanced head and neck cancer. This combination increases locoregional control and survival. Taxane-based induction chemotherapy can also be an alternative. Another validated approach is the association of radiotherapy with cetuximab (EGFR targeting) but only one randomized study has been published. Fractionation modifications, especially hyperfractionation, have given positive results on both tumour control and survival. Strategies targeting hypoxia improve locoregional control but have less clinical impact. PMID:26119219

  2. Development of a radiosensitizing antioxidant compound and its application in oncoradiological practice

    International Nuclear Information System (INIS)

    In vitro and in vivo testing of a new antioxidant and radiosensitizing compound (6,6'-methylene-bis(2,2,4-trimethyl-1,2-dihydroquinoline)sub(n), abbr. MTDQ) has been carried out. In the introduction a detailed review is given on the chemical radiosensitizing agents. The original results are as follows: MTDQ has no toxic effect neither in acute, nor in chronic treatment; the heamatologic status, the liver- and kidney functions of patients treated with MTDQ were continuously controlled and no changes were observed. The compound is concentrated in the neoplastic tissue where the H2O2 concentration is decreased in situ. MTDQ increases radiosensitivity of both isolated cells and experimental animals. The new compound inhibits the growth of several types of tumours by itself, (NK/Ly and Yoshida solid and ascites tumours). In clinical practice the effect of MTDQ+radiotherapy was examined in cases of 76 tumours of different types previously proved to be resistant to both surgical and radiotherapy, of 11 hepatic metastases, of 65 basaliomas and of 17 mamma-carcinomas in the late stadium. The results are presented in detailed case reports and tables. In the majority of cases MTDQ+radiotherapy resulted in local regression of the tumour and in improvement of the general condition of patients for 6-12 months. In the case of disseminated tumours only minor results were achieved. (L.E.)

  3. 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.

  4. 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

  5. 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

  6. 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)

  7. Location of radiosensitive organs, measurement of absorbed dose to radiosensitive organs and use of bismuth shields in paediatric anthropomorphic phantoms

    International Nuclear Information System (INIS)

    The aim of this study was to investigate: firstly, (i) location of radiosensitive organs in the interior of four (4) paediatric anthropomorphic phantoms, and, secondly, (ii) effectiveness of single and double bismuth thyroid shields, distance between shield and phantom surface, during paediatric multi-detector computed tomography (MDCT) using fixed tube current (FTC) and automatic exposure control (AEC) on dose reduction and image quality. Four (4) paediatric anthropomorphic phantoms representing the equivalent of a newborn, 1-, 5-, and 10-y-old child underwent head, thorax and abdomen computed tomography (CT) scans. CT and magnetic resonance imaging scans of all children aged 0-16 y-old performed during a 5-y-period at the University Hospital of Heraklion, Crete, Greece were reviewed, and five hundred and three (503) were found to be eligible for normal anatomy. Anterior-posterior and lateral dimensions of twelve (12) of the above children closely matched that of the phantoms' thoracic and abdominal region in each four (4) phantoms. The mid-sagittal plane (MSP) and mid-coronal plane (MCP) were drawn on selected matching axial images of patients and phantoms. Multiple points outlining large radiosensitive organs and centres of small organs in patient images were identified at each slice level and their orthogonal distances from the MSP and MCP were measured. The outlines and centres of all radiosensitive organs were reproduced using the coordinates of each organ on the corresponding phantom's transverse images. The four (4) phantoms were also subjected to routine head and neck, neck and thorax CT scans on a 16-slice CT system. Each phantom was first scanned with both FTC and AEC for with and without bismuth shields. Each scan was repeated ten (10) times to increase thermoluminescent dosimeters (TLDs) signal and reduce measurement statistical error. For neck CT, the effect of using single and double thickness of bismuth shields and 1-3 cm cotton spacers

  8. 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

  9. Dibutyryl cyclic AMP reduces the radiosensitivity of cultured endothelial cells

    International Nuclear Information System (INIS)

    The purpose of this study was to determine whether dibutyryl cyclic AMP modifies the radiosensitivity of confluent monolayers of bovine aortic endothelial cells (BAEC). Three indices of BAEC function were monitored from 4-24 hrs after exposure to 1-10 Gy of 60Co gamma rays: the release of 51Cr from prelabeled cells, and release of lactate dehydrogenase (LDH) and plasminogen activator (PLA) into the culture medium. There was a time- and radiation dose-dependent increase in 51Cr, LDH and PLA release from the BAEC, detectable within 12 hrs after 5 Gy or higher, and by 24 hrs after 1 Gy or higher. This increased release was accompanied by a radiation dose-dependent decrease in 51Cr and LDH, and an increase in PLA activity in the lysate of cells adherent to the monolayer at 24 hrs. The continuous presence of cAMP from 1 hr before to 24 hrs after irradiation reduced all of these radiation reactions, although mM concentrations of cAMP were required for significant sparing. The presence of cAMP from 1 hr before to 10 min after irradiation had no effect on BAEC sensitivity, whereas cAMP added 10 min after irradiation was fully as effective as continuously administered drug. Thus, cultured BAEC exhibit membrane dysfunction within 24 hrs after clinically relevant radiation doses, and this dysfunction is ameliorated by cAMP present after irradiation

  10. Effect of postirradiation anoxia on radiosensitivity of lymphocytes

    International Nuclear Information System (INIS)

    Radiosensitivity was measured by viable-lymphocyte counts and by uridine uptake. The viability of the lymphocytes was based on morphologic characteristics visualized by phase contrast microscopy of the cells in a special slide chamber. Low doses of x rays (10 to 1000 R) and incubation at 370C killed lymphocytes in interphase with the production of pyknotic nuclei (nuclear death), and large doses (6000 R) produced nuclei with clear nucleoplasm (cytoplasmic death). Nuclear, but not cytoplasmic, death was inhibited by incubation of the irradiated cells at 270C. Postirradiation anoxia had no effect on development of the nuclear and cytoplasmic death of lymphocytes irradiated with 100 to 6000 R. Anoxia had no effect on the early response of lymphocytes to phytohemagglutinin (PHA) [increase in ribonucleic acid (RNA) and protein synthesis] but inhibited completely the late effects [increase in deoxyribonucleic acid (DNA) synthesis and transformation into lymphoblastoid cells]. The PHA caused relative radioresistance of lymphocytes under aerobic conditions and, to a lesser extent, under anaerobic conditions. The slight radioresistance induced by PHA in anoxic lymphocytes apparently did not depend on an increase in DNA synthesis or on the transformation to lymphoblastoid cells

  11. 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.)

  12. Abnormal radiosensitizing and cytotoxic properties of ortho-substituted nitroimidazoles

    International Nuclear Information System (INIS)

    Various 5-substituted 4-nitroimidazoles have been shown to be much more efficient radiosensitizers and much more toxic than would have been predicted from their electron affinities, as measured by values of one-electron reduction potential, E71. Using Chinese hamster V79 cells in vitro, a comparison has been made with some isomeric 4-substituted 5-nitroimidazoles. These compounds have E71 values some 64 mV greater than the 4-nitroimidazoles, yet show much lower sensitizing efficiency and also lower toxicity. Neither series of compounds shows the greater toxicity towards hypoxic cells usually associated with nitroaromatic and nitroheterocyclic compounds. The second-order rate constants, k2, for reaction of these isomeric nitroimidazoles with glutathione and dithiothreitol were determined. Within each series the value of k2 increased with increasing electron affinity, however, the 4-nitroimidazoles were always more reactive than their corresponding 5-nitro isomers. The sensitizing and toxic properties of these compounds may involve depletion of intracellular thiols; this possibility is discussed. (author)

  13. Erythrocyte transfusion and calcium channel blockers: Effects on tumor radiosensitivity

    International Nuclear Information System (INIS)

    One approach to overcoming the radioresistance often associated with anemia is to give an erythrocyte transfusion prior to irradiation. When 0.5 ml packed erythrocytes were injected I.V. into anemic RIF-1 or SCCVII/St tumor bearing mice, just prior to X-rays, and tumor response was measured by an in vivo/in vitro survival assay, there was a 10-fold increase in cell killing in the RIF-1 tumor, compared to only a 4-fold increase for SCCVII/St. The differences in response to the treatments described may be related in part to the variation in normal hypoxic fraction, between the RIF-1 (20%) tumors. Calcium channel blockers have been shown to reduce the hypoxic fraction in some mouse tumors. Such compounds may therefore enhance the radiosensitivity produced by erythrocyte transfusion. One compound, cinnarizine, gave only a small enhancement of the radiation response in the RIF-1 tumor, compared to that for erythrocyte transfusion alone. Since the SCVII/St tumor has a greater hypoxic fraction, cinnarizine may give a greater enhancement of erythrocyte transfusion sensitization to X-rays than is observed in RIF-1 tumors. Additional results are presented and discussed with reference to adaptation to these treatments and the importance of the tumor hypoxic fractions

  14. Radiosensitization of hypoxic cells treated with some imidazole derivatives

    International Nuclear Information System (INIS)

    Extensive investigations to seek more effective and less toxic radiosensitizers to hypoxic cells than misonidazole were carried out. It has been considered that the neurotoxicity of misonidazole was mainly due to the nitro substituent which is bounded to the imidazole ring. Instead of the nitro group, many types of sulfur group were introduced to the imidazole ring. Usually the radiosensitizing ability of the compound is supposed to be related to the electron affinity. Therefore, as an indicator of the electron affinity, the lowest unoccupied molecular orbital (LUMO) level of these compounds was determined by the MO calculation using the CNDO/2 method. The LUMO level of these compounds was almost the same as that of misonidazole. Expecting good radiosensitizing effect of these compounds, the radiation enhancement ratio to the hypoxic cells was tested in vitro. To get the hypoxic cells in vitro, HeLa S3 cells were flushed by 95% N2 + 5% CO2 gas in minimum essential medium. The oxygen enhancement ratio (OER) was measured at about 3 in this system. Unfortunately, the sulfur compounds have no radiosensitization to the hypoxic cells. Since the radiosensitizing ability seemed not directly to be related to the electron affinity and the radiosensitizing effect of misonidazole must be mainly due to the nitro substituent, certain dinitroimidazole derivatives (e.g. 2.4-dinitroimidazole-1-ethanol) were further studied for the screening test. It was found that this compound had a radiosensitizing effect on the hypoxic cells about ten times greater than misonidazole. The cytotoxicity of this compound was also investigated in our hypoxic system and it was found to have twice as much as misonidazole. Further investigation of this compound is necessary to apply animal experiments and clinical use. (author)

  15. Use of single cell micro-gel electrophoresis to detect the cellular radiosensitivity of two fibroblast strains

    International Nuclear Information System (INIS)

    Single cell micro-gel electrophoresis (SCGE) and MTT assay were used to determine the relationships between radiation-induced initial DNA double-strand breaks (DSBs), the ability of cells to repair DSBs and cellular radiosensitivity in both AT5BIVA and GM637 cell lines. The results demonstrated that AT5BIVA cell line was significantly more radiosensitive than GM637. The initial DSBs in both AT5BIVA and GM637 lines increased with the rise of irradiation dose, and showed significant dependence on dose. At a given dose of 20 Gy, radiation-induced initial DSBs in AT5BIVA cell line was significantly higher than those in GM637. The ability of AT5BIVA cell line to repair DSBs was more powerful than that of GM637. The results suggested that the radiation-induced initial DSBs in cells and the ability of cells to repair DSBs both correlated with cellular radiosensitivity to a certain extent, and could be used as potential predictors of intrinsic radiosensitivity of cells

  16. Modulation in the radiosensitivity of MCF-7 human breast carcinoma cells by 17B-estradiol and tamoxifen

    International Nuclear Information System (INIS)

    Colony-forming ability after irradiation was compared for proliferating hormone response MCF-7 breast carcinoma cells and cells whose growth was inhibited by tamoxifen or 17B-estradiol. Compared with controls (D0=1.20 Gy, n=3.1), cells in 1 μM or 5 μM tamoxifen were less radiosensitive (D0=1.20 Gy, n=70; D0=1.22 Gy, n=7.0, respectively), the predominant effect being a widened shoulder on the survival curve, which could be abolished by co-incubation of 5 μM tamoxifen with 100 nM or 5 μM 17B-estradiol (D0=1.30 Gy, n=2.6; D0=1.20 Gy, n=2.6, respectively). The decrease in radiosensitivity was similar to that seen when replating of irradiated plateau-phase cultures was delayed for 24 h (D0=1.30 Gy, n=6.0). When proliferation of MCF-7 cultures was inhibited by 10 μM 17B-estradiol, radiosensitivity was increased with a markedly diminished survival curve shoulder (D0=1.40 Gy, n=1.0). Different hormonal manipulations of cycling human breast carcinoma cells may have profound but disparate effects on radiosensitivity such that tamoxifen and estrogens may serve as useful agents with which to study the biochemical mechanisms of repair. (author)

  17. 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

  18. Siah1 proteins enhance radiosensitivity of human breast cancer cells

    Directory of Open Access Journals (Sweden)

    Engenhart-Cabillic Rita

    2010-08-01

    Full Text Available Abstract Background Siah proteins play an important role in cancer progression. We evaluated the effect of Siah1, its splice variants Siah1L and the Siah1 mutant with the RING finger deleted (Siah1ΔR on radiosensitization of human breast cancer cells. Methods The status of Siah1 and Siah1L was analysed in five breast cancer cell lines. To establish stable cells, SKBR3 cells were transfected with Siah1, Siah-1L and Siah1ΔR. Siah1 function was suppressed by siRNA in MCF-7 cells. The impact of Siah1 overexpression and silencing on apoptosis, proliferation, survival, invasion ability and DNA repair was assessed in SKBR3 and MCF-7 cells, also in regards to radiation. Results Siah1 and Siah1L mRNA expression was absent in four of five breast cancer cells lines analysed. Overexpression of Siah1 and Siah1L enhanced radiation-induced apoptosis in stable transfected SKBR3 cells, while Siah1ΔR failed to show this effect. In addition, Siah1 and Siah1L significantly reduced cell clonogenic survival and proliferation. Siah1L sensitization enhancement ratio values were over 1.5 and 4.0 for clonogenic survival and proliferation, respectively, pointing to a highly cooperative and potentially synergistic fashion with radiation. Siah1 or Siah1L significantly reduced invasion ability of SKBR3 and suppressed Tcf/Lef factor activity. Importantly, Siah1 siRNA demonstrated opposite effects in MCF-7 cells. Siah1 and Siah1L overexpression resulted in inhibition of DNA repair as inferred by increased levels of DNA double-strand breaks in irradiated SKBR3 cells. Conclusion Our results reveal for the first time how overexpression of Siah1L and Siah1 can determine radiosensitivity of breast cancer cells. These findings suggest that development of drugs augmenting Siah1 and Siah1L activity could be a novel approach in improving tumor cell kill.

  19. Factors of late radiosensitivity of normal tissues

    International Nuclear Information System (INIS)

    The impact of curative radiotherapy depends mainly on the total dose delivered homogeneously in the targeted volume. Nevertheless, the dose delivered to the surrounding healthy tissues may reduce the therapeutic ratio of many radiation treatments. Two different side effects (acute and late) can occur during and after radiotherapy. Of particular interest are the radiation-induced sequelae due to their irreversibility and the potential impact on daily quality of life. In a same population treated in one centre with the same technique, it appears that individual radiosensitivity clearly exists. In the hypothesis that genetic is involved in this area of research, lymphocytes seem to be the tissue of choice due to easy accessibility. Recently, low percentage of CD4 and CD8 lymphocyte apoptosis were shown to be correlated with high grade of sequelae. In addition, recent data suggest that patients with severe radiation-induced late side effects possess four or more single nucleotide polymorphisms (SNP) in candidate genes (ATM, SOD2, TGFB1, XRCC1, and XRCC3) and low radiation-induced CD8 lymphocyte apoptosis in vitro. On-going studies are being analyzing the entire genome using a Genome-wide association study (GWAS) analysis. (authors)

  20. Cellular radiosensitivity in ataxia-telangiectasia

    International Nuclear Information System (INIS)

    Hypersensitivity to both the cell-killing and chromosome-damaging effects of ionizing radiations, and other agents causing DNA breakage, is a consistent feature of cells from individuals with the cancer-prone disorder ataxia-telangiectasia (A-T). Evidence for a defect in DNA strand break rejoining is slight, but a higher-than-normal level of chromosomal breaks persists in irradiated A-T cells. There is also evidence for elevated frequencies of DNA recombination and deletion mutation in A-T cells; these responses may be linked through a loss of fidelity in rejoining DNA breaks through recombination mechanisms. Additionally the regulation of cell-cycle responses is altered in A-T cells: in all phases of the cycle there is some loss of 'checkpoint' function shortly after irradiation, allowing cells to continue cycling despite extensive DNA damage. However, on present evidence, radiation hypersensitivity cannot be explained by this loss of regulatory function. It is suggested that the A-T gene product acts in the early stages of a DNA damage-recognition pathway, normally interacting with regulatory proteins such as p53, but also with proteins involved in the processing of DNA breaks. Reduced efficiency in this type of signalling function could well explain the link between radiosensitivity and cancer proneness. (author)

  1. 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)

  2. N-methylformamide: cytotoxic, radiosensitizer, or chemosensitizer

    International Nuclear Information System (INIS)

    N-methylformamide (NMF), a polar solvent, is currently being evaluated by the National Cancer Institute (NCI) as an antineoplastic agent because of its activity against colon, mammary, and lung tumor xenografts. Results from preclinical studies suggest that it has radiosensitizing, chemosensitizing, and differentiating activity. Its mechanism of action remains unknown, but may involve cellular depletion of glutathione, cell membrane changes, or modulation of proto-oncogene expression. Preclinical toxicology studies conducted in mice, rats, and beagle dogs showed reversible hepatotoxicity to be dose-limiting. Clinically, NMF is administered both orally and by intravenous (IV) injection. The bioavailability with oral administration is 90% to 95%. The highest reported plasma concentration of NMF is approximately 4 mmol/L in a patient who received a dose of 2,000 mg/m2 of IV NMF. Biphasic elimination with IV NMF is seen on both the daily for five days and weekly for 3 weeks schedule. Approximately 5% to 7% of the total administered IV dose is excreted in the urine. In phase I studies, dose-limiting toxicities included reversible hepatotoxicity, a generalized malaise syndrome, and nausea and vomiting. One partial response has been reported in the 111 patients treated on phase II trials in colorectal, head and neck, and renal carcinomas. Suggestions for the future development of this drug are presented. 82 references

  3. Radiosensitivity of cultured insect cells: I. Lepidoptera

    International Nuclear Information System (INIS)

    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 D0, 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 D0 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

  4. Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032

    International Nuclear Information System (INIS)

    Purpose: To assess the relative radiosensitivities of a large collection of melanoma cell lines and to determine whether pharmacologic inhibition of mutant B-RAF with PLX-4032 can radiosensitize B-Raf+ melanoma cells. Materials and methods: A large collection of melanoma cell lines (n = 37) were treated with 0-8 Gy IR and clonogenic survival assays used to generate survival curves to rank relative radiosensitivities among the cell lines. The ability of a B-RAF inhibitor, PLX-4032, to radiosensitize highly radioresistant B-Raf+ cells was also assessed by clonogenic cell survival and spheroid invasion assays and the effects of treatment on the cell cycle assessed by FACS. Results: Melanoma cell lines displayed a very large, heterogeneous range of SF2 values (1.002-0.053) with a mean of 0.51. Cell lines with surviving fractions of 0.29 or less at SF2 and SF4 were observed at a high frequency of 18.9% and 70.2%, respectively. Treatment of B-Raf+ cells with the B-RAF inhibitor PLX-4032 in combination with radiation provided enhanced inhibition of both colony formation and invasion, and radiosensitized cells through an increase in G1 arrest. Conclusions: Our data suggest that melanomas are not uniformly radioresistant with a significant subset displaying inherent radiosensitivity. Pharmacologic inhibition of B-RAF with PLX-4032 effectively radiosensitized B-Raf+ melanoma cells suggesting that this combination approach could provide improved radiotherapeutic response in B-Raf+ melanoma patients.

  5. Ecological variation of radiosensitivity in the seeds of Betula verrucosa

    International Nuclear Information System (INIS)

    A study was made on variation of radiosensitivity in the seeds of common birch (Betula verrucosa Ehrh). Investigations were carried on in three types of forest-whortleberry birch grove (the top of the hill), mountain cranberry (the middle part of the hill), mixed grass (the bottom of the hill). The seeds in each area were picked from 10 well fruit bearing trees (from the middle part of top). Air-dry seeds were irradiated by 137Cs gamma-rays with 10, 20, 4 krad doses at 138 r/min dose rate. The seeds were let germinate under conditions of natural lighting and room temperatures. Radiosensitivity was evaluated from seed germination and seeding survival, and radiosensitivity variability level - with the help of variation ratio. It was established that differences in radiosensitivity among trees of different types of forest for seed germination and seeding survival of common birch, were not revealed. Radiosensitivity variation, resulted from heterogeneity of ecological conditions in different areas, is lower, than the level of individual variability of this property inside each planting

  6. 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.

  7. Radiosensitization and radiation chemistry studies using CHO cells

    International Nuclear Information System (INIS)

    The cytotoxicity, radiosensitization and radiation chemistry studies on several recently synthesized isoindole-4,7-diones using chinese hamster ovary cells (CHO) have been carried out. The cytotoxicity studies have shown that these quinones have cytotoxic activity under oxic and hypoxic conditions. Radiosensitization studies using a Cs-137 irradiator at different radiation doses demonstrate that these isoindole-diones have radiosensitization characteristics under hypoxic conditions. The results are compared with the well known radiosensitizer, misoidazole, under the same conditions. The electron redox potential of these quinones are in the vicinity of -440mv to -360mv, which demonstrates that they have the appropriate electron affinity to transfer electrons quite readily. The interaction of glutathione, a well known radioprotector, with these quinones was also studied. The concentration of glutathione in CHO cells decreases very little in the presence of the isoindole-diones. The results of these experiments show that the radiosensitization mechanism of these isoindole-diones is mainly due to electron transfer reactions and not to interaction with chemical radioprotectors such as glutathione in the CHO cells

  8. 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.

  9. 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.

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

    International Nuclear Information System (INIS)

    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

  11. 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.

  12. Irradiation induced foci (IRIF) as a biomarker for radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Goodarzi, Aaron A. [Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ (United Kingdom); Jeggo, Penny A., E-mail: p.a.jeggo@sussex.ac.uk [Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ (United Kingdom)

    2012-08-01

    It has long been known that the level of radiosensitivity between individuals covers a considerable range. This range is reflected in analysis of patient cell lines with some cell lines showing significantly reduced sensitivity to in vitro radiation exposure. Our increased exposure to radiation from diagnostic medical procedures and other life style changes has raised concerns that there may be individuals who are at an elevated risk from the harmful impact of acute or chronic low dose radiation exposure. Additionally, a subset of patients show an enhanced normal tissue response following radiotherapy, which can cause significant discomfort and, at the extreme, be life threatening. It has long been realised that the ability to identify sensitive individuals and to understand the mechanistic basis underlying the range of sensitivity within the population is important. A reduced ability to efficiently repair DNA double strand breaks (DSB) and/or activate the DSB damage response underlies some, although not necessarily all, of this sensitivity. In this article, we consider the utility of the recently developed {gamma}H2AX foci analysis to provide insight into radiation sensitivity within the population. We consider the nature of sensitivity including the impact of radiation on cell survival, tissue responses and carcinogenesis and the range of responses within the population. We overview the current utility of the {gamma}H2AX assay for assessing the efficacy of the DNA damage response to low and high dose radiation and its potential future exploitation.

  13. Irradiation induced foci (IRIF) as a biomarker for radiosensitivity

    International Nuclear Information System (INIS)

    It has long been known that the level of radiosensitivity between individuals covers a considerable range. This range is reflected in analysis of patient cell lines with some cell lines showing significantly reduced sensitivity to in vitro radiation exposure. Our increased exposure to radiation from diagnostic medical procedures and other life style changes has raised concerns that there may be individuals who are at an elevated risk from the harmful impact of acute or chronic low dose radiation exposure. Additionally, a subset of patients show an enhanced normal tissue response following radiotherapy, which can cause significant discomfort and, at the extreme, be life threatening. It has long been realised that the ability to identify sensitive individuals and to understand the mechanistic basis underlying the range of sensitivity within the population is important. A reduced ability to efficiently repair DNA double strand breaks (DSB) and/or activate the DSB damage response underlies some, although not necessarily all, of this sensitivity. In this article, we consider the utility of the recently developed γH2AX foci analysis to provide insight into radiation sensitivity within the population. We consider the nature of sensitivity including the impact of radiation on cell survival, tissue responses and carcinogenesis and the range of responses within the population. We overview the current utility of the γH2AX assay for assessing the efficacy of the DNA damage response to low and high dose radiation and its potential future exploitation.

  14. 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

  15. 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

  16. 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)

  17. Radiosensitivity of the Philippine giant toad (Bufu marinus L.)

    International Nuclear Information System (INIS)

    The Philippine giant toad (Bufu marinus L.) were studied to establish their radiosensitivities and their possible use as a good biological indicator organism of radiation effects. Live male and female toads were exposed to ionizing doses of gamma irradiation. Chromosome analysis was done under the Carl Zeiss III photo microscope. Somatic and meiotic chromosome aberrations were induced in giant toad upon in vivo whole gamma irradiations. By cytogenetic analysis the aberrant chromosomes were observed and evaluated. In these studies, it was concluded that Bufo marinus L. is significantly radiosensitive and a good biological indicator organisms of radiation effects. (ISD). 2 figs.; 8 tabs

  18. Partition coefficient as a guide to the development of radiosensitizers which are less toxic than misonidazole

    International Nuclear Information System (INIS)

    Ten 2-nitroimidazole radiosensitizers of electron affinity equal to that of misonidazole, but differing in their octanol:water partition coefficient over a 100-fold range, were chosen to examine the effect of lipophilicity on the pharmacokinetics of these drugs in BALB/c mice bearing EMT6 tumors. Plasma, tumor, and brain concentrations were assayed, using high performance liquid chromatography (HPLC), as a function of time after a single ip injection of each drug. Peak concentrations in the tumor declined with decreasing lipophilicity. This was due to declining peak plasma concentrations resulting from slower drug absorption and could be overcome by iv injection. The tumor plasma ratio, once sufficient time had elapsed for it to reach its equilibrium value, was independent of partition coefficient (P) over the range 0.026 to 1.5 but showed a 50% reduction in this ratio for the most hydrophilic compound studied (P = 0.014). (This compound was also the one drug in the series which was significantly poorer than misonidazole in its radiosensitization as a function of drug concentration). The brain/plasma ratio, on the other hand, showed a marked dependence on lipophilicity. For misonidazole and more lipophilic compounds, the brain/plasma ratio was 1.0, but as the lipophilicity decreased below that of misonidazole, the compounds showed an increasing difficulty in penetration into the brain, and brain/plasma levels of less than 0.1 were found for the most hydrophilic drugs. These low brain/plasma ratios correlated with an increased acute LD50 of the drugs. Bilateral nephrectomy was used to increase the apparent plasma half-life of SR-2508 from 0.8 to 15 hr. This change, however, did not affect the tumor/brain ratio of approximately 10 for this drug. The significance of these pharmacokinetic data is discussed in terms of the development of a radiosensitizer superior to misonidazole for clinical use

  19. 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

  20. Effects of hypoxic cell radiosensitizer doranidazole (PR-350) on the radioresponse of murine and human tumor cells in vitro and in vivo

    International Nuclear Information System (INIS)

    We have investigated the radiosensitizing effect of doranidazole, a hypoxic cells radiosensitizer, using SCCVII tumor cells of C3H mice and CFPAC-1 and MIA PaCa-2 human pancreatic tumor cells. The radiosensitivity of hypoxic SCCVII cells in vitro increased with 1 mM doranidazole by a factor of 1.34 and 1.68, when determined by clonogenic survival and micronucleus (MN) formation, respectively. The radiation-induced growth delay of SCCVII tumors was significantly enhanced and the radiation dose required to care to care 50% of tumors 120 days after irradiation (TCD50/120) was reduced by a factor of 1.33 when 200 mg/kg doranidazole was injected, i.v., 20 min prior to tumor irradiation. The in vivo-in vitro excision assay showed that radiosensitivity of SCCVII cells in vivo increased by a factor of 1.47 with 200 mg/kg doranidazole. The radiation-induced growth delay of CFPAC-1 xenografts in nude mice was significantly enhanced and the radiation dose required to care 50% of tumors 90 days after irradiation (TCD50/90) was reduced by a factor of 1.30 by 200 mg/kg doranidazole. On the other hand, 200 mg/kg of doranidazole exerted no influence on the radiation-induced growth delay in MIA PaCa-2 xenografts. The tumor oxygenation status, as determined with an oxygen sensitive needle probe and the immunohistological study using pimonidazole, indicated that MIA PaCa-2 tumors are better oxygenated than CFPAC-1 tumors. The relatively well-oxygenated status in MIA PaCa-2 tumor may account for the lack of radiosensitization by doranidazole. It is concluded that the magnitude of radiosensitization of tumors by doranidazole is dependent on the oxygenation status of the tumors and that doranidazole may be useful in increasing the response of hypoxic human pancreatic tumor to intraoperative radiotherapy (IORT). (author)

  1. 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.

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

    OpenAIRE

    Danhier, Fabienne; Danhier, Pierre; Magotteaux, Nicolas; De Preter, Géraldine; Ucakar, Bernard; Karroum, Oussama; Jordan, Bénédicte; Gallez, Bernard; Préat, Véronique

    2012-01-01

    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 "oxy...

  3. Nutrient-associated modulation of growth kinetics and radiosensitivity of EMT6/Ro multicell spheroids

    International Nuclear Information System (INIS)

    The authors are studying the development of heterogeneously radiosensitive cell subpopulations in tumor microregions associated with nutrient and O/sub 2/ supply conditions. To date EMT6/Ro multicell spheroids have been grown in Eagle's Basal Medium (BME) 5.5mM glucose or BME 24.8 mM glucose or Dulbecco's Modified Essential Medium (DMEM) 24.8 mM glucose which were air-equilibrated and contained 15% bovine calf serum. The pH remained relatively constant (7.3) and glucose and O/sub 2/ were not substantially depleted between feedings. The spheroid growth rate in the different media was linear at 110μm/day diameter increase. The following results for 1100μm spheroids were obtained for BME and DMEM 24.8mM glucose compared to BME 5.5mM glucose respectively: 1) small increase in cells/shperoid; 2) slight shift to smaller cell volume; 3) increased clonogenicity; 4) decreased central necrosis; 5) similar fractions of cells with G/sub 1/ DNA content; 6) increased fraction of quiescent cells as defined by low RNA content using acridine orange staining and flow cytometry; 7) increased radiation resistance (slope) and fraction of resistant cells. The authors data show that nutrient conditions can affect subpopulation growth and radiosensitivity of spheroid cells

  4. Radiosensitizing activity and pharmacokinetics of multiple dose administered KU-2285 in peripheral nerve tissue in mice

    International Nuclear Information System (INIS)

    In a clinical trial in which a 2-nitroimidazole radiosensitizer was administered repeatedly, the dose-limiting toxicity was found to be peripheral neuropathy. In the present study, the in vivo radiosensitizing activity of KU-2285 in combination with radiation dose fractionation, and the pharmacokinetics of cumulative dosing of KU-2285 in the peripheral nerves were examined. The ability of three nitroimidazoles, misonidazole (MISO), etanidazole (SR-2508) and KU-2285, to sensitize SCCVII tumors to radiation treatment has been compared for drug doses in the range 0-200 mg/kg. Single radiation doses or two different fractionation schedules (6 Gy/fractions x three fractions/48 h or 5 Gy/fractions x five fractions/48 h) were used; the tumor cell survival was determined using an in vivo/in vitro colony assay. The pharmacokinetics in the sciatic nerves were undertaken, when KU-2285 or etanidazole were injected at a dose of 200 mg/kg intravenously one, two, three, or four times at 2-h intervals. At less than 100 mg/kg, KU-2285 sensitized SCCVII tumors more than MISO and SR-2508 by fractionated irradiation. Evaluation of pharmacokinetics in the peripheral nerves showed that the apparent biological half-life of SR-2508 increased with the increases in the number of administrations, whereas that of KU-2285 became shorter. Since most clinical radiotherapy is given in small multiple fractions, KU-2285 appears to be a hypoxic cell radiosensitizer that could be useful in such regimens, and that poses no risk of chronic peripheral neurotoxicity. 12 refs., 5 figs., 1 tab

  5. Radiosensitization by oxygen in ehrlich tumor receiving artificial blood substitute (FOB 20%)

    International Nuclear Information System (INIS)

    To enhance tissue PO2 of radioresistant hypoxic cells of tumor, artificial blood substitute (FOB) was applied, because it is excellent solvent for oxygen and allows the blood circulation system to recover and consequently increase the oxygen supply from blood to the tissue. When transplanted Ehrlich tumor of mice on thigh grew about 1,000 mm3 in volume, those were divided into three groups, group 1: 60Co γ-ray irradiation alone, group 2: irradiation under breathing oxygen, and group 3: irradiation under breathing oxygen after exchange transfusion with FOB. The radiosensitization of FOB was studied by compairing with the OER values of three groups for 50% TGD time, 50% SD time, and 50% and 75% TCP. The OER values of 50% TGD time, 5, 10 and 50% SD time 10 of oxygen group were 1.46, 1.29, and 1.22, respectively, and oxygen effect was observed in this group. Those values of FOB group were 2.02, 1.56, and 1.56, respectively and oxygen effect of FOB group was greater than those of oxygen group. Animals receiving FOB were apparently radiosensitized by oxygen against animals breathing oxygen at small doses irradiation effect (50% TGD time, and 50% SD time). The OER values of 50% and 75% TCP at 30 days and 90 days after irradiation of oxygen group were about 1.5 (1.46-1.61) and these of FOB group about 1.3 (1.15-1.38). Radiosensitization by oxygen of animals receiving FOB was not clearly recognized a gainst animals breathing oxygen in TCP effect at high dose irradiation. These results indicate that radioresistant hypoxic cells of tumor receiving artificial blood substitute (FOB) increase the sensitivity of 60Co γ-ray irradiation, especially at small dose irradiation. (author)

  6. 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

  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. 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.

  9. Cell cycle effects for radiosensitivity after heavy ion exposure

    International Nuclear Information System (INIS)

    In order to study the relative contribution of the two major DNA double-strand break (DSB) repair pathways, non-homologous end-joining (NHEJ) and homologous recombinational repair (HRR), to the repair of DSBs and non-DSB clustered DNA damage induced by high linear energy transfer (LET) ionizing radiation through the cell cycle, we exposed wild type (WT), NHEJ-deficient, and HRR-deficient Chinese hamster ovary (CHO) cells synchronized by mitotic shake-off to accelerated heavy ions and X-rays. The cell cycle-dependent variation in survival observed in WT cells after X-irradiation was not observed after exposure to 500 MeV/amu iron ions. Non-homologous end joining (NHEJ) and homologous recombinational repair (HRR)-defective cells showed different patterns of cell cycle-dependent radiosensitivity after X-irradiation compared to WT cells, that were likewise significantly attenuated after iron ion exposures. Higher relative biological effectiveness for several other accelerated heavy ions (C, Ne, Si, Ar) of differing LETs was observed for cells exposed in S phase compared to cells exposed in G1. We also observed that HRR deficiency, unlike NHEJ deficiency, did not affect the progression of irradiated G2 cells into mitosis, thus contributing to increased cell killing observed in G2-phase HRR-deficient cells. The HRR-deficient cells showed significantly increased levels of chromatid-type aberrations that correlated with their cell cycle pattern of survival after both X- and iron ion irradiation. Our results suggest that high LET radiation produces not only complex DSBs but also complex non-DSB clustered lesions that specifically require the HRR-mediated repair of these lesions if encountered during DNA replication. In this year, we focused on Fanconi Anemia DNA repair pathway. Only FancA mutant cells showed hypersensitivity to high LET ionizing radiation among other FancC, FancD1, FancD2, and FancG mutant cells. (author)

  10. Cell cycle effects for radiosensitivity after heavy ion exposure

    International Nuclear Information System (INIS)

    In order to study the relative contribution of the two major DNA double-strand break (DSB) repair pathways, non-homologous end-joining (NHEJ) and homologous recombinational repair (HRR), to the repair of DSBs and non-DSB clustered DNA damage induced by high linear energy transfer (LET) ionizing radiation through the cell cycle, we exposed wild type (WT), NHEJ-deficient, and HRR-deficient Chinese hamster ovary (CHO) cells synchronized by mitotic shake-off to accelerated heavy ions and X-rays. The cell cycle-dependent variation in survival observed in WT cells after X-irradiation was not observed after exposure to 500 MeV/amu iron ions. Non-homologous end joining (NHEJ) and homologous recombinational repair (HRR)-defective cells showed different patterns of cell cycle-dependent radiosensitivity after X-irradiation compared to WT cells, that were likewise significantly attenuated after iron ion exposures. Higher relative biological effectiveness for several other accelerated heavy ions (C, Ne, Si, Ar) of differing LETs was observed for cells exposed in S phase compared to cells exposed in G1. We also observed that HRR deficiency, unlike NHEJ deficiency, did not affect the progression of irradiated G2 cells into mitosis, thus contributing to increased cell killing observed in G2-phase HRR-deficient cells. The HRR-deficient cells showed significantly increased levels of chromatid-type aberrations that correlated with their cell cycle pattern of survival after both X- and iron ion irradiation. Our results suggest that high LET radiation produces not only complex DSBs but also complex non-DSB clustered lesions that specifically require the HRR-mediated repair of these lesions if encountered during DNA replication. (author)

  11. 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)

  12. Adenovirus E4orf6 protein inhibits DNA repair and radiosensitizes human tumor cells

    International Nuclear Information System (INIS)

    Full text: Double strand break repair (DSBR), although vital to normal cell survival and genomic stability, limits tumor cell kill following treatment with ionizing radiation (IR). The primary mechanism for DSBR in mammalian cells, non-homologous end joining (NHEJ), requires multiple proteins, one of which is DNA-dependent protein kinase (DNA-PK). Cells deficient in DNA-PK, although phenotypically normal, are among the most radiosensitive cells available. It has previously been shown that the E4orf6 gene product of adenovirus type 5 interacts with and inhibits the activity of DNA-PK. Therefore, we hypothesized that E4orf6, by interacting with DNA-PK, would inhibit the DSBR capacity of tumor cells and thus increase tumor cell kill upon treatment with IR. Stable clones expressing either wild type E4orf6, an E4orf6 mutant (L245P) that is defective at E1B-55K localization to the nucleus, or a neomycin control vector were established in colorectal carcinoma (RKO) cells. Based on clonogenic assays, we report a 10-fold increase in radiosensitivity of the wild type E4orf6 expressing clones at 6Gy of IR compared to both the neomycin and L245P mutant clones. Furthermore, the increase in sensitivity correlates with inhibition in DSBR based on sub-lethal damage repair assay. Preliminary data suggests that the transfected E4orf6 interacts with the endogenous DNA-PK and this results in a 20% decrease in the kinase activity of the DNA-PK compared to neomycin expressing control cells. These results indicate that E4orf6 radiosensitizes tumor cells by inhibiting their DSBR activity. We have constructed an adenoviral vector expressing E4orf6 in a tetracycline-inducible manner, which provides temporal control for E4orf6 expression. We are currently investigating the radiosensitizing properties of this expression vector. Successful use of this vector in vitro and in mouse xenografts, will set the stage for its future use in conjunction with localized radiotherapy of radioresistant

  13. 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

  14. Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest

    International Nuclear Information System (INIS)

    Purpose: How EGF receptor (EGFR) inhibition induces cellular radiosensitization and with that increase in tumor control is still a matter of discussion. Since EGFR predominantly regulates cell cycle and proliferation, we studied whether a G1-arrest caused by EGFR inhibition may contribute to these effects. Materials and methods: We analyzed human non-small cell lung cancer (NSCLC) cell lines either wild type (wt) or mutated in p53 (A549, H460, vs. H1299, H3122) and HCT116 cells (p21 wt and negative). EGFR was inhibited by BIBX1382BS, erlotinib or cetuximab; p21 was knocked down by siRNA. Functional endpoints analyzed were cell signaling, proliferation, G1-arrest, cell survival as well as tumor control using an A549 tumor model. Results: When combined with IR, EGFR inhibition enhances the radiation-induced permanent G1 arrest, though solely in cells with intact p53/p21 signaling. This increase in G1-arrest was always associated with enhanced cellular radiosensitivity. Strikingly, this effect was abrogated when cells were re-stimulated, suggesting the initiation of dormancy. In line with this, only a small non-significant increase in tumor control was observed for A549 tumors treated with fractionated RT and EGFR inhibition. Conclusion: For NSCLC cells increase in radiosensitivity by EGFR inhibition results from enhanced G1-arrest. However, this effect does not lead to improved tumor control because cells can be released from this arrest by re-stimulation

  15. 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

  16. 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.

  17. 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

  18. Analysis of individual differences in radiosensitivity using genome editing.

    Science.gov (United States)

    Matsuura, S; Royba, E; Akutsu, S N; Yanagihara, H; Ochiai, H; Kudo, Y; Tashiro, S; Miyamoto, T

    2016-06-01

    Current standards for radiological protection of the public have been uniformly established. However, individual differences in radiosensitivity are suggested to exist in human populations, which could be caused by nucleotide variants of DNA repair genes. In order to verify if such genetic variants are responsible for individual differences in radiosensitivity, they could be introduced into cultured human cells for evaluation. This strategy would make it possible to analyse the effect of candidate nucleotide variants on individual radiosensitivity, independent of the diverse genetic background. However, efficient gene targeting in cultured human cells is difficult due to the low frequency of homologous recombination (HR) repair. The development of artificial nucleases has enabled efficient HR-mediated genome editing to be performed in cultured human cells. A novel genome editing strategy, 'transcription activator-like effector nuclease (TALEN)-mediated two-step single base pair editing', has been developed, and this was used to introduce a nucleotide variant associated with a chromosomal instability syndrome bi-allelically into cultured human cells to demonstrate that it is the causative mutation. It is proposed that this editing technique will be useful to investigate individual radiosensitivity. PMID:27012844

  19. 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

  20. Voltammetry of hypoxic cells radiosensitizer etanidazole radical anion in water

    Czech Academy of Sciences Publication Activity Database

    Gál, Miroslav; Hromadová, Magdaléna; Pospíšil, Lubomír; Híveš, J.; Sokolová, Romana; Kolivoška, Viliam; Kocábová, Jana

    2010-01-01

    Roč. 78, č. 2 (2010), s. 118-123. ISSN 1567-5394 R&D Projects: GA ČR GP203/09/P502 Institutional research plan: CEZ:AV0Z40400503 Keywords : etanidazole * radiosensitizer * electron transfer * voltammetry Subject RIV: CG - Electrochemistry Impact factor: 3.520, year: 2010

  1. Radiosensitivity of Acacia catechu Willd. to gamma rays

    International Nuclear Information System (INIS)

    In the present study various traits of Acacia catechu were studied to assess their radiosensitivity. Analysis of variance for germination value, survival and height of plants of Acacia catechu following gamma irradiation of seeds were also carried out. 4 refs., 1 fig., 1 tab

  2. 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

  3. In vivo radiosensitizing effect of nitroimidazole derivative KIN-804

    International Nuclear Information System (INIS)

    In vivo characteristics of 2-nitroimidazole-1-methylacetohydroxamate (KIN-804), which is a newly developed hypoxic cell radiosensitizer, are presented. The toxicity, pharmacokinetics, and radiosensitizing effect of KIN-804 were studied by in vivo experiments using C3H/He mice bearing the SCCVII tumor. Results were compared with misonidazole (MISO). LD507 of KIN-804 and MISO were 3200 mg/kg and 2000 mg/kg, respectively. The peak concentration of KIN-804 in the tumor occurred 20 min after intraperitoneal injection and reached about 62% of the maximum concentration in the blood. The concentrations in brain and sciatic nerve were very low and clearance from sciatic nerve was rapid. Enhancement ratios of KIN-804 calculated using the growth delay method were 1.22, 1.50, and 1.71 at doses of 50, 100, and 200 mg/kg, respectively, compared with 1.36 for MISO at a dose of 100 mg/kg. In the TCD50 assay, enhancement ratios at a dose of 200 mg/kg were 1.69 for KIN-804 and 1.52 for MISO, respectively. KIN-804 is a promising radiosensitizer since it shows less toxicity and higher radiosensitizing activity than MISO. 10 refs., 5 figs

  4. 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...

  5. 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

  6. The effect of BW12C on radiosensitivity and necrosis of murine tissues and tumours

    International Nuclear Information System (INIS)

    BW12C is a drug that has the potential to induce normal tissue and tumour hypoxia by binding to haemoglobin, increasing its affinity for oxygen and thereby reducing oxygen availability to tissues. Initial results suggested that BW12C administration caused significant radioprotection of normal tissues and induced tumour necrosis, but variable results have been reported subsequently. This work was carried to extend the range of observations concerning the ability of BW12C to radioprotect normal tissues and tumours and to induce necrosis of tumours of the mouse. BW12C was administered as 70 mg/kg intravenous 15 min before irradiation of jejunum in CBA mice and of foot skin in WHT mice with single doses of 240 kVp X-rays while mice breathed gases of varying oxygen tensions. The radiosensitivities of these tissues were assessed by the crypt survival assay and the acute skin reaction, respectively. The radiosensitivity of CaNT tumours to single fraction irradiation was assessed by the regrowth delay assay following administration of single or multiple does of BW12C at varying times to air-breathing CBA mice. The radiation response was compared to the radiosensitivity of clamped tumours. The effect of BW12C alone on tumours was assessed by regrowth delay and histological examination for necrosis. Single or multiple doses of BW12C did not influence the radiosensitivity of CaNT tumours, although marked radioprotection could be induced by clamping the tumours during irradiation. Multiple doses of BW12C alone led to a slight increase in necrosis of the CaNT tumour but did not alter its growth rate. BW12C alone did not induce necrosis of the murine JT lymphoma. The results shown that BW12C did not have a significant effect as a radioprotective or necrotizing agent in these experimental systems. The reported differences in the radiomodifying effects of BW12C are probably tissue-specific and relate to complex biochemical and physiological interactions. 18 refs., 4 figs

  7. Radiosensitization of EMT6 cells by four platinum complexes.

    Science.gov (United States)

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

    1985-05-01

    The greatest research effort in producing radiation sensitizers has been directed toward organic compounds. However, platinum complexes also have radiosensitizing capabilities, perhaps because they bind to DNA. The compound 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 microM and 400 microM 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 microM and 1.8 at 400 microM. 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 microM 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 microM and 400 microM 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 microM 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. PMID:4039304

  8. 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.

  9. Effect of microenviroment hypoxia on glioma cells radiosensitivity through cancer stem cell pathway

    International Nuclear Information System (INIS)

    Objective: To investigate the effect of microenviroment hypoxia on glioma cells radiosensitivity through cancer stem pathway, and to explore the related mechanism. Methods: Glioma cell lines SHG44 and U251 were cultured in normoxia (20% O2) or continuous hypoxia (1% O2) for 12 and 24 h. The fraction of glioma cells with positive expression of CD133 was assayed by flow cytometry. The radiosensitivity of glioma cells was determined by clonogenic cell assay. Western blotting was used to investigate the expressions of HIF-1 α and its downstream gene Notch 1. Results: The fraction of glioma cells with positive expression of CD133 was higher after hypoxic culture for 12 and 24 h than that of the corresponding cells cultured in normoxia. Compared to the cells cultured in normoxia, SF2 (survival fraction at 2 Gy) were enhanced significantly in SHG44 and U251 cells cultured in hypoxia for 12 and 24 h. The OER (oxygen-enhancement ratio) of SHG44 cells in hypoxia for 12 and 24 h was 1.54 and 1.38, respectively. The OER of U251 cells was 1.44 and 1.23, respectively. The radiosensitivity of these two cell line was decreased in hypoxia. The protein expressions of HIF-1 α and Notch 1 genes were elevated more significantly for cells cultured in hypoxia for 12 and 24 h than for those in normoxia. Conclusions: Microenviroment hypoxia could increase the radioresistance of glioma cells through enrichment of cancer stem cells, and HIF-1 α-Notch 1 signal pathway may play an important role in this process. (authors)

  10. 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

  11. 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)

  12. REG Iα activates c-Jun through MAPK pathways to enhance the radiosensitivity of squamous esophageal cancer cells.

    Science.gov (United States)

    Wakita, Akiyuki; Motoyama, Satoru; Sato, Yusuke; Koyota, Souichi; Usami, Shuetsu; Yoshino, Kei; Sasaki, Tomohiko; Imai, Kazuhiro; Saito, Hajime; Minamiya, Yoshihiro

    2015-07-01

    Identification of the key molecules that mediate susceptibility to anticancer treatments would be highly desirable. Based on clinical and cell biological studies, we recently proposed that regenerating gene (REG) Iα may be such a molecule. In the present study, we hypothesized that REG Iα increases radiosensitivity through activation of mitogen-activated protein kinase (MAPK) pathways. To test that idea, we transfected TE-5 and TE-9 squamous esophageal cancer cells with REG Iα and examined its involvement in MAPK signaling and its effect on susceptibility to radiotherapy. We found that REG Iα-expressing cells showed increased expression of c-Jun messenger RNA (mRNA) and phospho-c-Jun protein mediated via the c-Jun N-terminal kinase (JNK) pathway and extracellular signal-regulated kinase (ERK) pathway, as well as increased radiosensitivity. Immunohistochemical analysis confirmed the activation of c-Jun in tumors expressing REG Iα. Collectively, these findings suggest that REG Iα activates c-Jun via the JNK and ERK pathway, thereby enhancing radiosensitivity. PMID:25656613

  13. 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

  14. 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

  15. 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...

  16. 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)

  17. The radiosensitivity of some trisomic variants of a diploid mammalian cell line

    International Nuclear Information System (INIS)

    The radiosensitivity of trisomic cells from a diploid BHK21 Cl3 cell line was investigated. The technique used confined measurement of most of the established criteria to a single set of direct observations on one population of cells, and the results from this method were compared with those obtained from some more conventional techniques. Trisomic cells were isolated after a chronic treatment of the diploid cells with low doses of colcemid, which increased the incidence of nondisjunction at anaphase. Over several cell cycles the incidence of trisomy in the population increased to the extent where standard cloning techniques yielded a tolerably high proportion of trisomic clones. The radiosensitivity of one of these clones was examined in detail and the results compared with those obtained by other workers. Other trisomic clones were also assayed for the incidence of chromosome aberrations, post irradiation colony-forming ability and tumourigenicity to identify any which display markedly individual characteristics. These results and their implications in the radiobiology of mammalian cells are discussed. (author)

  18. Influence of relative humidity on radiosensitivity of Aspergillus flavus Link. infecting cocoa beans

    International Nuclear Information System (INIS)

    The first part of this paper deals with the moisture sorption isotherms of dried cocoa beans under different relative humidities of 55, 65, 75, 85 or 95%. The second part evaluates the effects of relative humidity (RH), initial moisture content (m.c.) of cocoa beans, and different radiation exposure doses (0, 250, 350, 450, 500 or 550 krad) on Aspergillus flavus spore inoculated cocoa beans kept in fixed RH environmental chamber of 75 or 85% RH post-irradiation for forty days. The results discussed suggest that the m.c. of beans increased from an initial level of 6.4% to 7, 7.8 and 8.9% at 55, 65, and 75% respectively, after a storage period of 6-8 days. However, beans stored under 85% or 95% RH continued to absorb moisture from their respective environments indefinitely during the 64-day storage period. Furthermore, the ambient relative humidity to which the beans are subjected before or after irradiation significantly affect the radiosensitivity of toxigenic A. flavus; the differences in such radiosensitivity are influenced by either the available moisture or the initial m.c. of the beans to the inoculum. The authors conclude from their study that high environmental RH increased the radio-resistance of A. flavus spores making it difficult to establish a radiation decontamination level of practical value under a tropical environment with high ambient relative humidity. (author)

  19. Influence of Relative Humidity on Radiosensitivity of Aspergillus Flavus Link Infecting Cocoa Beans

    International Nuclear Information System (INIS)

    The first part of this paper deals with the moisture sorption isotherms of dried cocoa beans under different relative humidities of 55, 65, 75, 85 or 95%. The second part evaluates the effects of relative humidity (RH), initial moisture content (m.c.) of cocoa beans, and different radiation exposure doses (0, 250, 350, 450, 500 or 550 krad) on Aspergillus flavus spore inoculated cocoa beans kept in fixed RH environmental chamber of 75 or 85% RH postirradiation for forty days. The results discussed suggest that the m.c. of beans increased from an initial level of 6.4% to 7, 7.8 and 8.9% at 55, 65, and 75% respectively, after a storage period of 6-8 days. However, beans stored under 85% or 95% RH continued to absorb moisture from their respective environments indefinitely during the 64-day storage period. Furthermore, the ambient relative humidity to which the beans are subjected before or after irradiation significantly affect the radiosensitivity of toxigenic A. flavus; the differences in such radiosensitivity are influenced by either the available moisture or the initial m.c. of the beans to the inoculum. The authors conclude from their study that high environmental RH increased the radio-resistance of A. flavus spores making it difficult to establish a radiation decontamination level of practical value under a tropical environment with high ambient relative humidity. (author)

  20. 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

  1. 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)

  2. Effects of introducing wild-type p53 gene on the radiosensitivity of SKOV-3 ovarian cancer cells

    International Nuclear Information System (INIS)

    Objective: To study the effect of wild-type p53 gene on the radiosensitivity of SKOV-3 ovarian cancer cells. Methods: Recombinant eukaryotic expression vector pcDNA3 containing full-length human wild-type p53 cDNA was introduced by lipofectamine-mediated gene transfection into cultured SKOV-3 cells which had been irradiated with 2 and 4 Gy X-rays, respectively. The radiosensitivities of the tumor cells with different p53 status were studied. Results: The number of colonies in the SKOV-3, SKOV-3-vect, and SKOV-3-p53 groups decreased by 18.6%, 22.9% and 44.5%, respectively with 2 Gy irradiation, and decreased by 63.6%, 64.9% and 88.9%, respectively with 4 Gy irradiation. After introduction of p53 cDNA, the cell number in S phase and the ratio of G2/M phase of tumor cells decreased and the ratio of G1/G0 phase increased. The introduction of p53 gene into cells led to cell cycle arrest in G1 phase. Conclusion: Exogenous introduction of wild-type p53 cDNA into SKOV-3 ovarian cancer cells can increase their radiosensitivity

  3. The effect of p53 variation on radiosensitivity in a mouse prostate cancer model (work performed during ASTRO research fellowship year)

    International Nuclear Information System (INIS)

    Purpose: Prostate cancer has become the most common cancer by incidence in U.S. males, responsible for approximately 3% of all male deaths above the age of 55. p53 mutations are known to increase carcinogenic and metastatic potential and are a common genetic abnormality in prostate cancer. Examinations of p53 status in other cell lines and treated tumors have yielded mixed results regarding its effects on radiosensitivity. We have tested the effect of varying p53 status on radiosensitivity in a mouse prostate cancer model. Methods and Materials: Early passage cell lines of different p53 status were derived from an induced mouse prostate cancer model. Additional lines were used with restored wt-p53 or mutant status to examine external manipulation. The radiosensitivity was evaluated by clonogenic assays/survival curve generation and flow cytometry, before and after radiation Results: The presence of wt-p53 corresponded with increased radiosensitivity as mutant-p53 and the presence of mdm2 did with decreased sensitivity. Gene replacement studies with wild type and mutant p53 in p53 null cell lines corroborated the germline cell experiments. Evaluation of the cell lines with flow cytometry did not reveal the expected a significant increase in G1 with p53 replacement after radiation but did result in the expected (post-irradiation) G2 increase Conclusions: Variation and manipulation of wild type p53 status can result in changes in radiosensitivity, increasing with its presence and function, in vitro in the mouse prostate cancer model. This effect can be replicated in vitro with gene replacement therapy. The expected increase in G1 with wt-p53 after radiation was not seen. Further studies should include evaluation of apoptotic versus mitotic cell death, in vitro analysis of wt-p53 replacement and examination of replacement or enhancement therapy with other cycle-modifying cytokines

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

    International Nuclear Information System (INIS)

    Objective: To investigate the radiosensitive effect of hypoxia-inducible factor 1α (HIF-1α) inhibitor YC-1 on hypoxic glioma SHG44 cell line and its related mechanism. Methods: Glioma SHG44 cell line was cultured in normoxic (20% O2), continuous hypoxia (1% O2) for 12 h and 24 h, continuous hypoxia plus YC-1 was performed for 12 h and 24 h, respectively. The expression of HIF-1α was assessed by Western blot. The radiosensitivity was evaluated by the survival curve, and the sublethal damage repair (SLDR) ability was measured by dose-fraction experiment. Results: HIF-1α protein levels of glioma SHG44 cells were significantly increased after hypoxic cultures for 12 h and 24 h than those of the corresponding cells cultured in normoxic, while the radiosensitivity was lower. The OER (oxygen-enhancement ratio) of SHG44 cells in hypoxia for 12 h and 24 h were 1.22 and 1.37, respectively. By the further statistical analysis it was found that SLDR ability of glioma SHG44 was increased at hypoxia, and when irradiation was carried one at the interval of 8, 10, 12 h it was statistically significant (P<0.05). HIF-1α protein levels of glioma SHG44 cells cultured in hypoxia plus YC-1 for 12 h and 24 h were decreased significantly compared to the corresponding cells cultured in hypoxia only, while the radiosensitivity was significantly increased. the EF (enhancement factor) of YC-1 for glioma SHG44 cells at hypoxia for 12 h and 24 h was 1.27. By the further statistical analysis it was also found that SLDR ability was decreased significantly for hypoxic SHG44 cells which was co-cultured with YC-1, and at the interval of 8, 10, 12 h irradiation was statistically significant (P<0.05). Conclusion: YC-1 can increase the radiosensitivity of hypoxic glioma SHG44 cell line, and its mechanism is related to SLDR inhibited by YC-1. (authors)

  5. 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.

  6. 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.

  7. Small interfering RNA in silencing Bcl-2 expression and enhancing radiosensitivity of esophageal cancer cells

    International Nuclear Information System (INIS)

    Objective: To explore the effects of small interfering RNA (siRNA) specific to Bcl-2 gene on radiosensitivity of esophageal cancer cells. Methods: Bcl-2 gene siRNA ( Bcl-2 siRNA ) was induced into esophageal cancer EC9706 cells by lipofectamine. Bcl-2 protein expression and apoptosis of EC9706 cells were detected by flowcytometer. Clone forming assay was used to determine the inhibitory effects of X-ray radiation combined with Bcl-2 siRNA interference. Results: When Bcl-2 siRNA had been induced into EC9706 cells, Bcl-2 protein expression in EC9706 cells was inhibited, and cell apoptosis was increased. Bcl-2 protein expression rates of EC9706 cells induced with Bcl-2 siRNA1, A2, A3 (25.13% ±2.04%, 8.87% ± 3.34%, 30.55% ± 2.73%) were lower than the control group (84.28% ± 1.47%)(t =4.01, 3.043.64, P 0, Dq, and SF2 of combined treatment group were much lower than those of irradiation alone group . The sensitization enhancing ratio was 1.32 (ratio of D0 values). Conclusions: Bcl-2 gene siRNA could enhance the radiosensitivity of esophageal cancer EC9706 cells and may has a good future in clinical practice. (authors)

  8. 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.

  9. 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)

  10. 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

  11. Effect of a hypoxic radiosensitizer, AK 2123 (Sanazole), on Yeast Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Yeast Saccharomyces cerevisiae can exist in two physiological states, namely anaerobic and aerobic. They differ in their response to gamma- radiation and radiomodification. We report hereon our results concerning radiosensitization by Sanazole (AK-2123), a well-known hypoxic radio sensitizer, whose mechanism of action has been studied extensively. The results have revealed that Sanazole (1 mM) when present during irradiation could specifically sensitize wild-type anaerobic yeast cells with a DMF of 2.4. In a radiation-sensitive mutant which lacks a DNA repair pathway specific for the recovery from gamma-radiation induced DNA damage, the extent of sensitization was considerably lower and the DMF was only 1.3. Studies on the liquid holding recovery of cells of both wild-type and rad52 yeast cells exposed to radiation in presence of Sanazole revealed that sensitization by Sanazole is due to a preferential increase in the DNA damage, and not by impairing DNA repair. This system thus holds promise for screening potential hypoxic chemical radiosensitizers. (author)

  12. Radiosensitization effects of the mouse H22 hepatoma by sulfonamide imidazole

    International Nuclear Information System (INIS)

    The purpose of the present study was to investigate whether the sulfonamide-imidazole (IVb) had radiosensitization effects on H22 tumor. Mice with H22 hepatoma were randomized into eight groups:control; radiation alone; radiation + ip 0.58 g/kg IVb; radiation + ip 0.29 g/kg IVb; radiation + ip 0.14 g/kg IVb; ip 0.5 g/kg IVb alone; ip 0.29 g/kg IVb alone; ip 0.14 g/kg IVb alone. IVb was diluted with normal saline and administered to the mice before irradiation. The dose of radiation is 10 Gy. Each group was treated mentioned above. The volume of mice's tumors was measured every two days. The authors calculated relative tumor growth rates, tumor inhibition rates and days of tumor growth delay. At the doses of 0.58 g/kg, 0.29 g/kg and 0.14 g/kg IVb with γ-ray radiation, the relative growth rates decreased and the tumor inhibition rates, the days of tumor growth delay increased, respectively. Among the three doses, the inhibition effects on tumors was most significant at the dose of 0.29 g/kg. There was no effect when IVb was administered alone. The results indicated that IVb has some radiosensitization effects on H22 hepatoma in vivo

  13. C646, a selective small molecule inhibitor of histone acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic catastrophe

    International Nuclear Information System (INIS)

    Background and purpose: Chromatin remodeling through histone modifications, including acetylation, plays an important role in the appropriate response to DNA damage induced by ionizing radiation (IR). Here we investigated the radiosensitizing effect of C646, a selective small molecule inhibitor of p300 histone acetyltransferase, and explored the underlying mechanisms. Materials and methods: A549, H157 and H460 human non-small cell lung carcinoma (NSCLC) cells, and HFL-III human lung fibroblasts were assessed by clonogenic survival assay. Apoptosis and necrosis were assessed by annexin V staining. Senescence was assessed by Senescence-associated β-galactosidase staining. Mitotic catastrophe was assessed by evaluating nuclear morphology with DAPI staining. Cell cycle profiles were analyzed by flow cytometry. Protein expression was analyzed by immunoblotting. Results: C646 sensitized A549, H460 and H157 cells to IR with a dose enhancement ratio at 10% surviving fraction of 1.4, 1.2 and 1.2, respectively. C646 did not radiosensitize HFL-III cells. In A549 cells, but not in HFL-III cells, C646 (i) enhanced mitotic catastrophe but not apoptosis, necrosis, or senescence after IR; (ii) increased the hyperploid cell population after IR; and (iii) suppressed the phosphorylation of CHK1 after IR. Conclusions: C646 radiosensitizes NSCLC cells by enhancing mitotic catastrophe through the abrogation of G2 checkpoint maintenance

  14. Study of enhancement of radiosensitivity in colon cancer carcinoma cell line HT-29 by celecoxib in vitro and in vivo

    International Nuclear Information System (INIS)

    Objective: To evaluate the radiosensitizing effect of Celecoxib, a selective cyclooxygenase-2 inhibitor, on colonic carcinoma cell line HT-29 in vivo, and to probe the underlying mechanisms. Methods: Colonic carcinoma cell line HT-29 was managed in vitro, and was treated by different concentration of Celecoxib, and the cell radiosensitivity was analyzed by colony formation unit assays; the change of tumor volume was observed by establishing the bear-tumor mice model of colonic carcinoma and drawing the tumor growth curve under different conditions; the expression of VEGF in colonic carcinoma tissues was detected by Immunohistochemistry assay. Results: The colony formation unit assays showed SER was respectively 1.304 and 1.475 in different groups which were combined with Celecoxib (30 μmol/L and 50 μmol/L). The tumor growth curve was used to do determination in these groups. When radiation was used combined with Celecoxib increase of tumor volume was the slowest. The expression level of VEGF in group Celecoxib was proved lower than that in the other groups (P<0.05). Conclusion: Celecoxib in vitro and in vivo could enhance the radiosensitivity in colon cancer carcinoma cell line HT-29 and inhibiting tumor angiogenesis maybe one of the underlying mechanisms. (authors)

  15. 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.

  16. 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

  17. 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...

  18. 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)

  19. EGFR and its mutant EGFRvIII as modulators of tumor cell radiosensitivity

    International Nuclear Information System (INIS)

    Purpose: Exposure of human carcinoma and malignant glioma cells to ionizing radiation (IR)activates EGFR,which as a consequence mediates a cytoprotective response. We have demonstrated that expression of a dominant negative mutant, EGFR-CD533 disrupts this cytoprotective response, resulting in significant radiosensitization. During studies of in vivo radiosensitization with intratumoral delivery of the Adenovirus (Ad) vector, Ad-EGFR-CD533, it became apparent that xenografts from human carcinoma and malignant glioma cells invariably expressed the constitutively active EGFR mutant, EGFRvIII. This mutant EGFRvIII is frequently found in vivo in glioblastoma, breast, prostate, lung and ovarian carcinoma, but does not appear to be expressed in tumor cells under in vitro conditions. The functional consequences of EGFRvIII expression on tumor cell radiation responses are currently unknown. We have therefore investigated in a transient transfection cell system the responses of EGFRvIII and downstream signal transduction pathways to IR. In addition, the capacity of EGFR-CD533 to disrupt the function of EGFRvIII was tested. Materials and Methods: The MDA-MB-231, U-87 MG and U-373 MG cell lines were established as tumors and then intratumorally transduced with Ad-EGFR-CD533 or Ad-LacZ (control vector). The transduction efficiency was > 40% in MDA-MB-231 tumors and reached > 70% in the glioma xenografts. Radiosensitivity was measured by ex vivo colony formation and growth delay assays. The functional consequences of EGFRvIII expression on cellular IR responses were studied in transiently transfected Chinese hamster ovary (CHO) cells because tumor cells do not express EGFRvIII in vitro. Transfection with null vectors and vectors encoding either EGFRvIII or EGFR were performed and similar protein expression levels were verified by Western blot analyses. Results: The radiosensitivity of Ad-EGFR-CD533 transduced tumors was significantly increased compared with Ad-LacZ transduced

  20. 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

  1. 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.

  2. 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.)

  3. 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...

  4. 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

  5. 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

  6. 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.

  7. 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.)

  8. Radiosensitization of EMT6 cells by four platinum complexes

    International Nuclear Information System (INIS)

    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 μM and 400 μM 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 μM and 1.8 at 400 μM. 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 μM 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 μM and 400 μM 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 μM 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

  9. Towards Personalized Cancer Therapy : New Diagnostic Biomarkers and Radiosensitization Strategies

    OpenAIRE

    Spiegelberg, Diana

    2015-01-01

    This thesis focuses on the evaluation of biomarkers for radio-immunodiagnostics and radio-immunotherapy and on radiosensitization strategies after HSP90 inhibition, as a step towards more personalized cancer medicine. There is a need to develop new tracers that target cancer-specific biomarkers to improve diagnostic imaging, as well as to combine treatment strategies to potentiate synergistic effects. Special focus has been on the cell surface molecule CD44 and its oncogenic variants, which w...

  10. Radiosensitivity and in vitro studies of Citrus suhuiensis

    International Nuclear Information System (INIS)

    Radiosensitivity tests and in vitro studies were carried out on two varieties of Citrus suhuiensis, ‘limau madu’ and ‘limau langkat’. Fresh seeds were desiccated for periods of 1, 2, 3 and 4 days and irradiated with gamma ray doses of 50, 100, 150, 200 and 250Gy. Shoot tips were also irradiated with gamma ray doses of 5, 10, 15, 20 and 25Gy. Results showed that lower moisture content seeds were more resistant to irradiation dose. It was determined that the LD50 of the ‘limau madu’ seeds was 200Gy at 25.48% moisture content, while the LD50 for ‘limau langkat’ seeds was 50Gy at 44.97% moisture content. A test on the DNA content of irradiated and non-irradiated samples using flow cytometry methods proved that irradiation had affected the DNA content (C-value) of the plant cells. Generally the 2C DNA content (pg) increases with increasing dose of radiation. Though low doses of radiation (50-100 Gy) resulted in a prominent effect on 2C DNA content, a few plants showed another 4C DNA peak with various seed desiccation levels. In inducing multiple shoots from apical shoot tips, it was found that MS medium with the addition of 2.5mgL-1 BAP was the optimal medium, where one explant was able to produce a mean of 13.5 adventitious shoots. Further results showed that MS medium with the addition of 0.6mgL-1 GA3 was the best medium for shoot elongation. In inducing root formation, 0.2mgL-1 NAA in MS medium proved to be the best medium. MT medium with the addition of growth regulators at different concentrations were tested on mature and immature embryos for the production of somatic embryos. It was found that immature embryos cultured on MT medium with 500mgL-1 malt extract, 0.5-1.0mgL-1 2, 4-D and 0.5 1.0mgL-1 BAP could produce proembryonic callus, which progressed to develop viable somatic embryos. (author)

  11. 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.

  12. Pharmacokinetic and radiosensitizing properties of phenylalanine analogs of 2-nitroimidazole

    International Nuclear Information System (INIS)

    In the authors efforts to improve the pharmacokinetic properties of 2-nitroimidazoles to develop a superior radiosensitizer than misonidazole, they have synthesized new phenylalanine analogs to minimize the enzymatic hydrolysis of the amide bond between the amino function of 2-nitroimidazole-1-ethylamine (NEA) and carboxylic group of phenylalanine. Two major metabolites, NEA and its acetylated derivative, were identified in plasma tumor and brain tissues after the administration of the phenylalanine analogs with a free amino function, in B16 melanoma bearing C57 mice. The enzymatic hydrolysis of the peptide bond was significantly reduced in analogs containing an α-methyl function in the ethylamine side chain. Since the metabolites were more toxic than the parent compounds, the LD/sub 50/ values were directly related to the ease of hydrolysis of the amide bond. The L-amino acid analogs were found to be less toxic than the D-isomers. These agents were potent radiosensitizers against hypoxic Chinese hamster (V-79) cells producing enhancement ratio of 2.0 to 2.4 at concentrations between 0.25 and 1.0 mM. These results suggest that the pharmacokinetics of the amino acid analogs can be conveniently manipulated by creating steric hindrance to provide therapeutically effective radiosensitizers

  13. The HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells

    International Nuclear Information System (INIS)

    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

  14. The combination effect of sodium butyrate and 5-Aza-2'-deoxycytidine on radiosensitivity in RKO colorectal cancer and MCF-7 breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Oh Seong

    2009-05-01

    Full Text Available Abstract Background The overall level of chromatin compaction is an important mechanism of radiosensitivity, and modification of DNA methylation and histone deacetylation may increase radiosensitivity by altering chromatin compaction. In this study, we investigated the effect of a demethylating agent, a histone deacetylase(HDAC inhibitor, and the two agents combined on radiosensitivity in human colon and breast cancer cell lines. Methods In this study, we used RKO colorectal cancer cell line and MCF-7 breast cancer cell lines and normal colon cell lines. On each of the cell lines, we used three different agents: the HDAC inhibitor sodium butyrate(SB, the demethylating agent 5-Aza-2'-deoxycytidine(5-aza-DC, and radiation. We then estimated the percentage of the cell survival using the XTT method and experimented to determine if there was an augmentation in the therapeutic effect by using different combinations of the two or three of the treatment methods. Results After treatment of each cell lines with 5-aza-DC, SB and 6 grays of radiation, we observed that the survival fraction was lower after the treatment with 5-aza-DC or SB than with radiation alone in RKO and MCF-7 cell lines(p Conclusion In conclusion, 5-aza-DC and SB can enhance radiosensitivity in both MCF-7 and RKO cell lines. The combination effect of a demethylating agent and an HDAC inhibitor is more effective than that of single agent treatment in both breast and colon cancer cell lines.

  15. 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.

  16. Radiosensitivity of Various Stages of Callosobruchus Chinensis L

    International Nuclear Information System (INIS)

    The effects of irradiation on the eggs, larvae, pupae and adults of Callosobruchus chinensis L., a destructive pest of leguminous seeds, have been studied. Since the entire life-cycle except the egg and adult stages of this insect is passed in the seed itself, control by conventional means is very difficult. Insects were obtained from local grain shops and reared in .an incubator in the laboratory on moong (Phaseolus mungo L.) seeds at a temperature of 29oC ± 1oC and a humidity of 70-75%. Under these conditions the insect completed its life-cycle in 18-22 d. A 1-c iridium-192 source was used for initial experiments in irradiation. Later this was increased to 4 c. Exposures were made at very close range and the dose-rates were calculated on the basis of a measurement made at 50-cm distance with a Victoreen condenser r-meter. Eggs were irradiated at a distance of 0.5 cm from the source arid larvae, pupae and adults at 1.0 cm from the source, the respective dose-rates being 80 kr/h at 0.5 cm and 20 kr/h at 1 cm for a 4-c source. It was found that a dose of 15 krad gave 100% mortality in the case of eggs. Different doses below this level gave somewhat variable results and it is possible that there is a sensitive stage for a short period during the first 24 hours of development of the eggs. In the case of 8-day-old larvae 100% mortality was obtained with a dose of 20 000 rad. The pupae seem to be less radiosensitive than the eggs or larvae and doses of 47 000 rad were needed to give 100% mortality. Doses of 42 000 rad ''sterilized'' the males and females in the sense that, though mating took place after irradiation, the eggs produced when either of the parents had been irradiated with a dose of 42 000 rad did not hatch. Production of ''sterile'' eggs continued even when either or both parents had been exposed to doses of 67 000 rad - the highest dose tried. (author)

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. 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

  4. 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)

  5. Response of rat spinal cord to very small doses per fraction: lack of enhanced radiosensitivity

    International Nuclear Information System (INIS)

    Our previous work with rat spinal cord demonstrated that the linear quadratic (LQ) model based on data for large fraction sizes ((α(β)) of 2.4 Gy) failed to predict isoeffective doses between 1 and 2 Gy per fraction, and under-estimated the sparing effect of small doses per fraction given once daily. In contrast, data from mouse skin and kidney, and recent in vitro results revealed a paradoxical increase in radiosensitivity at below 1 Gy per fraction. To assess whether enhanced radiosensitivity is present in the spinal cord below 1 Gy per fraction, the rat spinal cord (C2-T2) was irradiated initially with three daily doses of 10.25 Gy (top-up doses representing 90% of tolerance), followed by graded single doses or fractionated doses in 1.5, 1.0, 0.8, 0.6 or 0.4 Gy fractions given once daily. To limit the overall treatment time to ≤ 8 weeks, a small number of the 0.6- and 0.4-Gy fractions were given twice daily with an interfraction interval of 16 h. The end-point was forelimb paralysis secondary to white matter necrosis, confirmed histologically. The ED50 values, excluding the top-up doses, were 5.8, 10.6, 14.8, 15.2, 15.9 and 19.1 Gy for a single dose and doses in 1.5-, 1.0-, 0.8-, 0.6- and 0.4-Gy fractions, respectively. The data gave an (α(β)) of 2.1 Gy (95% CI, 1.4, 2.7 Gy). Pooling the data separately, the (α(β)) value was 2.3 Gy (95% CI, 0.82, 3.7 Gy) for fraction sizes ≥ 1 Gy, and 1.2 Gy (95% CI, 0.16, 2.3 Gy) for the 0.8-, 0.6- and 0.4-Gy experiments. These results in which top-up doses were given initially are consistent with a large sparing effect of very small fraction sizes in rat spinal cord provided sufficient time is allowed for repair of sublethal damage between fractions, and provide no evidence for a paradoxical increase in radiosensitivity in the rat spinal cord below 1 Gy down to 0.4 Gy per fraction

  6. 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)

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Factors influencing intracellular uptake and radiosensitization by 2-nitroimidazoles in vitro

    International Nuclear Information System (INIS)

    In this study it is shown that the radiosensitization of hypoxic Chinese hamster ovary (HA-1) cells in vitro by misonidazole (MIS) and other 1-substituted 2-nitroimidazoles depends on the rate and extent of intracellular uptake of these radiosensitizers, which in turn is governed by their lipophilicity [expressed as the octanol:water partition coefficient (P)]. As the lipophilicity of the compounds decreased, the rate of drug entry into the cells was slower, and below P values of approximately 0.05, peak intracellular drug concentrations were found to be lower than that of MIS (P=0.43). In addition, the number of hydroxyl groups on the side chain of the nitroimidazole molecule influenced the uptake of drug into the cells. For compounds of similar P, but differing in the number of side-chain hydroxyl groups, the addition of a single hydroxyl group to the molecule decreased the amount of drug entering the cell by a factor of approximately 2. These compounds enter the cell by nonmediated passive diffusion since altering the energy (ATP) capacity of the cell by 2-deoxyglucose did not affect uptake. It is also shown that increases in temperature or decreases in pH can increase the intracellular uptake of MIS. For example, equal intracellular and extracellular concentrations (100% uptake) of MIS were obtained if cells were heated to 44-450C for 15 min compared to 20-40% uptake at 370C. Increases in MIS uptake by factors of 2 to 3 could be demonstrated within 30 min when cells were incubated in Hanks' balanced salt solution at pH between 6.0 and 6.3 without loss of cell viability. In addition, MIS uptake in aerobic cultured cells varied from 15 to 60% depending on the cell line and culure conditions used

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

    Science.gov (United States)

    Lacroix, Monique; Caillet, Stéphane; Shareck, Francois

    2009-07-01

    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.

  13. Implantable biodegradable polymers for IUdR radiosensitization of human glioma in vivo

    International Nuclear Information System (INIS)

    Purpose: Halogenated pyrimidines are potentially useful for the radiosensitization of human malignant glioma. Therefore, we tested a synthetic, implantable biodegradable polymer for the controlled in vitro release of 5-iodo-2'-deoxyuridine (IUdR) and measured the resultant in vivo radiosensitization in nude mice bearing intracranial U251 human malignant glioma xenografts. Materials and Methods: In vitro: To measure release, increasing (10%, 30%, 50%) proportions of IUdR in synthetic [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) (PCPP:SA ratio 20:80)] polymer discs were incubated in buffered physiologic saline solution. The supernatant fractions were periodically removed, replaced and assayed for IUdR. To test radiosensitization, U251 cells were incubated with or without 10 uM IUdR for 3 days followed by acute irradiation (0, 2.5, 5.0, or 10 Gy). In vivo: Polymer discs with 200 uCi of 125-IUdR were implanted intracranially in nude mice. Activity (cpm) was serially measured at specified times up to 311 hours after implantation via a collimated scintillation detector. To measure radiosensitization in vivo, mice had sequential intracranial inoculation of 2 x 105 U251 cells, implantation of polymer discs without (empty control) or with 50% IUdR, and radiation. We tested intensification and timing of radiation vs. timing of IUdR polymer implantation. When measured from the day of cellular inoculation, the days of implantation of empty (control) or 50% IUdR polymers and the subsequent schedules for radiation were: Expt. 1.) day 5 (5 Gy on days 7 and 8), Expt. 2.) days 4 or 7 (5 Gy on days 8 and 10), Expt. 3.) days 4 or 7 (2 Gy BID x 4 on days 7-10) and Expt. 4.) day 5 or 8 (2 Gy BID x 4 on days 8-11). Survival was measured. Results: In vitro: After 4 days the cumulative percentages of IUdR that were released were 43.7 ± 0.1, 70.0 ± 0.2, and 90.2 ± 0.2 (p 10) was -2.02 ± 0.02 or -3.68 ± 0.11 (p < 0.001), respectively. In vivo: The externally measured

  14. 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)

  15. 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)

  16. 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...... is crucial in evaluating the radiosensitization potential and in developing new and more effective drugs. The present work investigates the negative and positive electrospray ionization and subsequent collision-induced dissociation and electron-induced dissociation reactions of ions derived from...... nimorazole, misonidazole and related compounds using a hybrid linear ion trap – Fourier Transform Ion Cyclotron Resonance mass spectrometer (Finnigan-LTQ-FT). A key finding is that negative electrospray ionization of these radiosensitizers leads to the formation of radical anions, allowing their...

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

    International Nuclear Information System (INIS)

    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)

  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. 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

  20. 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).

  1. 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)

  2. Contribution to some radiobiological aspects of the investigation of radiosensitizers of hypoxic cells. 4

    International Nuclear Information System (INIS)

    Radiosensitizing effect of metronidazole (Entizol, Polfa, Poland) was tested on an experimental model of ischaemized bone marrow. The changes of bone marrow cellularity were recorded after whole-body irradiation of rats protected with abdomen compression during irradiation. With an increasing dose of irradiation proportional and significant decrease of nuclear elements in bone marrow occurred the third day after irradiation. Metronidazole administered to unprotected rats (without compression) did not show any effect. The abdomen compression led to a pronounced radioprotection but metronidazole administration reduced this effect significantly. Ischaemization of the lower half of rat body produced on the level of bone marrow cellularity the protection corresponding to DRF (dose reduction factor) = 1.96 the third day after irradiation. DRF value decreased to 1.52 by metronidazole application which corresponds to ER (enhancement ratio) = 1.29. (author)

  3. The influence of cell kinetics on the radiosensitivity of Down's syndrome lymphocytes

    International Nuclear Information System (INIS)

    In agreement with previous work, [60Co]γ-irradiation shortly after phytohemagglutinin (PHA) stimulation, induces higher frequencies of chromosomal aberrations in trisomy 21 lymphocytes compared to normal controls. However, equal frequencies of chromatid aberrations are induced in fully-stimulated trisomy 21 and normal lymphocytes by irradiation during G2. We have observed that trisomic lymphocytes respond more rapidly to PHA stimulation than normal lymphocytes. Furthermore, we have observed that chromosomal radiosensitivity increases as a function of time after PHA stimulation in normal lymphocytes. When normal lymphocytes are irradiated 8 h after PHA stimulation, the frequencies of chromosomal aberrations induced are comparable to those induced in trisomy 21 lymphocytes irradiated 30 min after PHA stimulation. (orig.)

  4. Radiosensitizer AK-2123 enhances sensitivity of mdr-tumors to mitomycin C

    International Nuclear Information System (INIS)

    The effect of the AK-2123 radiosensitizer, associated with the triazoles group, on the sensitivity of the mdr tumors to mitomycin C (MMC), etoposide and adriablastin is studied. It is shown, that the AK-2123 essentially increases the sensitivity of the R388 leucosis mdr strains to MMC. It is assumed, that the sensibilizer modulation effect is conditioned by its ability to change the calcium ions flows. The AK-2123 preparation dose not change the sensitivity of the R388 source strain to MMC; it is unable to overcome the cross-over stability of one of the mdr resistant strains, causing etoposide and adriablastin. The work may be of importance by studying the radiation sensitivity of the mdr-tumors

  5. Influence of physical and biological factors in cellular radiosensitivity

    International Nuclear Information System (INIS)

    The use of therapeutic radiopharmaceuticals is associated with radiation damage, and this at-nuclear physical properties of radionuclides used and the characteristics of the irradiated cells. The work deals with the damage caused by radiation to DNA, factors that condition and tools that can be used to measure it. It presents current concepts of death and cellular radiosensitivity, based on the pioneering work in this field. Enter the neighborhood effect and adaptive response and evaluates the influence of the same in the paradigms of classical radiobiology. (author)

  6. 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

  7. In vitro radiosensitivity of human leukemia cell lines

    International Nuclear Information System (INIS)

    The in vitro radiobiologic survival values (n, D0) of four tumor lines derived from human hematopoietic tumors were studied. These cell lines were HL50 (n . 1.3, D0 . 117 rad[1.17 Gy]), promyelocytic leukemia; K562 (n . 1.4, D0 . 165 rad[1.65 Gy]), erythroleukemia; 45 (n . 1.1, D0 . 147 rad[1.47 Gy]), acute lymphocyte leukemia; and 176 (n . 4.0, D0 . 76 rad[0.76 Gy]), acute monomyelogenous leukemia. More cell lines must be examined before the exact relationship between in vitro radiosensitivity and clinical radiocurability is firmly established

  8. 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.

  9. Neuropathy of nitroimidazole radiosensitizers: clinical and pathological description

    International Nuclear Information System (INIS)

    The dose limiting toxicity of the nitroimidazole radiosensitizers is peripherial neuropathy. Improved pharmacology of newer drugs has eliminated the encephalopathy. Peripheral neuropathies are predominently mild to moderate paresthesias of both hands and feet. Subjective changes occur with or without minimal objective changes on neurologic exam. All of the neuropathies occurred within 30 days of the last drug dose and are of varible duration. Sural nerve biopsies from patients indicate progressive axonal degeneration affecting both large and small caliber myelinated fibers. Axonal damage appears to be more severe in the distal portion of the nerves. More data are needed for correlation of clinical and pathological changes

  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. 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

  12. Effects of osteopontin inhibition on radiosensitivity of MDA-MB-231 breast cancer cells

    International Nuclear Information System (INIS)

    Osteopontin (OPN) is a secreted glycophosphoprotein that is overexpressed in various tumors, and high levels of OPN have been associated with poor prognosis of cancer patients. In patients with head and neck cancer, high OPN plasma levels have been associated with poor prognosis following radiotherapy. Since little is known about the relationship between OPN expression and radiosensitivity, we investigated the cellular and radiation induced effects of OPN siRNA in human MDA-MB-231 breast cancer cells. MDA-MB-231 cells were transfected with OPN-specific siRNAs and irradiated after 24 h. To verify the OPN knockdown, we measured the OPN mRNA and protein levels using qRT-PCR and Western blot analysis. Furthermore, the functional effects of OPN siRNAs were studied by assays to assess clonogenic survival, migration and induction of apoptosis. Treatment of MDA-MB-231 cells with OPN siRNAs resulted in an 80% decrease in the OPN mRNA level and in a decrease in extracellular OPN protein level. Transfection reduced clonogenic survival to 42% (p = 0.008), decreased the migration rate to 60% (p = 0.15) and increased apoptosis from 0.3% to 1.7% (p = 0.04). Combination of OPN siRNA and irradiation at 2 Gy resulted in a further reduction of clonogenic survival to 27% (p < 0.001), decreased the migration rate to 40% (p = 0.03) and increased apoptosis to 4% (p < 0.005). Furthermore, OPN knockdown caused a weak radiosensitization with an enhancement factor of 1.5 at 6 Gy (p = 0.09) and a dose modifying factor (DMF10) of 1.1. Our results suggest that an OPN knockdown improves radiobiological effects in MDA-MB-231 cells. Therefore, OPN seems to be an attractive target to improve the effectiveness of radiotherapy

  13. 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.

  14. 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

  15. 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.

  16. Hypoxic radiosensitization by the antimicrobial methyl paraben

    International Nuclear Information System (INIS)

    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

  17. 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)

  18. Radiosensitization by quaternary salts of 5-nitroimidazole derivatives

    International Nuclear Information System (INIS)

    The radiosensitizing effects of five newly synthesized quaternary salts of 5-nitroimidazole derivatives on the survival of TC-SV40 mammalian cells were measured. The OER for TC-SV40 cells was 2.74. None of the derivatives showed radiosensitizing activity in aerobic conditions, while in hypoxia dose-modifying factors (DMF) at the concentration of 0.2 mmol dm-3 range from 1.52 to 1.03 in this order: unsubstituted pyridinium>carbamoyl pyridinium>trimethyl pyridinium>t-butyl pyridinium>imidazolium. This latter product at a concentration of 2 mmol dm-3 has a DMF of 1.64. Metronidazole gave a DMF at 0.2 mmol dm-3 of 1.35. Response-concentration dependences for the unsubstituted pyridinium 5-nitro-imidazole derivative and metronidazole (comparing charged and uncharged structures) showed the flattening response-concentration curve of quaternary compounds. The electron affinity was evaluated through the CNDO/S theoretical method, and an exponential relationship between these values and DMFs of the pyridinium derivatives was demonstrated. (author)

  19. Protracted postnatal neurogenesis and radiosensitivity in the rabbit's dentate gyrus

    International Nuclear Information System (INIS)

    In the hippocampal formation of a 3-month-old rabbit submitted to a 4.5 Gy gamma irradiation a cytologic study with light and electron microscopy allowed us to make clear the dentate gyrus particular radiosensitivity as soon as the first hours after irradiation. The pycnosis lesion observed in the subgranular zone has drawn our attention in particular. We apply ourselves to describe and precise the lesion and its evolution; thanks to an autoradiographic study, we have shown its link with late postnatal neurogenesis which goes on in this zone and at last we have used the subgranular cells 'radiosensitivity as a biological test allowing to compare the various rays' effects (gamma and neutron rays). In the brain of a one-month-old monkey submitted to a 4 Gy total irradiation the same pycnotic lesion is observed: 1) in the dentate gyrus's subgranular zone and 2) in the cerebellum's outer granular layer. These two postnatal proliferative zones remain particularly sensitive to ionizing radiations. (orig.)

  20. Radiosensitization in vitro and in vivo by 3-nitrotriazoles

    International Nuclear Information System (INIS)

    A series of 3-nitro-1,2,4-triazole derivatives bearing various types of side chain (R) at the N1-position (AK-2000 series) were synthesized and their radiosensitizing effect and toxicity in vitro and in vivo were investigated, in comparison with those of Misonidazole (MISO), SR-2508, and RSU-1069. Of the fifteen 3-nitrotriazoles tested, all had sensitizing effects in vitro on hypoxic V79 cells. Also, all but one had definite effects on solid EMT6/KU and SCCVII tumors in vivo. For many of the triazole compounds, the degree of radiosensitization in vitro and in vivo appeared identical. However, they were generally less efficient, both in vitro and in vivo, than the corresponding 2-nitroimidazoles, whereas their aerobic cytotoxicity and toxicity to mice (LD50/7) were comparable to those of the 2-nitroimidazoles. Considering the sensitizing effect and toxicity, AK-2123 (R = CH2CONHC2H4OCH3) may be as useful as MISO, but none of the triazoles have been proved to be superior to SR-2508

  1. Advances in radiation biology: Radiosensitization in DNA and living cells

    Science.gov (United States)

    Lacombe, S.; Sech, C. Le

    2009-06-01

    One fundamental goal of radiation biology is the evolution of concepts and methods for the elaboration of new approaches and protocols for the treatment of cancers. In this context, the use of fast ions as ionizing particles offers the advantage of optimizing cell killing inside the tumor whilst preserving the surrounding healthy tissues. One extremely promising strategy investigated recently is the addition of radiosensitizers in the targeted tissue. The optimization of radiotherapy with fast ions implies a multidisciplinary approach to ionizing radiation effects on complex living systems, ranging from studies on single molecules to investigations of entire organisms. In this article we review recent studies on ion induced damages in simple and complex biological systems, from DNA to living cells. The specific aspect of radiosensitization induced by metallic atoms is described. As a fundamental result, the addition of sensitizing compounds with ion irradiation may improve therapeutic index in cancer therapy. In conclusion, new perspectives are proposed based on the experience and contribution of different communities including Surface Sciences, to improve the development of radiation biology.

  2. Radio-sensitivity of spruce population progeny in Bulgaria

    International Nuclear Information System (INIS)

    The radio-sensitivity of Picea abies (L.) Karst populations was investigated by comparing the effect of acute irradiation with different Co-60 rates on seed germination and the survival of the seedlings obtained from them. Spruce stands in the Rila, Pirin and Rhodopes, the Balkan, Vitosha and Ossogovo mountains have been studied at 1000 to 2000 m alt. into 200-300 m intervals. The seed material collected from them by individual trees, altitude belts and mountains has been irradiated with 200 krad, 500 krad, 1000 krad, 1500 krad and 7500 krad. The germination capacity of the seeds was calculated in technical germination, absolute germination, germination energy and seed dormancy, while the post-irradiation effect was established in accordance with the survival rate of the seedlings for one- and two-year periods in greenhouses on a sand substrate. Radio-sensitivity of every spruce population depended on its vitality and Vigour. The spruce population in the Rhodope Mountains exhibits highest radio-hardiness, followed by those in the Rila, Central Balkan, Pirin, Vitosha and Ossogovo mountains. Irradiation with 200 krad, and in certain cases with 500 krad, showed a stimulation effect on germination of spruce seeds and the survival rate of the seedlings. LD-50 for spruce seeds, taking into account one- and two-year-old seedlings, was within the 500 to 1000 krad range. (author)

  3. Cellular uptake and radiosensitization of SR-2508 loaded PLGA nanoparticles

    International Nuclear Information System (INIS)

    SR-2508 (etanidazole), a hypoxic radiosensitizer, has potential applications in radiotherapy. The poly(d,l-lactide-co-glycolide)(PLGA) nanoparticles containing SR-2508 were prepared by w/o/w emulsification-solvent evaporation method. The physicochemical characteristics of the nanoparticles (i.e. encapsulation efficiency, particle size distribution, morphology, in vitro release) were studied. The cellular uptake of the nanoparticles for the two human tumor cell lines: human breast carcinoma cells (MCF-7) and human carcinoma cervices cells (HeLa), was evaluated by fluorescence microscopy and transmission electronic microscopy. Cell viability was measured by the ability of single cell to form colonies in vitro. The prepared nanoparticles were spherical in shape with size between 90 nm and 190 nm. The encapsulation efficiency was 20.06%. The drug release pattern exhibited an initial burst followed by a plateau for over 24 h. The cellular uptake of nanoparticles was observed. Co-culture of MCF-7 and HeLa cells with SR-2508 loaded nanoparticles showed that released SR-2508 retained its bioactivity and effectively sensitized two hypoxic tumor cell lines to radiation. The radiosensitization of SR-2508 loaded nanoparticles was more significant than that of free drug.

  4. 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)

  5. p53: Biology and role for cellular radiosensitivity

    International Nuclear Information System (INIS)

    Purpose: p53 is the most commonly mutated gene in human tumors with large impact on cellular biology and response to radiation. Many excellent reviews are available on various aspects but for several years none about the role of p53 for radiosensitivity. The latter is the aim of the present paper. Methods: Review of the literature. Results: p53 is a regulator of apoptosis mainly in hematopoetic tissue. In normal tissue and solid tumors presumably other functions have more impact on the cellular response. p53 controls cell-cycle progression after irradiation and also DNA-repair, namely homologous and non-homologous recombination. Mutations of p53 alter these functions which may be responsible for an enhanced cellular and tumor radioresistance. At present only few reports were able to show that under tightly controlled conditions loss of p53 wild-type function leads to enhanced radioresistance. A general proof is still lacking. Conclusion: The emerging picture in the year 2000 shows p53 as a central protein in a multi-enzyme multi-function network which is far from being fully understood. Although p53 appears to be a major regulator it is certainly not the unreplacable component the loss of which uniformly determines radioresistance. Only further understanding of modifiers and cooperators in the cell and in the specific tissue context will elucidate p53's role for radiosensitivity and radiotherapy. (orig.)

  6. NLP-1: a DNA intercalating hypoxic cell radiosensitizer and cytotoxin

    International Nuclear Information System (INIS)

    The 2-nitroimidazole linked phenanthridine, NLP-1 (5-[3-(2-nitro-1-imidazoyl)-propyl]-phenanthridinium bromide), was synthesized with the rationale of targeting the nitroimidazole to DNA via the phenanthridine ring. The drug is soluble in aqueous solution (greater than 25 mM) and stable at room temperature. It binds to DNA with a binding constant 1/30 that of ethidium bromide. At a concentration of 0.5 mM, NLP-1 is 8 times more toxic to hypoxic than aerobic cells at 37 degrees C. This concentration is 40 times less than the concentration of misonidazole, a non-intercalating 2-nitroimidazole, required for the same degree of hypoxic cell toxicity. The toxicity of NLP-1 is reduced at least 10-fold at 0 degrees C. Its ability to radiosensitize hypoxic cells is similar to misonidazole at 0 degrees C. Thus the putative targeting of the 2-nitroimidazole, NLP-1, to DNA, via its phenanthridine group, enhances its hypoxic toxicity, but not its radiosensitizing ability under the present test conditions. NLP-1 represents a lead compound for intercalating 2-nitroimidazoles with selective toxicity for hypoxic cells

  7. Influence of heat on the intracellular uptake and radiosensitization of 2-nitroimidazole hypoxic cell sensitizers in vitro

    International Nuclear Information System (INIS)

    The effect of elevated temperature (44 degrees) on the intracellular uptake of the 2-nitroimidazole hypoxic cell radiosensitizer, misonidazole (MIS), and analogues more hydrophilic than MIS was studied in Chinese hamster ovary cells. It was found that the intracellular uptake of these compounds which enter cells by restricted passive diffusion can be enhanced approximately 4-fold when incubated at 44 degrees compared to the uptake at 37 degrees. Peak intracellular uptake (expressed as the ratio of intracellular concentration to extracellular concentration) following incubation of cells in 2 mM MIS was 100% at 44 degrees but only 25% at 37 degrees. Furthermore, a short-term nonlethal heat pulse (44 degrees for 15 min) with MIS present caused a 2-fold enhancement in uptake which was sustained for an additional 45 min at 37 degrees. This same nonlethal heat pulse was found to induce a similar enhancement in uptake even when MIS was added at subsequent time intervals at 37 degrees. The heat pulse induced a time-related enhancement of uptake at 37 degrees which increased for 1 hr and persisted for at least 6 hr. Finally, in vitro radiosensitization studies of hypoxic Chinese hamster ovary cells showed that the nonlethal heat pulse of 44 degrees for 15 min could greatly enhance the sensitization by low concentrations (0.5 mM) of MIS added after heating due to increased intracellular concentrations of the drug. MIS (0.5 mM) alone achieved a radiosensitization enhancement ratio of 1.29 (compared to irradiated hypoxic cells alone), while the addition of the short-term heat pulse, which had only a minor effect itself, achieved an enhancement ratio of 1.78

  8. 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

  9. Nuclear epidermal growth factor receptor modulates cellular radio-sensitivity by regulation of chromatin access

    International Nuclear Information System (INIS)

    Purpose: Nuclear EGFR is involved in cellular stress management and regulation of cellular radio-sensitivity. The aim of this study was to elucidate the molecular mode of nuclear EGFR action. Methods: Radiation induced nuclear EGFR-shuttling and EGFR-foci formation was analyzed with immunohistochemistry and confocal microscopy. Composition of γH2AX-protein complexes was analyzed by western-blotting after immuno-precipitation. Functional relevance of nuclear EGFR was analyzed after siRNA mediated depletion of EGFR with respect to activation of ATM, histone H3 acetylation, residual DNA-damage and cell survival after irradiation. Results: Following radiation nuclear EGFR was localized in foci similar to γH2AX. EGFR co-localized in a sub-fraction of γH2AX-foci. Analysis of composition of γH2AX-complexes revealed presence of EGFR, ATM, promyelocytic leukemia protein (PML), histone H3 and hetero-chromatin binding protein (HP1) in response to radiation. Depletion of EGFR protein inhibited ATM activation due to inhibition of acetylase TIP60 activity following irradiation. Consequently, histone H3 acetylation and phosphorylation was blocked and chromatin could not be opened for repair. Thus, residual DNA-damage was increased 24 h after irradiation and cells were radio-sensitized. Comparable results were obtained when cells were treated with EGFR-NLS-peptide, which blocks EGFR nuclear shuttling specifically. Conclusions: Nuclear EGFR is part of DNA-damage repair complex and is involved in regulation of TIP60-acetylase activity. TIP60 is essential for ATM activation and chromatin relaxation which is a prerequisite for DNA-repair in heterochromatic DNA. Thus interventional EGFR strategies during tumor treatment may also interact with DNA-repair by blocking access to damaged DNA.

  10. Radiosensitization of micro RNA-17-92 on human mantle cell lymphoma cells in vitro

    International Nuclear Information System (INIS)

    Objective: To investigate the effects of microRNA-17-92 on radiosensitivity of human mantle cell lymphoma cells. Methods: Tetracycline-regulated pRevTet-On expression system was established to generate cell line Z138c-miR-17-92 with over-expressed miR-17-92 and cell line Z138c-TMP2. Cell proliferation was measured by 3H-TdR incorporation and viable cell counting stained with typan blue. Cell cycle distribution was analysed by flow cytometry (FCM). Results: More viable and proliferous cells were counted in group miR-17-92, when exposure dose was greater than 2 Gy and incubation time was longer than 48 h under the same condition (t=-3.12 and -3.28, P2/M cell in group TMP2 was increased while no obvious cell cycle arrests were found in group miR-17-92 at 2 and 4 Gy (t=2.885, P<0.05). When cells were incubated for 96 h, higher percentage of propidium iodide (PI) positively stained cells were found in group TMP2 (24.02% vs. 36.16%) compared with group miR-17-92 (6.49% vs. 11.39%) at 2 and 4 Gy, respectively (t=-17.59, -4.972, P<0.05). Conclusions: Overexpression of microRNA-17-92 decreased the radiosensitivity of human mantle cell lymphoma cells by inhibition of cell cycle changes and cell apoptosis. (authors)

  11. Radiosensitization of pancreatic cancer cells by 2',2'-difluoro-2'-deoxycytidine

    International Nuclear Information System (INIS)

    Purpose: We have reported that the deoxycytidine analog 2',2'-difluoro-2'-deoxycytidine (dFdCyd) is a potent radiosensitizer of HT29 human colon cancer cells probably through its effects on intracellular deoxyribonucleotide (dNTP) pools. Because dFdCyd has activity against pancreatic cancer in clinical trials, we wished to determine if dFdCyd would radiosensitize human pancreatic cancer cells. Methods and Materials: We assessed the effect of dFdCyd on radiation sensitivity of two human pancreatic cancer cell lines, Panc-1 and BxPC-3. To begin to investigate the mechanism of sensitization, we determined the effect of dFdCyd on dNTP pools and cell cycle distribution. Results: We found that dFdCyd produced radiation enhancement ratios of 1.7-1.8 under noncytotoxic conditions in both cell lines. Sensitization was not associated with intracellular levels of 2',2'-difluoro-2'-deoxycytidine triphosphate, the cytotoxic metabolite of dFdCyd, but occurred when dATP pools were depleted below the level of approximately 1 μM. Although both cell lines showed substantial cell cycle redistribution after drug treatment, the flow cytogram of the BxPC-3 cells would not, by itself, be anticipated to result in increased radiation sensitivity. Conclusions: These findings demonstrate that dFdCyd is a potent radiation sensitizer of human pancreatic cancer cells and support the development of a clinical protocol using combined dFdCyd and radiation therapy in the treatment of pancreatic cancer

  12. 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.

  13. Screening human populations for abnormal radiosensitivity

    International Nuclear Information System (INIS)

    A relatively rapid and inexpensive in vitro growback assay was developed that uses the irradiated versus the unirradiated re-growth responses of lymphoblastoid cell lines developed from individual donors as an estimator of donor radioresponse. The purpose of this project was to furnish an estimate of the proportion of strains derived from various study populations that may be regarded as exhibiting abnormal radioresponse. The emphasis in this study was on hypersensitivity, because of the known radiation-hypersensitivity and cancer proneness associated with the genetic disorder ataxia-telangiectasia. Using methods developed especially for survival analyses, the percentage of significantly hypersensitive responses was 5.5% in a donor population composed of ostensibly normal individuals. We also examined lines derived from an unselected cancer patient population. These were not enriched, compared to the reference normal population, for hypersensitive responses. We thus conclude that hypersensitivity in vitro is not associated with increased risk for spontaneous development of cancer. However, the failure to observe an association between hypersensitivity and spontaneous cancer does not preclude a correlation between such sensitivity and radiogenic cancer. At the present stage, we would caution against the application of this assay or related in vitro tests to the situation of an individual, as opposed to a population. While we have clear indications that hypersensitivity in vitro is associated with abnormal radioresponse in vivo, this study has identified sources of variation that must be understood before attempts are made to unambiguously attribute a particular type of radioresponse to an individual

  14. Gamma Radiosensitivity Study on Chili (Capsicum annuum

    Directory of Open Access Journals (Sweden)

    Shairul R.  Omar

    2008-01-01

    Full Text Available Induced mutation by gamma irradiation has been found to be a very useful technique for crop improvement. Apart from this, the proper use of induced mutation in plant breeding has become a profitable approach. This investigation was carried out to determine the LD50 and effect of gamma rays on germination, plant height, survival percentage, root length, root dry weight and shoot dry weight of seedlings derived from irradiated seeds of chili (Capsicum annuum. Seeds of chili were treated with 300, 400, 500, 600 and 800 Gy gamma rays at Malaysian Institute of Nuclear Technology (MINT. The treated seeds including control were sown in sand beds in size 4.6 x 0.7 m2 in a greenhouse at Horticulture Unit, UPMKB. Water was applied manually to maintain the soil moisture at field capacity as well as weed was manually controlled. The experiment was designed as 5 x 6 factorial in completely randomized design (CRD with three replications. Lethal dose 50 % of population (LD50 was assayed. Observation showed that germination percentage, plant height, survival percentage, root length, root weight and shoot dry weight decreased with increasing dose of gamma rays. The 800 Gy gamma ray dose had a profound effect on these variables perhaps due to injury the higher doses may have caused to the seeds of chili. This resulted in poor growth and development of chili seedlings. The LD50 for chili (survival percentage was estimated at 445 Gy. Loan contracts performance determines the profitability and stability of the financial institutions and screening the loan applications is a key process in minimizing credit risk. Before making any credit In general, higher gamma ray doses particularly 600 and 800 Gy had negative effect on the morphological characteristics of chili seedlings derived from irradiated seeds.

  15. 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 effect of dose levels of gamma radiation applied to the germinated embryos (protocorms) of the three species. Also, it sought to determine the lethal dose and optimum dose of gamma radiation on the three species. The protocorms of the three species were irradiated at 10 Gy, 20 Gy, 30 Gy, 40 Gy, and 50 Gy dose level of gamma radiation. The three species have varied radiosensitivity as affected by their individual phenotype. Results showed that as the dose level and ministered increases, percent mortality of seedlings also increases whereas, the seedlings height, number of roots and root length decreased. However, there was an increase in the number of leaves at 10 and 20 Gy dose levels due to the emergence of furcations, but further increase in the dose levels of radiation decreased the number of leaves. Furthermore, some qualitative characters such as albinism, pigmentation, forked leaves, furcations, and multiple branching came out as responses to gamma irradiation

  16. 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...

  17. 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.

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

    International Nuclear Information System (INIS)

    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. (note)

  19. 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

  20. 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

  1. Fuzzy clustering analysis for the varietal radiosensitivity of triticum aestivum L

    International Nuclear Information System (INIS)

    Fussy clustering classification to the varietal radiosensitivity of wheat (Triticum aestivum L.) was carried out. According to their response to the radiation of gamma rays, 49 wheat varieties were classified into five groups: higher resistant, resistant, intermediate response, sensitive, and higher sensitive. The research presents a new approach for the classification of the varietal radiosensitivity of a certain plant species, and the result was valuable for choosing the adequate irradiated materials and determining the optimal dosage so as to enhance the mutagenic efficiency in wheat radiation breeding. The reliability and advantage of the Fussy clustering classification for the plant varietal radiosensitivity were briefly discussed

  2. Radiosensitivity of skin fibroblasts and lymphocytes from atomic bomb survivors in Hiroshima

    International Nuclear Information System (INIS)

    In the last 30 years or so, the existence of individual differences in in vivo radiation sensitivity has been well recognized in the response of normal tissues, particularly skin tissue, of cancer patients in the course of radiation therapy. If a large variation in radiosensitivity truly exists, it is very important to compare the radiosensitivity between the A-bomb survivors and a general population. If A-bomb survivors include a disproportionately large number of either radioresistant or radiosensitive persons, the surviving population would provide a biased estimate of the true risk of radiogenic cancer. 14 refs., 1 fig., 1 tab

  3. 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)

  4. 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)

  5. 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)

  6. 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

  7. Association between SNPs in defined functional pathways and risk of early or late toxicity as well as individual radiosensitivity

    International Nuclear Information System (INIS)

    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.)

  8. 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)

  9. 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.

  10. Apoptosis and radiosensitivity induced by N-acety1 phytosphingosine, in human cancer cell line

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Y. H.; Kim, K. S.; Han, Y. S.; Jeon, S. J.; Song, J. Y.; Jung, I. S.; Hong, S. H.; Yun, Y. S. [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Park, J. S. [Doosan Biotech, Yongin (Korea, Republic of)

    2004-07-01

    Ceramide is a key lipid molecule in signal transduction with a role in various regulatory pathways including differentiation, proliferation and especially apoptosis. Ionizing radiation-induced apoptosis is associated with accumulation of ceramide, and the sphingomyelinase deficiency results in radioresistance. We investigated the exogenous treatment of N-acetyl-phytosphingosine (NAPS), an analogue of N-acetyl-sphingosine (C{sub 2}-Ceramide), and C{sub 2}-ceramide exert apoptotic effect on human T cell lymphoma Jurkat cells and breast cancer cell line MDA-MB-231. NAPS and C{sub 2}-Ceramide has cytotoxic effect in time- and dose-dependent manner, and increased caspase-3, 8 activity. However, NAPS induced apoptosis more effectively, and increased caspase activity induced by NAPS is more higher than C{sub 2}-ceramide. Moreover, NAPS decreased clonogenicity of irradiated cells and increased radiation-induced apoptosis significantly. Increased cell death by irradiation in the presence of NAPS is owing to the increase of caspase activity. These data suggest that NAPS might be used for lead as a new type of radiosensitizing agent increasing radiation-induced apoptosis.

  11. Radiosensitivity of stromal cells human bone marrow precursors, irradiated in vitro inside bone and in cell suspension and a modifying effect of hypoxia

    International Nuclear Information System (INIS)

    A study was made of radiosensitivity of human bone marrow cells that form fibroblast colonies within monolayer cultures (CFUsub(f)) after exposure to 60Co-γ-radiation under different conditions: in pieces of an extirpated bone and in a cell suspension. Dose survival curves for CFUsub(f) obtained from both variants of the experiment vary merkedly in the value of median lethal dose (Dsub(O)) which constitute.s 89 rad for cell suspension and 328 rad for bone pieces. Radioresistance of CFUsub(f) increases (sub(o)=126 rad) in the suspension bubbled with argon whereas substitution of the atmosphere with argon does not influence the sensitivity of CFU irradiated in bone. The observed distinctions in radiosensitivity of human bone marrow CFU irradiated in suspension and bone pieces are probably related to different oxygen status of cells at time of irradiation. Maximum value of the oxygen effect for CFUsub(f) is 3.7

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

    International Nuclear Information System (INIS)

    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 radiation

  13. Radiosensitivity of hair follicles in mouse dorsum and tail

    International Nuclear Information System (INIS)

    The radiosensitivity of murine hair follicles was measured in two skin sites, dorsal body and tail. Follicles were considered viable if they appeared histologically similar to controls 4 or 8 weeks after irradiation or similar to growing follicles 12 days after plucking. Dorsal follicles were either unplucked or plucked after and/or before irradiation. Tail follicles were unplucked, but at the time of irradiation the tails were either in air or clamped to induce severe hypoxia, or the mice were anesthetized. The differences in dorsal follicle sensitivity were compared with other widely varying values reported in the literature. The relative sensitivities of the tail follicles in different conditions at the time of irradiation were similar to previous relative sensitivities measured for tail necrosis

  14. Potentiation of cellular radiosensitivity by nitroprusside and vitamin B12

    International Nuclear Information System (INIS)

    The effects of two cyano-metal complexes, sodium nitroprusside and vitamin B12 on the radiosensitivity of plateau-phase V-79 monolayers were studied. Cells were irradiated under aerobic conditions or hypoxic conditions following degassing and purging with nitrogen. Concentrations of nitroprusside as low as 10-6M resulted in potentiation of radiation cell killing under aerobic and hypoxic conditions. Potentiation of radiation cell killing was also observed with the less-toxic vitamin B12 at concentrations of 10-3M; this effect was observed only under anoxic irradiation conditions. These results suggest that cyanide-releasing compounds might be used to augment the effect of radiation therapy, providing a different effect on aerobic compared to hypoxic cells

  15. Radiosensitizing and cytotoxic properties of several hypoxiamediated drugs

    International Nuclear Information System (INIS)

    Many strategies have been suggested to overcome the resistance of hypoxic cells to x- and γ-rays, the most recent of which involves the use of electron affinic agents which mimic oxygen by differentially sensitizing hypoxic cells to the lethal effect of x-rays. Two of these compounds, Metronidazole and Misonidazole, have already entered phase III clinical trials; however, the dose of Misonidazole that can be used is limited due to the appearance of neurotoxicity. Consequently, attention has focussed on the need to synthesize or identify compounds with equal or greater effectiveness but at the same time exhibiting less troublesome side effects. This paper describes experiments with mammalian cells in vitro to compare the radiosensitizing and cytotoxic properties of five newly synthesized hypoxia-mediated drugs with the current drug in use, Misonidazole

  16. 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)

  17. Radiosensitivity and mutability of Prima and Melrose apple cultivars

    International Nuclear Information System (INIS)

    Winter buds of the two cultivars in early vegetation stage have been irradiated with gamma rays (Co 60) with 2, 3, 4, 5 and 6 krad (source power 800 rad/min). The second (V2) and the third (V3) vegetative generations are obtained. Their radiosensitivity and mutability are evaluated. The semi lethal doses have been detected. The recommended irradiation dose for selection is 3-4 krad at which the survival rate is satisfactory as well as the mutation changes can be expected. Three mutation forms were selected in V3 generation, having weak growth, short internods and compact habit. These mutants are an object of further studies. 15 refs., 2 tabs., 5 figs. (author)

  18. Isolation of microorganisms from red pepper powder and their radiosensitivity

    International Nuclear Information System (INIS)

    From samples of red pepper powder sold in Korea were isolated and identified 13 species of molds (Aspergillus amsteodami, Asp. chevalieri, Asp. clavatus, Asp. Flavus, Asp. janus var. effusus, Asp. oryzae, Asp. oryzae var. brevis, Asp. repens, Asp. sydowi, Asp. thomii, Asp. tubingensis, Penicillium thomii, Scopulariopsis brevicaulis) and 5 species of bacteria (Bacillus pumilus, Bac. subtilis, Micrococus luteus, M. varians, Staphylococcus aureus). Radiosensitivity of these microorganisms was examined to give D10 values of 14-41 krad for molds, 11-24 krad for bacterial vegetative cells and 190-250 krad for bacterial spores. The red pepper powder was contaminated with 2-3x102 mold counts/g and 3-6x107 bacterial counts/g, which would be sufficiently destroyed by irradiating 200 krad r-rays. (Author)

  19. 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.

  20. Ethanol decreases radiosensitivity of human breast cancer MCF-7 cells

    International Nuclear Information System (INIS)

    Objective: To investigate the effect of ethanol on radiosensitivity of human breast cancer MCF-7 cells. Methods: Human breast cancer MCF-7 cells were divided into four groups including control group,ethanol treatment group, X-ray exposed group,and ethanol combined with X-ray group. Clonogenic assay was used to determine cell survival. Flow cytometry was employed to analyze cell cycle progression. Annexin V-FITC kit was used to determine cell apoptosis induction.Results Ethanol (50 and 100 mmol/L, 50 h) had no influence on MCF-7 cell growth (t=0.82, 1.15, P>0.05). The radiosensitivity of MCF-7 cells was reduced when the cells were pretreated with 50 mmol/L ethanol (t=4.15, P<0.05) and 100 mmol/L ethanol (t=10.28, P<0.05) for 2 h. Compared with irradiation with X-ray alone, ethanol treatment decreased G2/M phase arrest (t=7.18, P<0.05) and sub-G1 population (an indicator of apoptosis induction) (t=5.39, P<0.05). A decrease of advanced and early apoptosis in the cells pretreated with ethanol was also confirmed by Annexin V-FITC apoptosis assay (t=4.86, 7.59, P<0.05). Conclusions: Ethanol causes radioresistance in human breast cancer MCF-7 cells, where the decreases of radiation-induced G2/M phase arrest and apoptosis may be involved. (authors)

  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. 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.

  3. 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)

  4. 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

  5. Glutathione depletion, radiosensitization, and misonidazole potentiation in hypoxic Chinese hamster ovary cells by buthionine sulfoximine

    International Nuclear Information System (INIS)

    Buthionine sulfoximine (BSO) inhibits the synthesis of glutathione (GSH), the major nonprotein sulfhydryl (NPSH) present in most mammalian cells. BSO exposures used in these experiments were not cytotoxic with the one exception that 2.0 mM BSO/24 hr reduced cell viability to approx.50%. However, alterations in either the cell doubling time(s) or the cell age density distribution(s) were not observed with the BSO exposures used to determine its radiosensitizing effect. BSO significantly radiosensitized hypoxic, but not aerobic, CHO cells when the GSH and NPSH concentrations were reduced to <10 and 20% of control, respectively, and maximum radiosensitivity was even achieved with μM concentrations of BSO. Furthermore, BSO exposure also enhanced the radiosensitizing effect of various concentrations of misonidazole on hypoxic CHO cells

  6. 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

  7. Thermal enhancement of radiosensitivity in normal and ataxia telangiectasia human cells

    International Nuclear Information System (INIS)

    Normal human and ataxia telangiectasia (AT) fibroblasts were tested for enhancement of radiosensitivity by hyperthermia. In normal fibroblasts, thermal enhancement of radiosensitivity occurred at 42.00 and 45.00C and was greatest for simultaneous treatments of heat and radiation. This thermal enhancement decreased, as an incubation time at 37.00C was introduced either between heat and X-ray, or X-ray and heat, treatments. AT cells were more radiosensitive (D0=0.67 Gy) than normal cells (D0=1.4 Gy). Heating at 42.00 or 45.00C resulted in enhanced radiosensitivity, which was equal for heating before, during or after irradiation. These data show that normal human fibroblasts can recover from heat and radiation treatments, while AT fibroblasts lack this ability

  8. 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)

  9. 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...

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

    International Nuclear Information System (INIS)

    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 γ-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 γ-irradiation of liposomes imply radiation-induced 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. (author)

  11. 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.

  12. 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

  13. 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

  14. 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

  15. A biological evaluation on in vitro radiosensitization of nitro-triazole derivatives

    International Nuclear Information System (INIS)

    Objective: To assess the radiosensitization of nitro-triazole derivatives and elucidate the structure-activity relationships within this group of compounds. Method: The partition coefficient (p), reduction potential (E1/2), cytotoxicity and sensitization activity were determined by HPLC, polarography and colony formation, respectively. Results: It was found that among these 22 derivatives, two compounds were more efficient than MISO, and other three were of the same efficiency as MISO was in radiosensitizing hypoxic cells, the rest showed poor radiosensitizing properties. As 2-nitroimidazoles, the radiosensitizing activity of a 3-nitro-triazole derivative correlates with its electron affinity, determined as E1/2, half-wave reduction potential. The greater is the electron affinity i.e. the more positive the E1/2, the greater is the radiosensitizing efficiency. The value of E1/2, partition coefficient p value and cytotoxicity of a nitro-triazole derivative are influenced by the structure and chemical properties of the substituent at N1 or 5 position of triazole ring. The nitro-triazoles examined show only limited differential hypoxic: aerobic toxicity. Conclusion: Although the nitro-triazole derivation are not viable hypoxia-mediated cytotoxins, the radiosensitization of some of them should be studied thoroughly

  16. 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

  17. 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)

  18. 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)

  19. 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

  20. Effect of N-Ras by RNA interference on radiosensitivity of hepatoma carcinoma cell MHCC97-H line

    International Nuclear Information System (INIS)

    Objective: To investigate the radiosensitivity of silencing N-Ras by RNA interference in hepatoma carcinoma cell MHCC-97. Methods: N-Ras RNA interference (RNAi) vector was constructed by using pcDNA 6.2-GW/EmGFP-mir plamid. The RNAi effect was detected by RT-PCR, Western bolt, immunohistochemistry and MTT method. Survival curve for each cell line were obtained by measuring the clone forming abilities of irradiated cell populations. Results: After silencing the N-Ras by RNAi. The expression level of N-Ras mRNA, N-Ras protein, immunohistochemistry were decreased 96.9% ±0.159% (t=40.377, P<0.05), 89.8%±0.012% (t=31.595, P<0.05), 90%, respectively, and The survival of hepatoma carcinoma cell MHCC-97 line were inhibited 21.9% (F = 4.63, P<0.05). Which have significant difference in statistics. The SER of hepatoma carcinoma cell MHCC-97 line after interference was 1.15. Conclusions: RNAi targeting silence N-Ras may increase the radiosensitivity of hepatoma carcinoma cell MHCC-97 line. (authors)

  1. The radiosensitization effect of titanate nanotubes as a new tool in radiation therapy for glioblastoma: A proof-of-concept

    International Nuclear Information System (INIS)

    Background and purpose: One of the new challenges to improve radiotherapy is to increase the ionizing effect by using nanoparticles. The interest of titanate nanotubes (TiONts) associated with radiotherapy was evaluated in two human glioblastoma cell lines (SNB-19 and U87MG). Materials and methods: Titanate nanotubes were synthetized by the hydrothermal treatment of titanium dioxide powder in a strongly basic NaOH solution. The cytotoxicity of TiONts was evaluated on SNB-19 and U87MG cell lines by cell proliferation assay. The internalization of TiONts was studied using Transmission Electron Microscopy (TEM). Finally, the effect of TiONts on cell radiosensitivity was evaluated using clonogenic assay. Cell cycle distribution was evaluated by flow cytometry after DNA labeling. DNA double-stranded breaks were evaluated using γH2AX labeling. Results: Cells internalized TiONts through the possible combination of endocytosis and diffusion with no cytotoxicity. Clonogenic assays showed that cell lines incubated with TiONts were radiosensitized with a decrease in the SF2 parameter for both SNB-19 and U87MG cells. TiONts decreased DNA repair efficiency after irradiation and amplified G2/M cell-cycle arrest. Conclusion: Our results indicated that further development of TiONts might provide a new useful tool for research and clinical therapy in the field of oncology

  2. 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)

  3. Association of single nucleotide polymorphisms in ATM, GSTP1, SOD2, TGFB1, XPD and XRCC1 with clinical and cellular radiosensitivity

    International Nuclear Information System (INIS)

    Purpose: To examine the association of polymorphisms in ATM (codon 158), GSTP1 (codon 105), SOD2 (codon 16), TGFB1 (position -509), XPD (codon 751), and XRCC1 (codon 399) with fibrosis and also individual radiosensitivity. Methods and materials: Retrospective analysis with 69 breast cancer patients treated with breast-conserving radiotherapy; total dose delivered was restricted to vary between 54 and 55 Gy. Fibrosis was evaluated according to LENT/SOMA score. DNA was extracted from blood samples; cellular radiosensitivity was measured using the G0 assay and polymorphisms by PCR-RFLP and MALDI-TOF, respectively. Results: Twenty-five percent of all patients developed fibrosis of grade 2 or 3. This proportion tends to be higher in patients being polymorphic in TGFB1 or XRCC1 when compared to patients with wildtype genotype, whereas for ATM, GSTP1, SOD2 and XPD the polymorphic genotype appears to be associated with a lower risk of fibrosis. However, none of these associations are significant. In contrast, when a risk score is calculated based on all risk alleles, there was significant association with an increased risk of fibrosis (per risk allele odds ratio (ORs) = 2.09, 95% confidence interval (CI): 1.32-3.55, p = 0.0005). All six polymorphisms were found to have no significant effect on cellular radiosensitivity. Conclusions: It is most likely that risk for radiation-induced fibrosis can be assessed by a combination of risk alleles. This finding needs to be replicated in further studies.

  4. Examining the effect of gene reduction in miR-95 and enhanced radiosensitivity in non-small cell lung cancer.

    Science.gov (United States)

    Ma, W; Ma, C-N; Li, X-D; Zhang, Y-J

    2016-02-01

    MicroRNAs (miRNAs) represent a group of novel therapeutic small molecules involved in the management of lung cancer treatment. Our study aims to investigate the potential role of miRNAs in the treatment of non-small cell lung cancer (NSCLC). Human miRNA microarray was performed in 60 recurrent NSCLC patient tissue samples following radiotherapy and their adjacent normal tissues. miRNA profiling results were validated using quantitative real-time PCR. Inner cell radiosensitivity and endogenous miRNA expression was determined by colony-formation assay and RT-PCR. We determined the effect of miRNA on cell proliferation, survival and metastasis; tumor xenografts were taken to identify the presence of miRNA in vivo. miRNA panel results indicated that a total of 14 miRNAs were differentially expressed in the recurrent NSCLC samples. In our study, miRNA-95 was highly overexpressed in recurrent NSCLC cells. Knockdown of miRNA-95 expression increased the radiosensitivity of NSCLC, promoted tumor cell apoptosis and decreased cellular proliferation. In vivo assays demonstrated reduced tumor growth and resistance to radiation in tumor xenografts by downregulating miRNA-95. Our study demonstrated a potential therapeutic measure of miRNA-95 as a radiosensitive marker for the treatment of non-small lung cancer. PMID:26915403

  5. 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

  6. Effect on the K/sub m/ for radiosensitization at 00C of thiol depletion by diethylmaleate pretreatment: quantitative differences found using the radiation sensitizing agent misonidazole or oxygen

    International Nuclear Information System (INIS)

    Pretreatment of V79-WNRE cells with 150 μM diethylmaleate for 1 hr at 370C caused a decrease in intracellular glutathione levels to approximately 10-15% of control levels. The cells could be washed free of diethylmaleate and held at 00C for several hours without toxicity and with no increase in glutathione concentration, although the glutathione concentration rapidly increased to normal levels at higher temperatures. Glutathione depletion itself caused a small but consistent radiosensitization of hypoxic cells (dose enhancement ratio of 1.2). However glutathione depletion caused a profound change in the radiosensitizing efficiency of misonidazole, with a decrease in K/sub m/ of about sevenfold from 0.6 to 0.09 mM. In contrast, only a 2.5-fold decrease was found in the K/sub m/ for radiosensitization by oxygen with diethylmaleate pretreatment. These results suggest a fundamental problem with the conventional theory of radiosensitivity whereby one considers a first-order competition for reaction with target radicals between radical-fixing versus radical-repairing species. It also suggests difficulties in the interpretation of glutathione as the only endogenous protective species

  7. Technical knowledge assessment in radiology in patients protection in collective environments and more radiosensitive organs

    International Nuclear Information System (INIS)

    The use of X-rays in medical fields has increased significantly in recent years, since various therapeutic procedures can be performed without the need for surgery, which presents the greatest risk to the patient. An example of this increase is the practice of cardiac catheterization, this procedure fluoroscopy is used for placement of central venous catheters and temporary pacemakers, and long-term use increases the risk of exposure to X-rays to the patient, doctor and his assistants. This has been observed with concern by many researchers, since many companies did not fit the standards of radiation protection. This failure can lead to exposure of professionals, patients and caregivers. It is therefore of fundamental importance, the use of personal protective equipment such as aprons and thyroid plumbíferos protectors, for dose reduction produced by the primary and secondary radiation. This study evaluated the knowledge of radiology professionals in Goiânia, on the use of lead apron in collective environments and use of guards in sensitive parts of patients to radiation. Through an information gathering technique based on a questionnaire with closed questions. From dista and focuses on the knowledge of professionals. The results showed that there is a serious deficiency as regards the most radiosensitive organ protection of patients when they are exposed to X-ray beams. (author)

  8. 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)

  9. Enhancement of cetuximab on radiosensitivity of colorectal cancer cells exposed to 125I seeds

    International Nuclear Information System (INIS)

    Objective: To investigate the effect of cetuximab (C225) on the radiosensitivity of colorectal cancer cells CL187 and underlying mechanism. Methods: Cell survival was detected by colony forming assay. The levels of apoptosis and cell cycle distribution were determined by flow cytometer. The mitotic ratio was measured by Wright's-Giemsa mixed coloring method. The protein levels of Bax and Bcl2 were detected by Western blot. Results: The sensitizing enhancement ratio of C225 was approximately 1.4. C225 treatment and 125I seed radiation induced G1 cell cycle arrest individually. C225 increased the radiation-induced apoptosis (t =6.6, P<0.05) and cellular Bax/Bcl-2 ratio (t =9.4, P<0.05), but did not increase radiation-induced G1 arrest. In addition, there was no difference in mitotic index among different groups. Conclusions: C225 sensitizes CL187 to 125I seed irradiation,which might be related with increase of radiation-induced apoptosis. (authors)

  10. Axin gene methylation status correlates with radiosensitivity of lung cancer cells

    International Nuclear Information System (INIS)

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

  11. 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)

  12. Studies of the in vivo radiosensitivity of human skin fibroblasts

    International Nuclear Information System (INIS)

    Background and purpose: To examine the radiosensitivity of skin cells obtained directly from the irradiated skin of patients undergoing fractionated radiation treatment prior to surgery for treatment of soft tissue sarcoma (STS) and to determine if there was a relationship with the development of wound healing complications associated with the surgery post-radiotherapy. Methods: Micronucleus (MN) formation was measured in cells (primarily dermal fibroblasts) obtained from human skin at their first division after being removed from STS patients during post-radiotherapy surgery (2-9 weeks after the end of the radiotherapy). At the time of radiotherapy (planned tumor dose - 50 Gy in 25 daily fractions) measurements were made of surface skin dose at predetermined marked sites. Skin from these sites was obtained at surgery and cell suspensions were prepared directly for the cytokinesis-blocked MN assay. Cultured strains of the fibroblasts were also established from skin nominally outside the edge of the radiation beam and DNA damage (MN formation) was examined following irradiation in vitro for comparison with the results from the in situ irradiations. Results: Extensive DNA damage (MN) was detectable in fibroblasts from human skin at extended periods after irradiation (2-9 weeks after the end of the 5-week fractionated radiotherapy). Analysis of skin receiving a range of doses demonstrated that the level of damage observed was dose dependent. There was no clear correlation between the level of damage observed after irradiation in situ and irradiation of cell strains in culture. Similarly, there was no correlation between the extent of MN formation following in situ irradiation and the propensity for the patient to develop wound healing complications post-surgery. Conclusions: Despite the presence of DNA damage in dermal fibroblasts weeks after the end of the radiation treatment, there was no relationship between this damage and wound healing complications following

  13. The alkylphospholipid, perifosine, radiosensitizes prostate cancer cells both in vitro and in vivo

    International Nuclear Information System (INIS)

    Perifosine is a membrane-targeted alkylphospholipid developed to inhibit the PI3K/Akt pathway and has been suggested as a favorable candidate for combined use with radiotherapy. In this study, we investigated the effect of the combined treatment of perifosine and radiation (CTPR) on prostate cancer cells in vitro and on prostate cancer xenografts in vivo. Human prostate cancer cell line, CWR22RV1, was treated with perifosine, radiation, or CTPR. Clonogenic survival assays, sulforhodamine B cytotoxity assays and cell density assays were used to assess the effectiveness of each therapy in vitro. Measurements of apoptosis, cell cycle analysis by flow cytometry and Western blots were used to evaluate mechanisms of action in vitro. Tumor growth delay assays were used to evaluate radiation induced tumor responses in vivo. In vitro, CTPR had greater inhibitory effects on prostate cancer cell viability and clonogenic survival than either perifosine or radiation treatment alone. A marked increase in prostate cancer cell apoptosis was noted in CTPR. Phosphorylation of AKT-T308 AKT and S473 were decreased when using perifosine treatment or CTPR. Cleaved caspase 3 was significantly increased in the CTPR group. In vivo, CTPR had greater inhibitory effects on the growth of xenografts when compared with perifosine or radiation treatment alone groups. Perifosine enhances prostate cancer radiosensitivity in vitro and in vivo. These data provide strong support for further development of this combination therapy in clinical studies

  14. Modification of radiosensitivity by ethidium bromide in nuclear division cycle of physarum polycephalum

    Energy Technology Data Exchange (ETDEWEB)

    Hosoda, Eiko (Tokyo Metropolitan Isotope Research Center (Japan))

    1990-02-01

    The effect of ethidium bromide (EB) on mitotic retardation by {sup 60}Co-{gamma} irradiation was investigated in the naturally synchronous nuclear division cycle of plasmodium of Physarum polycephalum, using EB in concentration experimentally found to be uninhibitory to plasmodial growth; 0.5 {mu}M. Plasmodia were cultured with nutrient medium containing or not containing 0.5 {mu} M EB, and after the start of the second nuclear division cycle, were irradiated at 4 time points (in the middle G{sub 2} phase, in the early G{sub 2} phase, in the middle S phase, and in the early S phase) by {gamma}-rays of 2.8 to 28 Gy (0.28 to 2.8 KRad). The delay of the next mitosis relative to non-irradiated controls were examined, in both EB treated and untreated plasmodia respectively. EB treatment increased mitotic delay in the middle G{sub 2} phase gradually with dose, and in the early G{sub 2} phase at doses higher than about 20 Gy. EB treatment, on the other hand, on the other hand, reduced mitotic delay in the early S phase especially at higher doses. In the middle S phase, significant effects of EB treatment were not shown. Thus it has been revealed that EB increases or reduces plasmodial radiosensitivity dependently both on nuclear division cycle and on {gamma}-ray intensity. (author).

  15. Gamma radiosensitivity in tomato plants and answers from irradiated seed at different salinity levels

    Energy Technology Data Exchange (ETDEWEB)

    Colaco, Waldeciro; Bidjeke, R. [Universidade Federal de Pernambuco, Recife, PE (Brazil). Dept. de Energia Nuclear]. E-mail: wcolaco@ufpe.br; Ferraz, Ednardo M. [Empresa Pernambucana de Pesquisa Agropecuaria (IPA), Recife (Brazil)

    2004-12-15

    Considering future studies of mutation induction as an auxiliary tool for the improvement of plants, preliminary experiments to evaluate the tomato plant (L. esculentum, Mill) radiosensitivity were carried out on the IPA-6, IPA-8 and L. hirsutum var. glabratum - H G varieties with a Co-60 gamma ray source, aiming to obtain varieties that are tolerant to salinity. Groups of seeds were irradiated with 300-600 Gy and with 100 to 400 Ge, were compared to a control without irradiation (0 Gy), under greenhouse conditions. The seeds were put into polystyrene boxes with 176 cells of 9 cm{sup 2} and at 5 cm in depth, containing vermiculite, soil, cow dung and washed sand (40, 20, 20, and 20% respectively). In a general way, there was stimulation in growth in the lower doses and a reduction with the increase in doses. For the IPA-6, the growth diminished with the increase in the levels of salinity, no significant interaction being observed between the levels of salinity and the doses. The ideal dosage level for tomato plant irradiation, suggested in literature (establishing themselves around 100 Gy), is not compatible with the two varieties and the wild species studies. (author)

  16. 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)

  17. Experimental study on central nervous toxicity of 'misonidazole' a hypoxic cell radiosensitizer

    International Nuclear Information System (INIS)

    'Misonidazole', a radiosensitizer for hypoxic cells is expected to be applied to the treatment of malignant tumors, but its side effect becomes a subject of study, because its effective dose is close to its lethal dose. The auther performed experiments with mice on the central nervous toxicity, which is the most lethal of the side effects of Misonidazole, with the following results; 1. The abrupt death seen after the administration of a large dose of Misonidazole was attributable to the central nervous toxicity. LD50 for d.d. strain mouse was 1.55 mg per body weight g. 2. The used mice always developed convulsion before death. But the administration of anticonvulsant failed to free them from death. 3. Autopsy findings were such abnormal ones as the degeneration and exfoliation of nerve cells and diapedetic focus. After sacrifice, however, no findings indicative of disturbance of central nerve could be detected. 4. Misonidazole, even in a small divided dose, left intracerebral retention, though slightly, indicating that its accumulation in the brain would be increased with increase in the dose. 5. The disturbance of central nerve was not exacerbated by the whole brain irradiation with Misonidazole. (author)

  18. 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

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

    International Nuclear Information System (INIS)

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

  20. Optical isomers of a new 2-nitroimidazole nucleoside analog (PR-350 series): radiosensitization efficiency and toxicity

    International Nuclear Information System (INIS)

    Purpose: A new 2-nitroimidazole nucleoside radiosensitizer, PR-350 (1-[1',3',4'-trihydroxy-2'-butoxy]-methyl-2-nitroimidazole), has been reported to be as efficient as and less toxic than etanidazole. This compound is racemic, and it was recently optically resolved into two isomers, PR-68 (2'R,3'S type) and PR-69 (2'S,3'R type). The other two isomers, PR-28 (2'S,3'S type) and PR-44 (2'R,3'R type), were asymmetrically synthesized. In the present study, we investigated the properties, sensitizing activity, and toxicity of PR-350 and the four optical isomers in comparison with those of other 2-nitroimidazole hypoxic cell radiosensitizers, etanidazole, KU-2285, KIN-804, and RP-170. Because PR-350 and PR-28 can be industrially synthesized, we evaluated whether either of these two drugs are suitable for further investigation. Methods and Materials: In an in vitro study, EMT-6 cells were irradiated at a dose of 1-3 Gy under hypoxic conditions in the presence of the drugs at a concentration of 1 mM. A combined cytokinesis-block micronucleus and chromosomal aberration assay was performed. To assess the in vivo effects, colony assay and growth delay assay were performed using SCCVII tumor-bearing C3H mice. The mice received 16-24 Gy 10-40 min after administration of 50-200 mg/kg of the drugs. Toxicity and pharmacokinetics in mice were also investigated. Results: The sensitizer enhancement ratio (SER) in the in vitro cytokinesis-block micronucleus assay increased in the following order: PR-69 (1.27) ≅ PR-28 (1.31) ≅ PR-44 (1.38) ≅ PR-350 (1.41) ≅ PR-68 (1.47) 50 in mice were 5.8 g/kg for PR-350, approximately 7 g/kg for PR-28, 4 g/kg for PR-68, and 6 g/kg for PR-44 and PR-69. The concentration of PR-28 in the murine sciatic nerve was lower than that of PR-350. Conclusion: In vivo radiosensitizing activity differed among the four optical isomers, which appeared to be due, at least in part, to differences in lipophilicity. Although PR-28 was the least toxic, its low

  1. 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

  2. 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

  3. Rejoining of prematurely condensed chromosomes in radiosensitive xrs-5 cells

    International Nuclear Information System (INIS)

    Xrs-5 cells, a radiosensitive, DNA double strand break repair deficient mutant of CHO cells have been studied with the premature chromosome condensation (PCC) technique. This mutant displayed a higher number of initial chromosome breaks with x-ray treatment as well as partial deficiency in the rejoining of interphase chromosome breaks with the standard PCC protocol. Moreover, hypertonic treatment during the incubation period which allowed for PCC did not change the yield of PCC breaks in x-irradiated xrs-5 cells. Notably the number of PCC breaks after treatment with hypertonic media is similar in CHO and xrs-5 cells. Recently, a gene product responsible for the xrs phenotype was identified as a Ku-like DNA end binding protein. The present paper summarizes completed information regarding the induction and repair of the α- and β-forms of PCC breaks in xrs-5 cells and demonstrates that this gene product predominantly affects the fast form (β-form) of interphase chromosome breaks

  4. 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)

  5. 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 pathw