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Sample records for radiosensitivity dose curves

  1. Construction and validation of a dose-response curve using the comet assay to determine human radiosensitivity to ionizing radiation.

    Science.gov (United States)

    Güerci, A; Zúñiga, L; Marcos, R

    2011-01-01

    Individual radiosensitivity is an individual characteristic associated with an increased reaction to ionizing radiation. The purpose of our work is to establish a dose-response curve useful to classify individuals as radiosensitive or radioresistant. Thus, a dose-response curve was constructed by measuring in vitro responses to increasing doses (0 to 8 Gy) of gamma radiation in the comet assay. The obtained curve fit well with a linear equation in the range of 0 to 8 Gy. The overall dose-response curve was constructed for percent DNA in tail, as a measure of the genetic damage induced by irradiation. To probe the goodness of the constructed curve, a validation study was carried out with whole blood from two donors in a blind study. Results show that, for the two applied doses (2 and 6 Gy), the obtained values fit well inside the interval of confidence of the curve. In conclusion, our results demonstrate the usefulness of the comet assay in determining individual responses to defined doses of gamma radiation. The standard dose-response curve constructed may be used to detect individuals departing from reference values.

  2. Insect radiosensitivity: dose curves and dose-fractionation studies of dominant lethal mutations in the mature sperm of 4 insect species

    Energy Technology Data Exchange (ETDEWEB)

    LaChance, L.E.; Graham, C.K. (Department of Agriculture, Fargo, ND (USA))

    1984-06-01

    Males of 4 species of insects: Musca domestica L. (housefly) (Diptera), Oncopeltus fasciatus (Dallas) (milkweed bug) (Hemiptera), Anagasta kuhniella (Zeller) (mealmoth) (Lepidoptera) and Heliothis virescens (Fab.) (tobacco budworm) (Lepidoptera) were irradiated as adults. Dose-response curves for the induction of dominant lethal mutations in the mature sperm were constructed. The curves were analyzed mathematically and compared with theoretical computer simulated curves requiring 1, 2, 4, 8 and 16 'hits' for the induction of a dominant lethal mutation. The 4 species belonging to 3 different orders of insects showed a wide range in radiation sensitivity and vastly different dose-response curves. When the data were analyzed by several mathematical models the authors found that a logistic response curve gave reasonably good fit with vastly different parameters for the 4 species. Dose-fractionation experiments showed no reduction in the frequency of lethal mutations induced in any species when an acute dose was fractionated into 2 equal exposures separated by an 8-h period.

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

    Science.gov (United States)

    Gordon, J. J.; Snyder, K.; Zhong, H.; Barton, K.; Sun, Z.; Chetty, I. J.; Matuszak, M.; Ten Haken, R. K.

    2015-09-01

    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 (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.

  4. 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.

  5. [Radiosensitivity curve of different stages of spermatogenesis of Anopheles atroparvus (Diptera:Nematocera)].

    Science.gov (United States)

    Lecis, A R; Figus, V; Santarini, C

    1975-01-01

    In order to obtain a dose-hatchability curve for irradiated spermatogenetic stages of Anopheles atroparvus, we have irradiated with the same dose "4500 r" young fourth larval stages, old fourth larval stages, nymphae and adult males. Those different stages represent different phases of spermatogenesis. The peak of radiosensitivity for embryonic mortality, was found in spermatids, lowest appeared in spermatogonies.

  6. 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

  7. Gemcitabine radiosensitization after high-dose samarium for osteoblastic osteosarcoma.

    Science.gov (United States)

    Anderson, Peter M; Wiseman, Gregory A; Erlandson, Linda; Rodriguez, Vilmarie; Trotz, Barbara; Dubansky, Stephen A; Albritton, Karen

    2005-10-01

    Osteoblastic metastases and osteosarcoma can avidly concentrate bone-seeking radiopharmaceuticals. We sought to increase effectiveness of high-dose (153)Samarium ethylenediaminetetramethylenephosphonate (153Sm-EDTMP, Quadramet) on osteosarcomas using a radiosensitizer, gemcitabine. Fourteen patients with osteoblastic lesions were treated with 30 mCi/kg 153Sm-EDTMP. Gemcitabine was administered 1 day after samarium infusion. Residual total body radioactivity was within the safe range of 1 year, there have been no durable responses. Thus, although high-dose 153Sm-EDTMP + gemcitabine has moderate palliative activity (improved pain; radiologic responses) in this poor-risk population, additional measures of local and systemic control are required for durable control of relapsed osteosarcoma with osteoblastic lesions. The strategy of radioactive drug binding to a target followed by a radiosensitizer may provide synergy and improved response rate.

  8. Description of dose response curve

    OpenAIRE

    Al-Samarai, Firas

    2011-01-01

    The book included several methods to estimate LD50, in addition to explain how to use several programs to estimate LD50. Moreover the book illustrate the description of the dose response curves. Firas Al-Samarai

  9. Dose rate effect on low-dose hyper-radiosensitivity with cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Geon-Min; Kim, Eun-Hee [Seoul National University, Seoul (Korea, Republic of)

    2016-10-15

    Low-dose hyper-radiosensitivity (HRS) is the phenomenon that mammalian cells exhibit higher sensitivity to radiation at low doses (< 0.5 Gy) than expected by the linear-quadratic model. At doses above 0.5Gy, the cellular response is recovered to the level expected by the linear-quadratic model. This transition is called the increased radio-resistance (IRR). HRS was first verified using Chinese hamster V79 cells in vitro by Marples and has been confirmed in studies with other cell lines including human normal and tumor cells. HRS is known to be induced by inactivation of ataxia telangiectasia-mutated (ATM), which plays a key role in repairing DNA damages. Considering the connection between ATM and HRS, one can infer that dose rate may affect cellular response regarding HRS at low doses. In this study, we quantitated the effect of dose rate on HRS by clonogenic assay with normal and tumor cells. The HRS of cells at low dose exposures is a phenomenon already known. In this study, we observed HRS of rat normal diencephalon cells and rat gliosarcoma cells at doses below 1 Gy. In addition, we found that dose rate mattered. HRS occurred at low doses, but only when total dose was delivered at a rate below certain level.

  10. Evaluation of the Entrance Surface Dose (ESD and Radiation Dose to the Radiosensitive Organs in Pediatric Pelvic Radiography

    Directory of Open Access Journals (Sweden)

    Vahid Karami

    2017-06-01

    Full Text Available Background Patients' dosimetry is crucial in order to enhance radiation protection optimization and to deliver low radiation dose to the patients in a radiological procedure. The aim of this study was to assess the entrance surface dose (ESD and radiation dose to the radiosensitive organs in pediatric pelvic radiography. Materials and Methods The studied population included 98 pediatric patients of both genders referred to anteroposterior (AP projection of pelvic radiography. The radiation dose was directly measured using high radiosensitive cylindrical lithium fluoride thermo-luminescent dosimeters (TLD-GR200. Two TLDs were placed at the center point of the radiation field to measure the ESD of pelvis. Moreover for each patient, 2 TLDs were placed upon each eyelid, 2 TLDs upon each breast, 2 TLDs upon the surface anatomical position of the thyroid gland and finally 2 TLDs at the surface anatomical position of the gonads to measure the received dose. Results The ESD ± standard deviation for AP pelvic radiography was obtained 591.7±76 µGy. Statistically significant difference was obtained between organs located outside and inside of the radiation field with respect to dose received (P

  11. Inferring mechanisms from dose-response curves

    OpenAIRE

    Chow, Carson C.; Ong, Karen M.; Dougherty, Edward J.; Simons, S. Stoney

    2011-01-01

    The steady state dose-response curve of ligand-mediated gene induction usually appears to precisely follow a first-order Hill equation (Hill coefficient equal to 1). Additionally, various cofactors/reagents can affect both the potency and the maximum activity of gene induction in a gene-specific manner. Recently, we have developed a general theory for which an unspecified sequence of steps or reactions yields a first-order Hill dose-response curve (FHDC) for plots of the final product vs. ini...

  12. Radiation dose to radiosensitive organs in PET/CT myocardial perfusion examination using versatile optical fibre

    Science.gov (United States)

    Salasiah, M.; Nordin, A. J.; Fathinul Fikri, A. S.; Hishar, H.; Tamchek, N.; Taiman, K.; Ahmad Bazli, A. K.; Abdul-Rashid, H. A.; Mahdiraji, G. A.; Mizanur, R.; Noor, Noramaliza M.

    2013-05-01

    Cardiac positron emission tomography (PET) provides a precise method in order to diagnose obstructive coronary artery disease (CAD), compared to single photon emission tomography (SPECT). PET is suitable for obese and patients who underwent pharmacologic stress procedures. It has the ability to evaluate multivessel coronary artery disease by recording changes in left ventricular function from rest to peak stress and quantifying myocardial perfusion (in mL/min/g of tissue). However, the radiation dose to the radiosensitive organs has become crucial issues in the Positron Emission Tomography/Computed Tomography(PET/CT) scanning procedure. The objective of this study was to estimate radiation dose to radiosensitive organs of patients who underwent PET/CT myocardial perfusion examination at Centre for Diagnostic Nuclear Imaging, Universiti Putra Malaysia in one month period using versatile optical fibres (Ge-B-doped Flat Fibre) and LiF (TLD-100 chips). All stress and rest paired myocardial perfusion PET/CT scans will be performed with the use of Rubidium-82 (82Rb). The optic fibres were loaded into plastic capsules and attached to patient's eyes, thyroid and breasts prior to the infusion of 82Rb, to accommodate the ten cases for the rest and stress PET scans. The results were compared with established thermoluminescence material, TLD-100 chips. The result shows that radiation dose given by TLD-100 and Germanium-Boron-doped Flat Fiber (Ge-B-doped Flat Fiber) for these five organs were comparable to each other where the p>0.05. For CT scans,thyroid received the highest dose compared to other organs. Meanwhile, for PET scans, breasts received the highest dose.

  13. Multiple dose study of the combined radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole)

    Energy Technology Data Exchange (ETDEWEB)

    Bleehen, N.M.; Newman, H.F.; Maughan, T.S.; Workman, P.

    1989-04-01

    The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.

  14. Low Dose Hyper-radiosensitivity in Human Lung Cancer Cell Line A549 and Its Possible Mechanisms

    Institute of Scientific and Technical Information of China (English)

    Xiaofang DAI; Dan TAO; Hongge WU; Jing CHENG

    2009-01-01

    The low dose hyper-radiosensitivity (HRS) in human lung cancer cell line A549 was in-vestigated,the changes of ATM kinase,cell cycle and apoptosis of cells at different doses of radiation were observed,and the possible mechanisms were discussed.A549 cells in logarithmic growth phase were irradiated with 60Co γ-rays at doses of 0-2 Gy.Together with flow cytometry for precise cell sorting,cell survival fraction was measured by means of conventional colony-formation assay.The expression of ATM1981Ser-P protein was examined by Western blot 1 h after radiation.Apoptosis was detected by Hoechst 33258 fluorescent staining,and Annexin V-FITC/PI staining flow cytometry 24 h after radiation.Cell cycle distribution was observed by flow cytometly 6,12 and 24 h after ra-diation.The results showed that the expression of ATM1981Ser-P protein was observed at 0.2 Gy,followed by an increase at >0.2 Gy,and reached the peak at 0.5 Gy,with little further increase as the dose exceeded 0.5 Gy.Twenty-four h after radiation,partial cells presented the characteristic mor-phological changes of apoptosis,and the cell apoptosis curve was coincident with the survival curve.As compared with control group,the cell cycle almost had no changes after exposure to 0.1 and 0.2 Gy radiation (P>0.05).After exposure to 0.3,0.4 and 0.5 Cry radiation,G2/M phase arrest occurred 6 and 12 h after radiation (P<0.05),and the ratio of G2/M phase cells was decreased 24 h after radiation (P<0.05).It was concluded that A549 cells displayed the phenomenon of HRS/IRR.The mode of cell death was mainly apoptosis.The activity of ATM and cell cycle change may take an important role in HRS/IRR.

  15. Nonparallel nephrotoxicity dose-response curves of aminoglycosides.

    OpenAIRE

    1981-01-01

    Nephrotoxicity comparisons of aminoglycosides in rats, utilizing large multiples of human doses, have indicated an advantage for netilmicin. However, no nephrotoxicity advantage of netilmicin has been demonstrated at the lower doses used in clinics. Some high-dose studies in rats have also suggested that the slope of the nephrotoxicity dose-response curve of netilmicin was less steep than the slopes of other aminoglycosides. Therefore, the slopes of the nephrotoxicity dose-response curves of ...

  16. Review of dose-response curves for acute antimigraine drugs

    DEFF Research Database (Denmark)

    Hougaard, Anders; Tfelt-Hansen, Peer

    2015-01-01

    INTRODUCTION: Dose-response curves for efficacy and tolerability are the important determinants for the choice of doses of acute migraine drugs. Areas covered: Dose-response curves for the efficacy of seven triptans (5-HT1B/1D receptor agonists), a 5-HT1F receptor agonist (lasmiditan) and four oral...... calcitonin-gene related peptide receptor antagonists (telcagepant, MK-3207, BI 44370 TA and BMS-927711) in placebo-controlled trials were reviewed. In addition, dose-response curves for adverse events (AEs) were reviewed. Expert opinion: For most triptans, the dose-response curve for efficacy is flat......, whereas AEs often increase with increasing doses. The two other groups of drugs also have flat dose-response curves for efficacy. Overall, the triptans still have the most favorable efficacy-tolerability profile. Current acute antimigraine drugs do not fulfill the expectations of the patients, and thus...

  17. Prospective study evaluating the radiosensitizing effect of reduced doses of temozolomide in the treatment of Egyptian patients with glioblastoma multiforme

    Directory of Open Access Journals (Sweden)

    Gaber M

    2013-10-01

    Full Text Available May Gaber, Hanan Selim, Tamer El-NahasDepartment of Clinical Oncology, Cairo University, Cairo, EgyptPurpose: In view of the documented toxicity of continuous daily radiosensitizer doses of temozolomide concomitant with radiation in the treatment of glioblastoma multiforme, we aimed to compare it with a different schedule of abbreviated radiosensitizer dosing.Patients and methods: This was a randomized prospective study comparing toxicity and survival in 60 Egyptian patients with glioblastoma multiforme. Patients in arm I received temozolomide at a dose of 75 mg/m2 daily with radiotherapy for 42 days, starting 4 weeks after surgery and reaching to a total radiation dose of 60 Gy/30 Fractions/6 weeks, while patients in arm II received temozolomide at a dose of 75 mg/m2 concomitantly with the same radiotherapy schedule daily in the first and last weeks of the same radiotherapy program.Results: Common grade 1–2 adverse events were malaise in 28 patients (46.7%, followed by alopecia (40% and nausea (26.7%. Grade 3–4 convulsion and decreased level of consciousness was seen in only four patients who were all from arm I. The median progression-free survival (PFS for the entire study population was 10.6 months (95% confidence interval [CI] 7.3–14, and PFS at 12 months was 32%. The median PFS in arm I was 8.8 months (95% CI 5.9–11.7 and in arm II 11.5 months (95% CI 8.9–14.2, and PFS at 12 months for both arms was 32% and 30% respectively (P=0.571. The median overall survival (OS of the whole group of patients was 14.2 months (95% CI 13–15.5, and OS was 70% at 12 months and 25% at 18 months. The median OS for patients in arm I was 12.3 months (95% CI 7.7–16.9, whereas in arm II it was 14.3 months (95% CI 14–14.7 (P=0.83.Conclusion: Reduced radiosensitizer dosing of temozolomide concomitant with radiotherapy in glioblastoma multiforme exhibited comparable efficacy with a classic continuous daily schedule, though with better tolerability

  18. Construction of a cytogenetic dose-response curve for low-dose range gamma-irradiation in human peripheral blood lymphocytes using three-color FISH.

    Science.gov (United States)

    Suto, Yumiko; Akiyama, Miho; Noda, Takashi; Hirai, Momoki

    2015-12-01

    In order to estimate biological doses after low-dose ionizing radiation exposure, fluorescence in situ hybridization (FISH) using three differentially colored chromosome painting probes was employed to detect exchange-type chromosome aberrations. A reference dose response curve was constructed using blood samples from a female donor whose lymphocytes consistently exhibited a low frequency of cells at the second mitosis under routine culture conditions. Aberration yields were studied for a total of about 155 thousand metaphases obtained from seven dose-points of gamma irradiations (0, 50, 100, 150, 200, 250 and 300mGy). In situ hybridization was performed using commercially available painting probes for chromosomes 1, 2 and 4. With the aid of an automated image-capturing method, exchange-type aberrations involving painted chromosomes were detected with considerable accuracy and speed. The results on the exchange-type aberrations (dicentrics plus translocations) at the seven dose-points showed a good fit to the linear-quadratic model (y=0.0023+0.0015x+0.0819x(2), P=0.83). A blind test proved the reproducibility of the reference dose-response relationship. In the control experiments using blood samples from another donor, the estimated doses calculated on the basis of the present reference curve were proved to be in good agreement with the actual physical doses applied. The present dose-response curve may serve as a means to assess the individual differences in cytogenetical radio-sensitivities.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-07-01

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

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

    Science.gov (United States)

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

    2016-01-01

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

  1. The Antiproton Depth Dose Curve Measured with Alanine Detectors

    DEFF Research Database (Denmark)

    Bassler, Niels; Hansen, Johnny Witterseh; Palmans, Hugo;

    2008-01-01

    In this paper we report on the measurement of the antiproton depth dose curve, with alanine detectors. The results are compared with simulations using the particle energy spectrum calculated by FLUKA, and using the track structure model of Hansen et Olsen for conversion of calculated dose...

  2. The antiproton depth–dose curve in water

    CERN Document Server

    Bassler, N; Jäkel, O; Knudsen, H V; Kovacevic, S

    2008-01-01

    We have measured the depth–dose curve of 126 MeV antiprotons in a water phantom using ionization chambers. Since the antiproton beam provided by CERN has a pulsed structure and possibly carries a high-LET component from the antiproton annihilation, it is necessary to correct the acquired charge for ion recombination effects. The results are compared with Monte Carlo calculations and were found to be in good agreement. Based on this agreement we calculate the antiproton depth–dose curve for antiprotons and compare it with that for protons and find a doubling of the physical dose in the peak region for antiprotons.

  3. Enhancement of viability of radiosensitive (PBMC) and resistant (MDA-MB-231) clones in low-dose-rate cobalt-60 radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Falcao, Patricia Lima, E-mail: patricialfalcao@gmail.com [Universidade Federal do Amazonas (UFAM), Manaus, AM (Brazil); Motta, Barbara Miranda; Lima, Fernanda Castro de; Lima, Celso Vieira; Campos, Tarcisio Passos Ribeiro [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil)

    2015-05-15

    Objective: in the present study, the authors investigated the in vitro behavior of radio-resistant breast adenocarcinoma (MDA-MB-231) cells line and radiosensitive peripheral blood mononuclear cells (PBMC), as a function of different radiation doses, dose rates and postirradiation time kinetics, with a view to the interest of clinical radiotherapy. Materials and methods: the cells were irradiated with Co-60, at 2 and 10 Gy and two different exposure rates, 339.56 cGy.min{sup -1} and the other corresponding to one fourth of the standard dose rates, present over a 10-year period of cobalt therapy. Post-irradiation sampling was performed at pre-established kinetics of 24, 48 and 72 hours. The optical density response in viability assay was evaluated and a morphological analysis was performed. Results: radiosensitive PBMC showed decrease in viability at 2 Gy, and a more significant decrease at 10 Gy for both dose rates. MDAMB-231 cells presented viability decrease only at higher dose and dose rate. The results showed MDA-MB-231 clone expansion at low dose rate after 48-72 hours post-radiation. Conclusion: low dose rate shows a possible potential clinical impact involving decrease in management of radio-resistant and radiosensitive tumor cell lines in cobalt therapy for breast cancer. (author)

  4. Enhancement of viability of radiosensitive (PBMC and resistant (MDA-MB-231 clones in low-dose-rate cobalt-60 radiation therapy

    Directory of Open Access Journals (Sweden)

    Patrícia Lima Falcão

    2015-06-01

    Full Text Available Abstract Objective: In the present study, the authors investigated the in vitro behavior of radio-resistant breast adenocarcinoma (MDA-MB-231 cells line and radiosensitive peripheral blood mononuclear cells (PBMC, as a function of different radiation doses, dose rates and postirradiation time kinetics, with a view to the interest of clinical radiotherapy. Materials and Methods: The cells were irradiated with Co-60, at 2 and 10 Gy and two different exposure rates, 339.56 cGy.min–1 and the other corresponding to one fourth of the standard dose rates, present over a 10-year period of cobalt therapy. Post-irradiation sampling was performed at pre-established kinetics of 24, 48 and 72 hours. The optical density response in viability assay was evaluated and a morphological analysis was performed. Results: Radiosensitive PBMC showed decrease in viability at 2 Gy, and a more significant decrease at 10 Gy for both dose rates. MDAMB- 231 cells presented viability decrease only at higher dose and dose rate. The results showed MDA-MB-231 clone expansion at low dose rate after 48–72 hours post-radiation. Conclusion: Low dose rate shows a possible potential clinical impact involving decrease in management of radio-resistant and radiosensitive tumor cell lines in cobalt therapy for breast cancer.

  5. Radiation dose rate affects the radiosensitization of MCF-7 and HeLa cell lines to X-rays induced by dextran-coated iron oxide nanoparticles.

    Science.gov (United States)

    Khoshgard, Karim; Kiani, Parvaneh; Haghparast, Abbas; Hosseinzadeh, Leila; Eivazi, Mohammad Taghi

    2017-08-01

    The aim of radiotherapy is to deliver lethal damage to cancerous tissue while preserving adjacent normal tissues. Radiation absorbed dose of the tumoral cells can increase when high atomic nanoparticles are present in them during irradiation. Also, the dose rate is an important aspect in radiation effects that determines the biological results of a given dose. This in vitro study investigated the dose-rate effect on the induced radiosensitivity by dextran-coated iron oxide in cancer cells. HeLa and MCF-7 cells were cultured in vitro and incubated with different concentrations of dextran-coated iron oxide nanoparticles. They were then irradiated with 6 MV photons at dose rates of 43, 185 and 370 cGy/min. The MTT test was used to obtain the cells' survival after 48 h of irradiations. Incubating the cells with the nanoparticles at concentrations of 10, 40 and 80 μg/ml showed no significant cytotoxicity effect. Dextran-coated iron oxide nanoparticles showed more radiosensitivity effect by increasing the dose rate and nanoparticles concentration. Radiosensitization enhancement factors of MCF-7 and HeLa cells at a dose-rate of 370 cGy/min and nanoparticles' concentration of 80 μg/ml were 1.21 ± 0.06 and 1.19 ± 0.04, respectively. Increasing the dose rate of 6 MV photons irradiation in MCF-7 and HeLa cells increases the radiosensitization induced by the dextran-coated iron nanoparticles in these cells.

  6. Optimal designs for dose response curves with common parameters

    OpenAIRE

    Feller, Chrystel; Schorning, Kirsten; Dette, Holger; Bermann, Georgina; Bornkamp, Björn

    2016-01-01

    A common problem in Phase II clinical trials is the comparison of dose response curves corresponding to different treatment groups. If the effect of the dose level is described by parametric regression models and the treatments differ in the administration frequency (but not in the sort of drug) a reasonable assumption is that the regression models for the different treatments share common parameters. This paper develops optimal design theory for the comparison of different regression models ...

  7. The Antiproton Depth-Dose Curve in Water

    DEFF Research Database (Denmark)

    Bassler, Niels; Holzscheiter, Michael; Jäkel, Oliver

    2008-01-01

    We have measured the depth-dose curve of 126 MeV antiprotons in a water phantom using ionization chambers. Since the antiproton beam provided by CERN has a pulsed structure and possibly carries a high-LET component from the antiproton annihilation, it is necessary to correct the acquired charge...

  8. Dose-response curve estimation: a semiparametric mixture approach.

    Science.gov (United States)

    Yuan, Ying; Yin, Guosheng

    2011-12-01

    In the estimation of a dose-response curve, parametric models are straightforward and efficient but subject to model misspecifications; nonparametric methods are robust but less efficient. As a compromise, we propose a semiparametric approach that combines the advantages of parametric and nonparametric curve estimates. In a mixture form, our estimator takes a weighted average of the parametric and nonparametric curve estimates, in which a higher weight is assigned to the estimate with a better model fit. When the parametric model assumption holds, the semiparametric curve estimate converges to the parametric estimate and thus achieves high efficiency; when the parametric model is misspecified, the semiparametric estimate converges to the nonparametric estimate and remains consistent. We also consider an adaptive weighting scheme to allow the weight to vary according to the local fit of the models. We conduct extensive simulation studies to investigate the performance of the proposed methods and illustrate them with two real examples.

  9. An Update on the Depth-Dose Curve of Antiprotons

    DEFF Research Database (Denmark)

    Taasti, Vicki Trier; Holzscheiter, Michael H.; Knudsen, Helge

    we refine the experimental set-up to obtain absolute dose per primary particle, and compare these with simulations. Materials and Methods: Scrutinizing the geometrical setup, we could calculate beam scattering along the antiproton beam, which enables replotting the depth-dose curve as absolute dose...... improves the situation, in particular on the upstream side of the Bragg-peak. This is attributed to a different spectrum of annihilation products created in the entrance window of the ionization chamber in comparison to the case of simply simulating annihilation taking place on water. Yet, a large portion...... of dose still is missing in the Bragg-peak. This effect is also visible in the tail where the dose is underestimated in both types of simulations because of the missing annihilation energy/products. Conclusions: The shape of the Bragg-peak has some dependence on what material the antiprotons...

  10. AT cells are not radiosensitive for simple chromosomal exchanges at low dose

    Energy Technology Data Exchange (ETDEWEB)

    Hada, Megumi; Huff, Janice L.; Patel, Zarana S. [USRA Division of Life Sciences, Houston, TX 77058 (United States); Kawata, Tetsuya [Department of Radiology, School of Medicine, Keio University, Tokyo (Japan); Pluth, Janice M. [Lawrence Berkeley National Laboratory, Life Sciences Division, One Cyclotron Road, Building 74, Berkeley, CA 94720 (United States); George, Kerry A. [Wyle, 1290 Hercules Drive, Houston, TX 77058 (United States); Cucinotta, Francis A., E-mail: Francis.A.Cucinotta@nasa.gov [NASA, Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, TX 77058 (United States)

    2011-11-01

    Cells deficient in ATM (product of the gene that is mutated in ataxia telangiectasia patients) or NBS (product of the gene mutated in the Nijmegen breakage syndrome) show increased yields of both simple and complex chromosomal aberrations after high doses (>0.5 Gy) of ionizing radiation (X-rays or {gamma}-rays), however less is known on how these cells respond at low dose. Previously we had shown that the increased chromosome aberrations in ATM and NBS defective lines was due to a significantly larger quadratic dose-response term compared to normal fibroblasts for both simple and complex exchanges. The linear dose-response term for simple exchanges was significantly higher in NBS cells compared to wild type cells, but not for AT cells. However, AT cells have a high background level of exchanges compared to wild type or NBS cells that confounds the understanding of low dose responses. To understand the sensitivity differences for high to low doses, chromosomal aberration analysis was first performed at low dose-rates (0.5 Gy/d), and results provided further evidence for the lack of sensitivity for exchanges in AT cells below doses of 1 Gy. Normal lung fibroblast cells treated with KU-55933, a specific ATM kinase inhibitor, showed increased numbers of exchanges at a dose of 1 Gy and higher, but were similar to wild type cells at 0.5 Gy or below. These results were confirmed using siRNA knockdown of ATM. The present study provides evidence that the increased radiation sensitivity of AT cells for chromosomal exchanges found at high dose does not occur at low dose.

  11. The antiproton depth–dose curve measured with alanine detectors

    CERN Document Server

    Bassler, Niels; Palmans, Hugo; Holzscheiter, Michael H; Kovacevic, Sandra

    2008-01-01

    n this paper we report on the measurement of the antiproton depth–dose curve, with alanine detectors. The results are compared with simulations using the particle energy spectrum calculated by FLUKA, and using the track structure model of Hansen and Olsen for conversion of calculated dose into response. A good agreement is observed between the measured and calculated relative effectiveness although an underestimation of the measured values beyond the Bragg-peak remains unexplained. The model prediction of response of alanine towards heavy charged particles encourages future use of the alanine detectors for dosimetry of mixed radiation fields.

  12. Maximum likelihood estimation for cytogenetic dose-response curves

    Energy Technology Data Exchange (ETDEWEB)

    Frome, E.L; DuFrain, R.J.

    1983-10-01

    In vitro dose-response curves are used to describe the relation between the yield of dicentric chromosome aberrations and radiation dose for human lymphocytes. The dicentric yields follow the Poisson distribution, and the expected yield depends on both the magnitude and the temporal distribution of the dose for low LET radiation. A general dose-response model that describes this relation has been obtained by Kellerer and Rossi using the theory of dual radiation action. The yield of elementary lesions is kappa(..gamma..d + g(t, tau)d/sup 2/), where t is the time and d is dose. The coefficient of the d/sup 2/ term is determined by the recovery function and the temporal mode of irradiation. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting models are intrinsically nonlinear in the parameters. A general purpose maximum likelihood estimation procedure is described and illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.

  13. Quantitative Dose-Response Curves from Subcellular Lipid Multilayer Microarrays

    Science.gov (United States)

    Kusi-Appiah, A. E.; Lowry, T. W.; Darrow, E. M.; Wilson, K.; Chadwick, B. P.; Davidson, M. W.; Lenhert, S.

    2015-01-01

    The dose-dependent bioactivity of small molecules on cells is a crucial factor in drug discovery and personalized medicine. Although small-molecule microarrays are a promising platform for miniaturized screening, it has been a challenge to use them to obtain quantitative dose-response curves in vitro, especially for lipophilic compounds. Here we establish a small-molecule microarray assay capable of controlling the dosage of small lipophilic molecules delivered to cells by varying the sub-cellular volumes of surface supported lipid micro- and nanostructure arrays fabricated with nanointaglio. Features with sub-cellular lateral dimensions were found necessary to obtain normal cell adhesion with HeLa cells. The volumes of the lipophilic drug-containing nanostructures were determined using a fluorescence microscope calibrated by atomic-force microscopy. We used the surface supported lipid volume information to obtain EC-50 values for the response of HeLa cells to three FDA-approved lipophilic anticancer drugs, docetaxel, imiquimod and triethylenemelamine, which were found to be significantly different from neat lipid controls. No significant toxicity was observed on the control cells surrounding the drug/lipid patterns, indicating lack of interference or leakage from the arrays. Comparison of the microarray data to dose-response curves for the same drugs delivered liposomally from solution revealed quantitative differences in the efficacy values, which we explain in terms of cell-adhesion playing a more important role in the surface-based assay. The assay should be scalable to a density of at least 10,000 dose response curves on the area of a standard microtiter plate. PMID:26167949

  14. Estimation of absorbed dose of radiosensitive organs and effective sose in patients underwent abdominopelvic spiral CT scan using impact CT patient dosimetry

    Directory of Open Access Journals (Sweden)

    Ayoub Amirnia

    2017-05-01

    Full Text Available Background: Due to the presence of radiosensitive organs in the abdominopelvic region and increasing the number of requests for CT scan examinations, concerns about increasing radiation doses in patients has been greatly elevated. Therefore, the goal of this study was to determine the absorbed dose of radiosensitive organs and the effective dose in patients underwent abdominopelvic CT scan using ImPACT CT patient dosimetry Calculator (version 1.0.4, Imaging Performance Assessment on Computed Tomography, www.impactscan.org. Methods: This prospective cross-sectional study was conducted in Imam Reza Hospital from November to February 2015 February 2015 in the Imam Reza Hospital, in Urmia, Iran. The demographic and dosimetric information of 100 patients who underwent abdominopelvic CT scan in a 6-slice CT scanner were obtained through the data collection forms. The demographic data of the patients included age, weight, gender, and BMI. The dosimetric parameters included pitch value, CT dose volume index (CTDIvol, dose-length product (DLP, tube voltage, tube current, exposure time, collimation size, scan length, and scan time. To determine the absorbed dose of radiosensitive organs and also the effective dose in patients, ImPACT CT patient dosimetry calculator was used. Results: The results of this study demonstrated that the mean and standard deviation (SD of patients' effective dose in abdominopelvic CT scan was 4.927±0.164 mSv. The bladder in both genders had the greatest mean organ dose, which was 64.71±17.15 mGy for men and 77.56±18.48 mGy for women (P<0.001. Conclusion: The effective dose values of this examination are in the same range as previous studies, as well as International Commission on Radiological Protection (ICRP recommendations. However, the radiation dose from CT scan has the largest contribution to the medical imaging. According to the ALARA principle, it is recommended that the scan parameters, especially mAs, should be

  15. Low-Dose Hyper-Radiosensitivity Is Not a Common Effect in Normal Asynchronous and G2-Phase Fibroblasts of Cancer Patients

    Energy Technology Data Exchange (ETDEWEB)

    Słonina, Dorota, E-mail: z5slonin@cyfronet.pl [Department of Applied Radiobiology, Centre of Oncology, Maria-Skłodowska-Curie Memorial Institute Kraków, Kraków (Poland); Biesaga, Beata; Janecka, Anna [Department of Applied Radiobiology, Centre of Oncology, Maria-Skłodowska-Curie Memorial Institute Kraków, Kraków (Poland); Kabat, Damian [Department of Medical Physics, Centre of Oncology, Maria-Skłodowska-Curie Memorial Institute Kraków, Kraków (Poland); Bukowska-Strakova, Karolina [Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Kraków (Poland); Gasińska, Anna [Department of Applied Radiobiology, Centre of Oncology, Maria-Skłodowska-Curie Memorial Institute Kraków, Kraków (Poland)

    2014-02-01

    Purpose: In our previous study, using the micronucleus assay, a low-dose hyper-radiosensitivity (HRS)-like phenomenon was observed for normal fibroblasts of 2 of the 40 cancer patients investigated. In this article we report, for the first time, the survival response of primary fibroblasts from 25 of these patients to low-dose irradiation and answer the question regarding the effect of G2-phase enrichment on HRS elicitation. Methods and Materials: The clonogenic survival of asynchronous as well as G2-phase enriched fibroblast populations was measured. Separation of G2-phase cells and precise cell counting was performed using a fluorescence-activated cell sorter. Sorted and plated cells were irradiated with single doses (0.1-4 Gy) of 6-MV x-rays. For each patient, at least 4 independent experiments were performed, and the induced-repair model was fitted over the whole data set to confirm the presence of HRS effect. Results: The HRS response was demonstrated for the asynchronous and G2-phase enriched cell populations of 4 patients. For the rest of patients, HRS was not defined in either of the 2 fibroblast populations. Thus, G2-phase enrichment had no effect on HRS elicitation. Conclusions: The fact that low-dose hyper-radiosensitivity is not a common effect in normal human fibroblasts implies that HRS may be of little consequence in late-responding connective tissues with regard to radiation fibrosis.

  16. Investigating quartz optically stimulated luminescence dose-response curves at high doses

    Energy Technology Data Exchange (ETDEWEB)

    Lowick, Sally E., E-mail: lowick@geo.unibe.c [Institut fuer Geologie, Universitaet Bern, Baltzerstrasse 1-3, 3012 Bern (Switzerland); Preusser, Frank [Institut fuer Geologie, Universitaet Bern, Baltzerstrasse 1-3, 3012 Bern (Switzerland); Wintle, Ann G. [Institute of Geography and Earth Sciences, Aberystwyth University, AberystwythSY23 3DB (United Kingdom)

    2010-10-15

    Despite the general expectation that optically stimulated luminescence (OSL) growth should be described by a simple saturating exponential function, an additional high dose component is often reported in the dose response of quartz. Although often reported as linear, it appears that this response is the early expression of a second saturating exponential. While some studies using equivalent doses that fall in this high dose region have produced ages that correlate well with independent dating, others report that it results in unreliable age determinations. Two fine grain sedimentary quartz samples that display such a response were used to investigate the origin of this additional high dose component: three experiments were conducted to examine their dose-response up to >1000 Gy. The high dose rates provided by laboratory irradiation were found not to induce a sensitivity change in the response to a subsequent test dose, with the latter not being significantly different from those generated following naturally acquired doses. The relative percentage contributions of the fast and medium OSL components remained fixed throughout the dose-response curve, suggesting that the electron traps that give rise to the initial OSL do not change with dose. An attempt was made to investigate a change in luminescence centre recombination probability by monitoring the depletion of the '325 {sup o}C' thermoluminescence (TL) during the optical stimulation that would result in depletion of the OSL signal. The emissions measured through both the conventional ultraviolet (UV), and a longer wavelength violet/blue (VB) window, displayed similar relative growth with dose, although it was not possible to resolve the origin of the VB emissions. No evidence was found to indicate whether the additional component at high doses occurs naturally or is a product of laboratory treatment. However, it appears that these samples display an increased sensitivity of quartz OSL to high doses

  17. CALUX measurements: statistical inferences for the dose-response curve.

    Science.gov (United States)

    Elskens, M; Baston, D S; Stumpf, C; Haedrich, J; Keupers, I; Croes, K; Denison, M S; Baeyens, W; Goeyens, L

    2011-09-30

    Chemical Activated LUciferase gene eXpression [CALUX] is a reporter gene mammalian cell bioassay used for detection and semi-quantitative analyses of dioxin-like compounds. CALUX dose-response curves for 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD] are typically smooth and sigmoidal when the dose is portrayed on a logarithmic scale. Non-linear regression models are used to calibrate the CALUX response versus TCDD standards and to convert the sample response into Bioanalytical EQuivalents (BEQs). Several complications may arise in terms of statistical inference, specifically and most important is the uncertainty assessment of the predicted BEQ. This paper presents the use of linear calibration functions based on Box-Cox transformations to overcome the issue of uncertainty assessment. Main issues being addressed are (i) confidence and prediction intervals for the CALUX response, (ii) confidence and prediction intervals for the predicted BEQ-value, and (iii) detection/estimation capabilities for the sigmoid and linearized models. Statistical comparisons between different calculation methods involving inverse prediction, effective concentration ratios (ECR(20-50-80)) and slope ratio were achieved with example datasets in order to provide guidance for optimizing BEQ determinations and expand assay performance with the recombinant mouse hepatoma CALUX cell line H1L6.1c3.

  18. Slope of the dose-response curve: usefulness in assessing bronchial responses to inhaled histamine.

    OpenAIRE

    Cockcroft, D. W.; Berscheid, B A

    1983-01-01

    The value of determining the slope of the histamine dose-response curve, in addition to the histamine provocation concentration producing a 20% reduction in FEV1 (PC20-FEV1), was assessed by analysis of histamine dose-response curves in 40 patients selected as having a wide range of increased non-specific bronchial responsiveness to inhaled histamine. The histamine dose-response curves were found to be fit the linear curve (dose v response, mean r2 = 0.97) better than the logarithmic curve (l...

  19. Establishment and validation of a dose-effect curve for {gamma}-rays by cytogenetic analysis

    Energy Technology Data Exchange (ETDEWEB)

    Barquinero, Joan F.; Caballin, Maria Rosa [Unitat d`Antropologia, Departament de Biologia Animal, Biologia Vegetal i Ecologia, Facultat de Ciencies, Universitat Autonoma de Barcelona, Bellaterra (Spain); Barrios, Leonardo; Ribas, Montserrat [Unitat de Biologia Cel.lular, Departament de Biologia Cel.lular i Fisiologia, Facultat de Ciencies, Universitat Autonoma de Barcelona, Bellaterra (Spain); Miro, Rosa [Institut de Biologia Fondamental `Vicent Villar Palasi`, Universitat Autonoma de Barcelona, Barcelona (Spain); Egozcue, Josep [Servei d`Oncologia, Hospital de la Santa Crue i Sant Pau, Universitat Autonome de Barcelona, Barcelona (Spain)

    1995-01-01

    A dose-effect curve obtained by analysis of dicentric chromosomes after irradiation of peripheral blood samples, from one donor, at 11 different doses of {gamma}-rays is presented. For the elaboration of this curve, more than 18,000 first division metaphases have been analyzed. The results fit very well to the linear-quadratic model. To validate the curve, samples from six individuals (three controls and three occupationally exposed persons) were irradiated at 2 Gy. The results obtained, when compared with the curve, showed that in all cases the 95% confidence interval included the 2 Gy dose, with estimated dose ranges from 1.82 to 2.19 Gy.

  20. Steepness of the radiation dose-response curve for dose-per-fraction escalation keeping the number of fractions fixed.

    Science.gov (United States)

    Bentzen, Søren M

    2005-01-01

    Clinically, there is growing interest in strategies for intensifying radiation therapy by escalating the dose per fraction. This paper considers the steepness of the dose-response curve in this case. The steepness of a radiation dose-response curve is most conveniently quantified by the normalized dose-response gradient, gamma. Under the assumption of a linear-quadratic dose-effect model, a simple analytical relationship is derived between the gamma-value for a dose-response curve generated by varying the total dose while keeping the number of fractions constant, i.e. escalating the dose per fraction, and the gamma-value for a dose-response curve generated by varying the total dose while keeping the dose per fraction constant. This formulation is compared with clinical dose-response data from the literature and shown to be in good agreement with the observations. Some implications of this formulation for non-uniform dose distributions delivered using 3D conformal radiotherapy or intensity modulated radiotherapy (IMRT) are briefly discussed.

  1. A Grid Algorithm for High Throughput Fitting of Dose-Response Curve Data

    OpenAIRE

    Wang, Yuhong; Jadhav, Ajit; Southal, Noel; Huang, Ruili; Nguyen, Dac-Trung

    2010-01-01

    We describe a novel algorithm, Grid algorithm, and the corresponding computer program for high throughput fitting of dose-response curves that are described by the four-parameter symmetric logistic dose-response model. The Grid algorithm searches through all points in a grid of four dimensions (parameters) and finds the optimum one that corresponds to the best fit. Using simulated dose-response curves, we examined the Grid program’s performance in reproducing the actual values that were used ...

  2. In vitro studies on the modification of low-dose hyper-radiosensitivity in prostate cancer cells by incubation with genistein and estradiol

    Directory of Open Access Journals (Sweden)

    Thelen Paul

    2008-07-01

    Full Text Available Abstract Background As the majority of prostate cancers (PC express estrogen receptors, we evaluated the combination of radiation and estrogenic stimulation (estrogen and genistein on the radiosensitivity of PC cells in vitro. Methods PC cells LNCaP (androgen-sensitive and PC-3 (androgen-independent were evaluated. Estrogen receptor (ER expression was analyzed by means of immunostaining. Cells were incubated in FCS-free media with genistein 10 μM and estradiol 10 μM 24 h before irradiation and up to 24 h after irradiation. Clonogenic survival, cell cycle changes, and expression of p21 were assessed. Results LNCaP expressed both ER-α and ER-β, PC-3 did not. Incubation of LNCaP and PC-3 with genistein resulted in a significant reduction of clonogenic survival. Incubation with estradiol exhibited in low concentrations (0.01 μM stimulatory effects, while higher concentrations did not influence survival. Both genistein 10 μM and estradiol 10 μM increased low-dose hyper-radiosensitivity [HRS] in LNCaP, while hormonal incubation abolished HRS in PC-3. In LNCaP cells hormonal stimulation inhibited p21 induction after irradiation with 4 Gy. In PC-3 cells, the proportion of cells in G2/M was increased after irradiation with 4 Gy. Conclusion We found an increased HRS to low irradiation doses after incubation with estradiol or genistein in ER-α and ER-β positive LNCaP cells. This is of high clinical interest, as this tumor model reflects a locally advanced, androgen dependent PC. In contrast, in ER-α and ER-β negative PC-3 cells we observed an abolishing of the HRS to low irradiation doses by hormonal stimulation. The effects of both tested compounds on survival were ER and p53 independent. Since genistein and estradiol effects in both cell lines were comparable, neither ER- nor p53-expression seemed to play a role in the linked signalling. Nevertheless both compounds targeted the same molecular switch. To identify the underlying molecular

  3. An association between low-dose hyper-radiosensitivity and the early G2-phase checkpoint in normal fibroblasts of cancer patients.

    Science.gov (United States)

    Słonina, Dorota; Gasińska, Anna; Biesaga, Beata; Janecka, Anna; Kabat, Damian

    2016-03-01

    In our previous study, low-dose hyper-radiosensitivity (HRS) effect was demonstrated for normal fibroblasts (asynchronous and G2-phase enriched) of 4 of the 25 cancer patients investigated. For the rest of patients, HRS was not defined in either of the 2 fibroblast populations. Thus, the study indicated that G2-phase enrichment had no influence on HRS identification. The conclusion contradicts that reported for human tumor cells, and suggests different mechanism of HRS in normal human cells. In the present paper we report, for the first time, the activity of early G2-phase checkpoint after low-dose irradiation in normal fibroblasts of these 4 HRS-positive patients and 4 HRS-negative patients and answer the question regarding the role of this checkpoint in normal human cells. The response of the early G2-phase checkpoint was determined by assessment of the progression of irradiated cells into mitosis using the mitotic marker, phosphorylated histone H3. We found evident differences in the activity of the early G2-phase checkpoint between HRS-positive and HRS-negative fibroblasts. In HRS-positive fibroblasts the checkpoint was not triggered and DNA damage was not recognized after doses lower than 0.2Gy resulting in HRS response. On the contrary, in HRS-negative fibroblasts the early G2-phase checkpoint was activated regardless of the dose in the range 0.1-2Gy. In conclusion, although cell cycle phase has no effect on the presence of HRS effect in normal human fibroblasts, the data reported here indicate that HRS response in these cells is associated with the functioning of early G2-phase checkpoint in a threshold-dose dependent manner, similarly as it takes place in most of human tumor and other cells. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Dose-Finding when the Target Dose Is on a Plateau of a Dose-Response Curve: Comparison of Fully Sequential Designs

    OpenAIRE

    Ivanova, Anastasia; Xiao, Changfu

    2013-01-01

    Consider the problem of estimating a dose with a certain response rate. Many multistage dose-finding designs for this problem were originally developed for oncology studies where the mean dose-response is strictly increasing in dose. In non-oncology Phase II dose-finding studies the dose-response curve often plateaus in the range of interest and there are several doses with the mean response equal to the target. In this case it is usually of interest to find the lowest of these doses since hi...

  5. Ecological Dose Modeling of Aquatic and Riparian Receptors to Strontium-90 with an Emphasis on Radiosensitive Organs

    Energy Technology Data Exchange (ETDEWEB)

    Poston, Ted M.; Traub, Richard J.; Antonio, Ernest J.

    2011-07-20

    The 100-NR-2 site is the location of elevated releases of strontium-90 to the Columbia River via contaminated groundwater. The resulting dose to aquatic and riparian receptors was evaluated in 2005 (DOE 2009) and compared to U.S. Department of Energy (DOE) dose guidance values. We have conducted additional dose assessments for a broader spectrum of aquatic and riparian organisms using RESRAD Biota and specific exposure scenarios. Because strontium-90 accumulates in bone, we have also modeled the dose to the anterior kidney, a blood-forming and immune system organ that lies close to the spinal column of fish. The resulting dose is primarily attributable to the yttrium-90 progeny of strontium-90 and very little of the dose is associated with the beta emission from strontium-90. All dose modeling results were calculated with an assumption of secular equilibrium between strontium-90 and yttrum-90.

  6. Patients who do not respond to the "usual" dose: why Terry fell off the dose-response curve.

    Science.gov (United States)

    Preskorn, Sheldon H

    2009-11-01

    Clinical trials are aimed at determining what happens in the "usual" patient; however, clinicians are interested in what happens in their patients even if they are not usual. The usual dose-response relationship is determined as part of the drug development process required for approval of a new drug. However, clinicians are likely to encounter patients who "fall off" the usual dose-response curve because they are either sensitive or resistant to the beneficial (efficacy) or adverse effects of a drug. This column is the first in a series that will examine why specific patients fall off the usual dose-response curve and how clinicians can manage such patients when they encounter them. This column discusses what a dose-response curve is, how it is determined, and why it is clinically important.

  7. A dose-response curve for biodosimetry from a 6 MV electron linear accelerator

    Energy Technology Data Exchange (ETDEWEB)

    Lemos-Pinto, M.M.P.; Cadena, M.; Santos, N.; Fernandes, T.S.; Borges, E.; Amaral, A., E-mail: marcelazoo@yahoo.com.br [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Departamento de Energia Nuclear

    2015-10-15

    Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates. (author)

  8. A dose-response curve for biodosimetry from a 6 MV electron linear accelerator

    Science.gov (United States)

    Lemos-Pinto, M.M.P.; Cadena, M.; Santos, N.; Fernandes, T.S.; Borges, E.; Amaral, A.

    2015-01-01

    Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates. PMID:26445334

  9. A dose-response curve for biodosimetry from a 6 MV electron linear accelerator.

    Science.gov (United States)

    Lemos-Pinto, M M P; Cadena, M; Santos, N; Fernandes, T S; Borges, E; Amaral, A

    2015-10-01

    Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates.

  10. A dose-response curve for biodosimetry from a 6 MV electron linear accelerator

    Directory of Open Access Journals (Sweden)

    M.M.P. Lemos-Pinto

    2015-01-01

    Full Text Available Biological dosimetry (biodosimetry is based on the investigation of radiation-induced biological effects (biomarkers, mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA. Two software programs, CABAS (Chromosomal Aberration Calculation Software and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates.

  11. Dose-Response Curve of Chromosome Aberrations in Human Lymphocytes Induced by Gamma-Rays

    Directory of Open Access Journals (Sweden)

    Y. Lusiyanti

    2013-12-01

    Full Text Available Chromosome aberration is a biomarker to predict the level of cell damage caused by exposure to ionizing radiation on human body. Dicentric chromosome is a specific chromosome aberration caused by ionizing radiation and is used as a gold standard biodosimetry of individuals over exposed to ionizing radiation. In radiation accident the dicentric assays has been applied as biological dosimetry to estimate radiation absorbed dose and also to confirm the radiation dose received to radiation workers.The purpose of this study was to generate a dose response curve of chromosome aberration (dicentric in human lymphocyte induced by gamma radiation. Peripheral blood samples from three non smoking healthy volunteers aged between 25-48 years old with informed consent were irradiated with dose between 0.1-4.0 Gy and a control using gamma teletherapy source. The culture procedure was conducted following the IAEA standard procedures with slight modifications. Analysis of dose-response curves used was LQ model Y = a + αD + βD2. The result showed that α and β values of the curve obtained were 0.018 ± 0.006 and 0.013 ± 0.002, respectively. Dose response calibration curve for dicentric chromosome aberrations in human lymphocytes induced by gamma-radiation fitted to linear quadratic model. In order to apply the dose response curve of chromosome aberration disentric for biodosimetry, this standar curve still need to be validated.

  12. The analysis of dose-response curve from bioassays with quantal response: Deterministic or statistical approaches?

    Science.gov (United States)

    Mougabure-Cueto, G; Sfara, V

    2016-04-25

    Dose-response relations can be obtained from systems at any structural level of biological matter, from the molecular to the organismic level. There are two types of approaches for analyzing dose-response curves: a deterministic approach, based on the law of mass action, and a statistical approach, based on the assumed probabilities distribution of phenotypic characters. Models based on the law of mass action have been proposed to analyze dose-response relations across the entire range of biological systems. The purpose of this paper is to discuss the principles that determine the dose-response relations. Dose-response curves of simple systems are the result of chemical interactions between reacting molecules, and therefore are supported by the law of mass action. In consequence, the shape of these curves is perfectly sustained by physicochemical features. However, dose-response curves of bioassays with quantal response are not explained by the simple collision of molecules but by phenotypic variations among individuals and can be interpreted as individual tolerances. The expression of tolerance is the result of many genetic and environmental factors and thus can be considered a random variable. In consequence, the shape of its associated dose-response curve has no physicochemical bearings; instead, they are originated from random biological variations. Due to the randomness of tolerance there is no reason to use deterministic equations for its analysis; on the contrary, statistical models are the appropriate tools for analyzing these dose-response relations.

  13. Assessment of target volume doses in radiotherapy based on the standard and measured calibration curves

    Directory of Open Access Journals (Sweden)

    Gholamreza Fallah Mohammadi

    2015-01-01

    Full Text Available Context: In radiation treatments, estimation of the dose distribution in the target volume is one of the main components of the treatment planning procedure. To estimate the dose distribution, the information of electron densities is necessary. The standard curves determined by computed tomography (CT scanner that may be different from that of other oncology centers. In this study, the changes of dose calculation due to the different calibration curves (HU-ρel were investigated. Materials and Methods: Dose values were calculated based on the standard calibration curve that was predefined for the treatment planning system (TPS. The calibration curve was also extracted from the CT images of the phantom, and dose values were calculated based on this curve. The percentage errors of the calculated values were determined. Statistical Analysis Used: The statistical analyses of the mean differences were performed using the Wilcoxon rank-sum test for both of the calibration curves. Results and Discussion: The results show no significant difference for both of the measured and standard calibration curves (HU-ρel in 6, 15, and 18 MeV energies. In Wilcoxon ranked sum nonparametric test for independent samples with P < 0.05, the equality of monitor units for both of the curves to transfer 200 cGy doses to reference points was resulted. The percentage errors of the calculated values were lower than 2% and 1.5% in 6 and 15 MeV, respectively. Conclusion: From the results, it could be concluded that the standard calibration curve could be used in TPS dose calculation accurately.

  14. Modeling and regression analysis of semiochemical dose-response curves of insect antennal reception and behavior

    Science.gov (United States)

    Dose-response curves with semiochemicals are reported in many articles in insect chemical ecology regarding neurophysiology and behavioral bioassays. Most such curves are shown in figures where the x-axis has order of magnitude increases in dosages versus responses on the y-axis represented by point...

  15. A grid algorithm for high throughput fitting of dose-response curve data.

    Science.gov (United States)

    Wang, Yuhong; Jadhav, Ajit; Southal, Noel; Huang, Ruili; Nguyen, Dac-Trung

    2010-10-21

    We describe a novel algorithm, Grid algorithm, and the corresponding computer program for high throughput fitting of dose-response curves that are described by the four-parameter symmetric logistic dose-response model. The Grid algorithm searches through all points in a grid of four dimensions (parameters) and finds the optimum one that corresponds to the best fit. Using simulated dose-response curves, we examined the Grid program's performance in reproducing the actual values that were used to generate the simulated data and compared it with the DRC package for the language and environment R and the XLfit add-in for Microsoft Excel. The Grid program was robust and consistently recovered the actual values for both complete and partial curves with or without noise. Both DRC and XLfit performed well on data without noise, but they were sensitive to and their performance degraded rapidly with increasing noise. The Grid program is automated and scalable to millions of dose-response curves, and it is able to process 100,000 dose-response curves from high throughput screening experiment per CPU hour. The Grid program has the potential of greatly increasing the productivity of large-scale dose-response data analysis and early drug discovery processes, and it is also applicable to many other curve fitting problems in chemical, biological, and medical sciences.

  16. Cell division cycle 25 homolog c effects on low-dose hyper-radiosensitivity and induced radioresistance at elevated dosage in A549 cells.

    Science.gov (United States)

    Zhao, Yanxia; Cui, Yingshan; Han, Jun; Ren, Jinghua; Wu, Gang; Cheng, Jing

    2012-09-01

    The underlying mechanisms behind both low-dose hyper-radiosensitivity (HRS) and induced radioresistance (IRR), generally occurring at elevated radiation levels, remain unclear; however, elucidation of the relationship between cell cycle division 25 homolog c (Cdc25c) phosphatase and HRS/IRR may provide important insights into this process. Two cell lines with disparate HRS status, A549 and SiHa cells, were selected as cell models for comparison of dose-dependent Cdc25c phosphatase expression subsequent to low-dose irradiation. Knockdown of Cdc25c in A549 cells was mediated by transfection with a pGCsi-RAN-U6neo vector containing hairpin siRNA sequences. S216-phosphorylated Cdc25c protein [p-Cdc25c (Ser216)], cell survival and mitotic ratio were measured by western blot, colony-forming assay and histone H3 phosphorylation analysis. Variant p-Cdc25c (Ser216) expression was observed in the two cell lines after irradiation. The p-Cdc25c (Ser216) expression noted in SiHa cells after administration of 0-1 Gy radiation was similar to the radioresistance model; however, in A549 cells, the dose response for the phosphorylation of the Cdc25c Ser216 residue overlapped the level required to overcome the HRS response. Furthermore, Cdc25c repression prior to low-dose radiation induced more distinct HRS and prevented the development of IRR. The dose required to overcome the HRS response coincided with the effect of early G2-phase checkpoint arrest in A549 cells (approximately 0.3 Gy), and Cdc25c knockdown in A549 cells (approximately 0.5 Gy) corresponded to the phosphorylation of the Cdc25c Ser216 residue. Resultant data confirmed that dose-dependent Cdc25c phosphatase does effectively act as an early G2-phase checkpoint, thus indicating mechanistic importance in the HRS to IRR transition in A549 cells.

  17. Radiosensitivity of children: potential for overexposure in CR and DR and magnitude of doses in ordinary radiographic examinations

    Energy Technology Data Exchange (ETDEWEB)

    Don, S. [Mallinckrodt Inst. for Radiology, St. Louis Children' s Hospital, Washington Univ. School of Medicine, St. Louis, MO (United States)

    2004-10-01

    The linear, no-threshold model is currently the best estimate of risk from radiation exposure with no level below which radiation is safe. Plain-film radiography has a much lower patient dose than CT or fluoroscopy. With the advent of computed radiography (CR) the dose to patients is higher than screen-film radiography and overexposure is quite common. Task-oriented adjustment of technique, commonly used in CT, is rarely used in CR. Exposure reduction is important in CR as research indicates an increased risk of childhood acute lymphocytic leukemia from plain-film studies and an increased risk of fatal breast cancer from scoliosis series. Future needs include better documentation of the dose the patient receives, dose-based research on the radiation risk, and accreditation in CR and digital radiography for public assurance. (orig.)

  18. Dose finding when the target dose is on a plateau of a dose-response curve: comparison of fully sequential designs.

    Science.gov (United States)

    Ivanova, Anastasia; Xiao, Changfu

    2013-01-01

    Consider the problem of estimating a dose with a certain response rate. Many multistage dose-finding designs for this problem were originally developed for oncology studies where the mean dose-response is strictly increasing in dose. In non-oncology phase II dose-finding studies, the dose-response curve often plateaus in the range of interest, and there are several doses with the mean response equal to the target. In this case, it is usually of interest to find the lowest of these doses because higher doses might have higher adverse event rates. It is often desirable to compare the response rate at the estimated target dose with a placebo and/or active control. We investigate which of the several known dose-finding methods developed for oncology phase I trials is the most suitable when the dose-response curve plateaus. Some of the designs tend to spread the allocation among the doses on the plateau. Others, such as the continual reassessment method and the t-statistic design, concentrate allocation at one of the doses with the t-statistic design selecting the lowest dose on the plateau more frequently.

  19. Eosinophils in the bronchial mucosa in relation to methacholine dose-response curves in atopic asthma

    NARCIS (Netherlands)

    G.M. Moller (Trude); S.E. Overbeek (Shelley); C.G. van Helden-Meeuwsen; H.C. Hoogsteden (Henk); J.M. Bogaard (Jan)

    1999-01-01

    textabstractAsthma is characterized by both local infiltration of eosinophils in the bronchial mucosa and bronchial hyperreactivity (BHR). A detailed characterization of BHR implies analysis of a histamine or methacholine dose-response curve yielding not only the dose a

  20. The impact of pediatric-specific dose modulation curves on radiation dose and image quality in head computed tomography

    Energy Technology Data Exchange (ETDEWEB)

    Santos, Joana; Paulo, Graciano [Instituto Politecnico de Coimbra, ESTESC, DMIR, Coimbra (Portugal); Foley, Shane; Rainford, Louise [University College Dublin, School of Medicine and Medical Science, Health Science Centre, Dublin 4 (Ireland); McEntee, Mark F. [The University of Sydney, Faculty of Health Sciences, Cumberland Campus, Sydney (Australia)

    2015-11-15

    The volume of CT examinations has increased with resultant increases in collective dose values over the last decade. To analyze the impact of the tube current and voltage modulation for dose values and image quality of pediatric head CT examinations. Head CT examinations were performed on anthropomorphic phantoms and four pediatric age categories before and after the introduction of dedicated pediatric curves for tube voltage and current modulation. Local diagnostic reference levels were calculated. Visual grading characteristic image quality evaluation was performed by four pediatric neuroradiologists and image noise comparisons were performed. Pediatric-specific modulation curves demonstrated a 49% decrease in mean radiation dose for phantom examinations. The local diagnostic reference levels (CTDIvol) for clinical examinations decreased by 52%, 41%, 46% and 40% for newborn, 5-, 10- and 15-year-old patients, respectively. Visual grading characteristic image quality was maintained for the majority of age categorizations (area under the curve = 0.5) and image noise measurements did not change (P = 0.693). Pediatric-specific dose modulation curves resulted in an overall mean dose reduction of 45% with no significant differences in subjective or objective image quality findings. (orig.)

  1. Effects of shielding the radiosensitive superficial organs of ORNL pediatric phantoms on dose reduction in computed tomography

    Directory of Open Access Journals (Sweden)

    Parisa Akhlaghi

    2014-01-01

    Full Text Available In computed tomography (CT, some superficial organs which have increased sensitivity to radiation, receive doses that are significant enough to be matter of concern. Therefore, in this study, the effects of using shields on the amount of dose reduction and image quality was investigated for pediatric imaging. Absorbed doses of breasts, eyes, thyroid and testes of a series of pediatric phantoms without and with different thickness of bismuth and lead were calculated by Monte Carlo simulation. Appropriate thicknesses of shields were chosen based on their weights, X-ray spectrum, and the amount of dose reduction. In addition, the effect of lead shield on image quality of a simple phantom was assessed quantitatively using region of interest (ROI measurements. Considering the maximum reduction in absorbed doses and X-ray spectrum, using a lead shield with a maximum thickness of 0.4 mm would be appropriate for testes and thyroid and two other organs (which are exposed directly should be protected with thinner shields. Moreover, the image quality assessment showed that lead was associated with significant increases in both noise and CT attenuation values, especially in the anterior of the phantom. Overall, the results suggested that shielding is a useful optimization tool in CT.

  2. The cytokinesis-blocked micronucleus assay: dose-response calibration curve, background frequency in the population and dose estimation.

    Science.gov (United States)

    Rastkhah, E; Zakeri, F; Ghoranneviss, M; Rajabpour, M R; Farshidpour, M R; Mianji, F; Bayat, M

    2016-03-01

    An in vitro study of the dose responses of human peripheral blood lymphocytes was conducted with the aim of creating calibrated dose-response curves for biodosimetry measuring up to 4 Gy (0.25-4 Gy) of gamma radiation. The cytokinesis-blocked micronucleus (CBMN) assay was employed to obtain the frequencies of micronuclei (MN) per binucleated cell in blood samples from 16 healthy donors (eight males and eight females) in two age ranges of 20-34 and 35-50 years. The data were used to construct the calibration curves for men and women in two age groups, separately. An increase in micronuclei yield with the dose in a linear-quadratic way was observed in all groups. To verify the applicability of the constructed calibration curve, MN yields were measured in peripheral blood lymphocytes of two real overexposed subjects and three irradiated samples with unknown dose, and the results were compared with dose values obtained from measuring dicentric chromosomes. The comparison of the results obtained by the two techniques indicated a good agreement between dose estimates. The average baseline frequency of MN for the 130 healthy non-exposed donors (77 men and 55 women, 20-60 years old divided into four age groups) ranged from 6 to 21 micronuclei per 1000 binucleated cells. Baseline MN frequencies were higher for women and for the older age group. The results presented in this study point out that the CBMN assay is a reliable, easier and valuable alternative method for biological dosimetry.

  3. Environmental standards for ionizing radiation: theoretical basis for dose-response curves.

    Science.gov (United States)

    Upton, A C

    1983-10-01

    The types of injury attributable to ionizing radiation are subdivided, for purposes of risk assessment and radiological protection, into two broad categories: stochastic effects and nonstochastic effects. Stochastic effects are viewed as probablistic phenomena, varying in frequency but not severity as a function of the dose, without any threshold; nonstochastic effects are viewed as deterministic phenomena, varying in both frequency and severity as a function of the dose, with clinical thresholds. Included among stochastic effects are heritable effects (mutations and chromosome aberrations) and carcinogenic effects. Both types of effects are envisioned as unicellular phenomena which can result from nonlethal injury of individual cells, without the necessity of damage to other cells. For the induction of mutations and chromosome aberrations in the low-to-intermediate dose range, the dose-response curve with high-linear energy transfer (LET) radiation generally conforms to a linear nonthreshold relationship and varies relatively little with the dose rate. In contrast, the curve with low-LET radiation generally conforms to a linear-quadratic relationship, rising less steeply than the curve with high-LET radiation and increasing in slope with increasing dose and dose rate. The dose-response curve for carcinogenic effects varies widely from one type of neoplasm to another in the intermediate-to-high dose range, in part because of differences in the way large doses of radiation can affect the promotion and progression of different neoplasms. Information about dose-response relations for low-level irradiation is fragmentary but consistent, in general, with the hypothesis that the neoplastic transformation may result from mutation, chromosome aberration or genetic recombination in a single susceptible cell.

  4. A strategy to model nonmonotonic dose-response curve and estimate IC50.

    Science.gov (United States)

    Zhang, Hui; Holden-Wiltse, Jeanne; Wang, Jiong; Liang, Hua

    2013-01-01

    The half-maximal inhibitory concentration IC[Formula: see text] is an important pharmacodynamic index of drug effectiveness. To estimate this value, the dose response relationship needs to be established, which is generally achieved by fitting monotonic sigmoidal models. However, recent studies on Human Immunodeficiency Virus (HIV) mutants developing resistance to antiviral drugs show that the dose response curve may not be monotonic. Traditional models can fail for nonmonotonic data and ignore observations that may be of biologic significance. Therefore, we propose a nonparametric model to describe the dose response relationship and fit the curve using local polynomial regression. The nonparametric approach is shown to be promising especially for estimating the IC[Formula: see text] of some HIV inhibitory drugs, in which there is a dose-dependent stimulation of response for mutant strains. This model strategy may be applicable to general pharmacologic, toxicologic, or other biomedical data that exhibits a nonmonotonic dose response relationship for which traditional parametric models fail.

  5. Mutations induced in Tradescantia by small doses of X-rays and neutrons - Analysis of dose-response curves.

    Science.gov (United States)

    Sparrow, A. H.; Underbrink, A. G.; Rossi, H. H.

    1972-01-01

    Dose-response curves for pink somatic mutations in Tradescantia stamen hairs were analyzed after neutron and X-ray irradiation with doses ranging from a fraction of a rad to the region of saturation. The dose-effect relation for neutrons indicates a linear dependence from 0.01 to 8 rads; between 0.25 and 5 rads, a linear dependence is indicated for X-rays also. As a consequence the relative biological effectiveness reaches a constant value (about 50) at low doses. The observations are in good agreement with the predictions of the theory of dual radiation action and support its interpretation of the effects of radiation on higher organisms. The doubling dose of X-rays was found to be nearly 1 rad.

  6. Inter-Relationship between Low-Dose Hyper-Radiosensitivity and Radiation-Induced Bystander Effects in the Human T98G Glioma and the Epithelial HaCaT Cell Line.

    Science.gov (United States)

    Fernandez-Palomo, Cristian; Seymour, Colin; Mothersill, Carmel

    2016-02-01

    Over the past several years, investigations in both low-dose hyper-radiosensitivity and increased radioresistance have been a focus of radiation oncology and biology research, since both conditions occur primarily in tumor cell lines. There has been significant progress in elucidating their signaling pathways, however uncertainties exist when they are studied together with radiation-induced bystander effects. Therefore, the aim of this work was to further investigate this relationship using the T98G glioma and HaCaT cell lines. T98G glioma cells have demonstrated a strong transition from hyper-radiosensitivity to induced radioresistance, and HaCaT cells do not show low-dose hypersensitivity. Both cell lines were paired using a mix-and-match protocol, which involved growing nonirradiated cells in culture media from irradiated cells and covering all possible combinations between them. The end points analyzed were clonogenic cell survival and live calcium measurements through the cellular membrane. Our data demonstrated that T98G cells produced bystander signals that decreased the survival of both reporter T98G and HaCaT cells. The bystander effect occurred only when T98G cells were exposed to doses below 1 Gy, which was corroborated by the induction of calcium fluxes. However, when bystander signals originated from HaCaT cells, the survival fraction increased in reporter T98G cells while it decreased in HaCaT cells. Moreover, the corresponding calcium data showed no calcium fluxes in T98G cells, while HaCaT cells displayed a biphasic calcium profile. In conclusion, our findings indicate a possible link between low-dose hyper-radiosensitivity and bystander effects. This relationship varies depending on which cell line functions as the source of bystander signals. This further suggests that the bystander mechanisms are more complex than previously expected and caution should be taken when extrapolating bystander results across all cell lines and all radiation doses.

  7. [Dose response curve of paclitaxel measured by histoculture drug response assay].

    Science.gov (United States)

    Yoshimasu, Tatsuya; Oura, Shoji; Hirai, Issei; Kokawa, Yozo; Okamura, Yoshitaka; Furukawa, Tomoko

    2005-04-01

    Dose response curves of paclitaxel were measured by histoculture drug response assay (HDRA) in 11 lung cancer patients. Inhibition rates of paclitaxel at several concentrations were measured and fitted to the sigmoid dose response curve, using non-linear least square analysis, with fitting equation y=A (1-1/(1+exp (b (x-log (ED50)). Parameters A, b, and ED50 were 88.3+/-6.0 (80.0-100.0) %, 9.57+/-4.32 (2.25-15.0), and 26.8+/-8.1 (15.0-41.0) microg/ml, respectively. The parameter b was lower in well-differentiated tumors compared with moderately and poorly-differentiated tumors. Dose response curves of paclitaxel could be measured by HDRA in lung cancer. This method provides us more information for drug sensitivity than the usual HDRA method. This may lead to the improved accuracy of HDRA.

  8. Establishment of a Dose-response Curve for X-ray-Induced Micronuclei in Human Lymphocytes.

    Science.gov (United States)

    Lusiyanti, Yanti; Alatas, Zubaidah; Syaifudin, Mukh; Purnami, Sofiati

    2016-01-01

    The cytokinesis-block micronucleus assay in peripheral blood lymphocytes is an established technique for biodosimetry. The aim of this project was to generate a X-ray induced micronuclei (MN) curve for peripheral blood lymphocytes taken from five healthy donors. The blood samples were irradiated with X-rays of 122 KeV at a dose rate of 0.652 Gy/min to doses of 0.5, 1, 2, 3, and 4 Gy. The blood samples were then cultured for 72 h at 37°C and processed following the International Atomic Energy Agency standard procedure with slight modifications. The result showed that the yields of MN frequencies were increased with the increase of radiation dose. Reconstruction of the relationship of MN with dose was fitted to a linear-quadratic model using Chromosome Aberration Calculation Software version 2.0. Due to their advantages, mainly, the dependence on radiation dose and dose rate, despite their limitation, these curves will be useful as alternative method for in vitro dose reconstruction and can support the preparedness for public or occupational radiation overexposure and protection. The results reported here also give us confidence to apply the obtained calibration curve of MN for future biological dosimetry requirements in Indonesia.

  9. Interpreting 'dose-response' curves using homeodynamic data: with an improved explanation for hormesis.

    Science.gov (United States)

    Stebbing, A R D

    2009-04-15

    A re-interpretation of the 'dose-response' curve is given that accommodates homeostasis. The outcome, or overall effect, of toxicity is the consequence of toxicity that is moderated by homeodynamic responses. Equilibrium is achieved by a balance of opposing forces of toxic inhibition countered by a stimulatory response. A graphical model is given consisting of two linked curves (response vs concentration and effect vs concentration), which provide the basis for a re-interpretation of the 'dose-response' curve. The model indicates that such relationships are non-linear with a threshold, which is due to homeodynamic responses. Subthreshold concentrations in 'dose-response' curves provide the sum of toxic inhibition minus the homeodynamic response; the response itself is unseen in serving its purpose of neutralizing perturbation. This interpretation suggests why the alpha- and beta-curves are non-linear. The beta-curve indicates adaptive overcorrection to toxicity that confers greater resistance to subsequent toxic exposure, with hormesis as an epiphenomenon.

  10. Pulsed-dose-rate and low-dose-rate brachytherapy : Comparison of sparing effects in cells of a radiosensitive and a radioresistant cell line

    NARCIS (Netherlands)

    Pomp, J; Woudstra, EC; Kampinga, HH

    Pulsed-dose-rate regimens are an attractive alternative to continuous low-dose-rate brachytherapy. However, apart from data obtained from modeling, only a few irt vitro results are available for comparing the biological effectiveness of both modalities. Cells of two human cell lines with survival

  11. A Strategy to Model Nonmonotonic Dose-Response Curve and Estimate IC50

    OpenAIRE

    Hui Zhang; Jeanne Holden-Wiltse; Jiong Wang; Hua Liang

    2013-01-01

    The half-maximal inhibitory concentration IC[Formula: see text] is an important pharmacodynamic index of drug effectiveness. To estimate this value, the dose response relationship needs to be established, which is generally achieved by fitting monotonic sigmoidal models. However, recent studies on Human Immunodeficiency Virus (HIV) mutants developing resistance to antiviral drugs show that the dose response curve may not be monotonic. Traditional models can fail for nonmonotonic data and igno...

  12. Resveratrol enhances the radiosensitivity of nasopharyngeal carcinoma cells by downregulating E2F1.

    Science.gov (United States)

    Tan, Yuhui; Wei, Xianli; Zhang, Wenyin; Wang, Xiaolan; Wang, Kun; Du, Biaoyan; Xiao, Jianyong

    2017-03-01

    Identification of safe, effective radiosensitizing agents is urgently needed to improve the outcome of radiotherapy in nasopharyngeal cancer (NPC). In this study, we assessed the ability of the polyphenol resveratrol to act as a radiosensitizer in vitro and in vivo. CNE-1 cells were treated with 50 µM resveratrol for 24 h, then irradiated. E2F transcription factor 1 (E2F1) was stably knocked down and overexpressed using lentiviruses. A xenograft model of NPC was established in nude mice using CNE-1 cells. Compared to control DMSO‑treated CNE-1 cells, resveratrol inhibited colony-forming ability and induced G1 phase cell cycle arrest. Radiation survival curves confirmed resveratrol significantly sensitized CNE-1 cells, and resveratrol in combination with 2 Gy irradiation synergistically increased apoptosis. Immunoblotting showed resveratrol dose- and time-dependently downregulated E2F1 and phospho-AKT (p-AKT). Knockdown of E2F1 significantly increased radiosensitivity and downregulated p-AKT; overexpression of E2F1 reversed resveratrol-induced radiosensitivity and upregulated p-AKT. In vivo, 50 mg/kg/day resveratrol and 4 Gy irradiation led to significantly lower tumor volume and tumor weight compared to resveratrol or irradiation alone. Our findings show that resveratrol increases the radiosensitivity of NPC cells by downregulating E2F1 and inhibiting p-AKT, and therefore has potential as a radiosensitizer for NPC.

  13. 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)

  14. Fundamental investigations of natural and laboratory generated SAR dose response curves for quartz OSL in the high dose range

    DEFF Research Database (Denmark)

    Timar-Gabor, Alida; Constantin, Daniela; Buylaert, Jan-Pieter

    2015-01-01

    SAR-OSL investigations on quartz from Romanian loess resulted in non concordant fine and coarse-grain ages for equivalent doses higher than ~100 Gy. The laboratory dose response for both grain sizes is well represented by a sum of two saturating exponential functions, fine and coarse grains chara...... equivalent dose of 2000e2500 Gy were found to be below the saturation level of the laboratory dose response curve for both grain sizes; this also applied to the luminescence signals measured after >5000 Gy given on top of natural doses. © 2015 Elsevier Ltd. All rights reserved....... characterised by D01 and D02 values of ~140 and ~1400 Gy and ~65 and ~650 Gy respectively. Pulsed OSL experiments confirmed that this behaviour is almost certainly inherent to quartz and not caused by contamination with another mineral. Natural doseeresponse curves do not follow the same pattern and enter...... saturation much earlier. Analysis of time resolved spectra indicated similar luminescence lifetimes for both fine and coarse quartz grains, and natural and laboratory generated OSL signals seem to use the same non-dosedependent recombination pathways. The natural signals of a sample with an expected...

  15. Dose-response curve to salbutamol during acute and chronic treatment with formoterol in COPD

    Directory of Open Access Journals (Sweden)

    La Piana GE

    2011-07-01

    Full Text Available Giuseppe Emanuele La Piana¹, Luciano Corda², Enrica Bertella¹, Luigi Taranto Montemurro¹, Laura Pini¹, Claudio Tantucci¹¹Cattedra di Malattie dell'Apparato Respiratorio, Università di Brescia, ²Prima Divisione di Medicina Interna, Spedali Civili, Brescia, ItalyBackground: Use of short-acting ß2-agonists in chronic obstructive pulmonary disease (COPD during treatment with long-acting ß2-agonists is recommended as needed, but its effectiveness is unclear. The purpose of this study was to assess the additional bronchodilating effect of increasing doses of salbutamol during acute and chronic treatment with formoterol in patients with COPD.Methods: Ten patients with COPD underwent a dose-response curve to salbutamol (until 800 µg of cumulative dose after a 1-week washout (baseline, 8 hours after the first administration of formoterol 12 µg (day 1, and after a 12-week and 24-week period of treatment with formoterol (12 µg twice daily by dry powder inhaler. Peak expiratory flow, forced expiratory volume in one second (FEV1, forced vital capacity, and inspiratory capacity were measured at the different periods of treatment and at different steps of the dose-response curve.Results: Despite acute or chronic administration of formoterol, maximal values of peak expiratory flow, FEV1, and forced vital capacity after 800 µg of salbutamol were unchanged compared with baseline. The baseline FEV1 dose-response curve was steeper than that at day 1, week 12, or week 24 (P < 0.0001. Within each dose-response curve, FEV1 was different only at baseline and at day 1 (P < 0.001, when FEV1 was still greater at 800 µg than at 0 µg (P < 0.02. In contrast, the forced vital capacity dose-response curves were similar at the different periods, while within each dose-response curve, forced vital capacity was different in all instances (P < 0.001, always being higher at 800 µg than at 0 µg (P < 0.05.Conclusion: In patients with stable COPD, the maximal effect

  16. Mixed-effects Gaussian process functional regression models with application to dose-response curve prediction.

    Science.gov (United States)

    Shi, J Q; Wang, B; Will, E J; West, R M

    2012-11-20

    We propose a new semiparametric model for functional regression analysis, combining a parametric mixed-effects model with a nonparametric Gaussian process regression model, namely a mixed-effects Gaussian process functional regression model. The parametric component can provide explanatory information between the response and the covariates, whereas the nonparametric component can add nonlinearity. We can model the mean and covariance structures simultaneously, combining the information borrowed from other subjects with the information collected from each individual subject. We apply the model to dose-response curves that describe changes in the responses of subjects for differing levels of the dose of a drug or agent and have a wide application in many areas. We illustrate the method for the management of renal anaemia. An individual dose-response curve is improved when more information is included by this mechanism from the subject/patient over time, enabling a patient-specific treatment regime.

  17. Quantitative structure-activity relationships of selected phenols with non-monotonic dose-response curves

    Institute of Scientific and Technical Information of China (English)

    GAO ChangAn; ZHANG AiQian; LIN Yuan; YIN DaQiang; WANG LianSheng

    2009-01-01

    Particular non-monotonic dose-response curves of many endocrine disrupting chemicals (EDCs) suggest the existence of diverse toxicity mechanisms at different dose levels. As a result, the biologi-cal activities of EDCs cannot be simply exhibited by unique EC/LD<,50. values, and the quantitative structure-activity relationship (QSAR) analysis for non-monotonic dose-response relationship be-comes an unknown field in the environmental science. In this paper, nine phenols with inverted U-shaped dose-response curves in lymphocyte proliferation test of Carassius auratus were selected. The binding interactions between the phenols and several typical EDCs-related receptors were then explored in a molecular simulation study. The estrogen receptor (ER), androgen receptor (AR), thyroid hormone receptor (TR), bacterial O2 sensing FixL protein (FixL), aryl hydrocarbon receptor (AhR), and the peroxisome proliferator-activated receptor (PPAR) were the target receptors in the study. Linear regression QSAR models for the low and high exposure levels of the compounds were developed separately. The results indicated that the lymphocyte proliferation in the low-dose range might involve ER-mediated process, while the proliferation inhibition in the high dose range was dominated by the acute toxicity of phenols due to receptor occupancy and cell damage.

  18. Radiosensitivity of cultured insect cells: I. Lepidoptera

    Energy Technology Data Exchange (ETDEWEB)

    Koval, T.M.

    1983-10-01

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

  19. Modeling and regression analysis of semiochemical dose-response curves of insect antennal reception and behavior.

    Science.gov (United States)

    Byers, John A

    2013-08-01

    Dose-response curves of the effects of semiochemicals on neurophysiology and behavior are reported in many articles in insect chemical ecology. Most curves are shown in figures representing points connected by straight lines, in which the x-axis has order of magnitude increases in dosage vs. responses on the y-axis. The lack of regression curves indicates that the nature of the dose-response relationship is not well understood. Thus, a computer model was developed to simulate a flux of various numbers of pheromone molecules (10(3) to 5 × 10(6)) passing by 10(4) receptors distributed among 10(6) positions along an insect antenna. Each receptor was depolarized by at least one strike by a molecule, and subsequent strikes had no additional effect. The simulations showed that with an increase in pheromone release rate, the antennal response would increase in a convex fashion and not in a logarithmic relation as suggested previously. Non-linear regression showed that a family of kinetic formation functions fit the simulated data nearly perfectly (R(2) >0.999). This is reasonable because olfactory receptors have proteins that bind to the pheromone molecule and are expected to exhibit enzyme kinetics. Over 90 dose-response relationships reported in the literature of electroantennographic and behavioral bioassays in the laboratory and field were analyzed by the logarithmic and kinetic formation functions. This analysis showed that in 95% of the cases, the kinetic functions explained the relationships better than the logarithmic (mean of about 20% better). The kinetic curves become sigmoid when graphed on a log scale on the x-axis. Dose-catch relationships in the field are similar to dose-EAR (effective attraction radius, in which a spherical radius indicates the trapping effect of a lure) and the circular EARc in two dimensions used in mass trapping models. The use of kinetic formation functions for dose-response curves of attractants, and kinetic decay curves for

  20. DOSE RESPONSE CURVE OF 60Co FOR PREMATURE CONDENSED CHROMOSOME FRAGMENTS OF HUMAN LYMPHOCYTES

    Institute of Scientific and Technical Information of China (English)

    高锦声; 郑斯英; 等

    1995-01-01

    The dose-response curves obtained by premature condensed chromosome(PCC) and conventional cellular genetic methods can be represented by two linear equations.The ratio of the slopes,KPCC/KM1,is about 28,In compartison to the conventional method.The PCC method has many advantages;e.g.it is faster,simopler,more sensitive and accurate.Its significance in the study of radiation damage is also discussed.

  1. Bayesian fitting of a logistic dose-response curve with numerically derived priors.

    Science.gov (United States)

    Huson, L W; Kinnersley, N

    2009-01-01

    In this report we describe the Bayesian analysis of a logistic dose-response curve in a Phase I study, and we present two simple and intuitive numerical approaches to construction of prior probability distributions for the model parameters. We combine these priors with the expert prior opinion and compare the results of the analyses with those obtained from the use of alternative prior formulations.

  2. Linearization of dose-response curve of the radiochromic film dosimetry system

    Energy Technology Data Exchange (ETDEWEB)

    Devic, Slobodan; Tomic, Nada; Aldelaijan, Saad; DeBlois, Francois; Seuntjens, Jan; Chan, Maria F.; Lewis, Dave [Medical Physics Unit, McGill University, Montreal, Quebec H3G 1A4 (Canada) and Department of Radiation Oncology, SMBD Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2 (Canada); Executive Administration for Radiation Protection and Safety Medical Devices Sector, Saudi Food and Drug Authority, Riyadh, Kingdom of Saudi Arabia 13312 (Saudi Arabia); Medical Physics Unit, McGill University, Montreal, Quebec H3G 1A4 (Canada) and Department of Radiation Oncology, SMBD Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2 (Canada); Medical Physics Unit, McGill University, Montreal, Quebec H3G 1A4 (Canada); Department of Medical Physics, Memorial Sloan-Kettering Cancer Center Basking Ridge, New Jersey 07920 (United States); Ashland Inc., Wayne, New Jersey 07470 (United States)

    2012-08-15

    Purpose: Despite numerous advantages of radiochromic film dosimeter (high spatial resolution, near tissue equivalence, low energy dependence) to measure a relative dose distribution with film, one needs to first measure an absolute dose (following previously established reference dosimetry protocol) and then convert measured absolute dose values into relative doses. In this work, we present result of our efforts to obtain a functional form that would linearize the inherently nonlinear dose-response curve of the radiochromic film dosimetry system. Methods: Functional form [{zeta}= (-1){center_dot}netOD{sup (2/3)}/ln(netOD)] was derived from calibration curves of various previously established radiochromic film dosimetry systems. In order to test the invariance of the proposed functional form with respect to the film model used we tested it with three different GAFCHROMIC Trade-Mark-Sign film models (EBT, EBT2, and EBT3) irradiated to various doses and scanned on a same scanner. For one of the film models (EBT2), we tested the invariance of the functional form to the scanner model used by scanning irradiated film pieces with three different flatbed scanner models (Epson V700, 1680, and 10000XL). To test our hypothesis that the proposed functional argument linearizes the response of the radiochromic film dosimetry system, verification tests have been performed in clinical applications: percent depth dose measurements, IMRT quality assurance (QA), and brachytherapy QA. Results: Obtained R{sup 2} values indicate that the choice of the functional form of the new argument appropriately linearizes the dose response of the radiochromic film dosimetry system we used. The linear behavior was insensitive to both film model and flatbed scanner model used. Measured PDD values using the green channel response of the GAFCHROMIC Trade-Mark-Sign EBT3 film model are well within {+-}2% window of the local relative dose value when compared to the tabulated Cobalt-60 data. It was also

  3. Melatonin entrains free-running blind people according to a physiological dose-response curve.

    Science.gov (United States)

    Lewy, Alfred J; Emens, Jonathan S; Lefler, Bryan J; Yuhas, Krista; Jackman, Angela R

    2005-01-01

    The specific circadian role proposed for endogenous melatonin production was based on a study of sighted people who took low pharmacological doses (500 microg) of this chemical signal for the "biological night": the magnitude and direction of the induced phase shifts were dependent on what time of day exogenous melatonin was administered and were described by a phase-response curve that turned out to be the opposite of that for light. We now report that lower (physiological) doses of up to 300 microg can entrain (synchronize) free-running circadian rhythms of 10 totally blind subjects that would otherwise drift later each day. The resulting log-linear dose-response curve in the physiological range adds support for a circadian function of endogenous melatonin in humans. Efficacy of exogenous doses in the physiological range are of clinical significance for totally blind people who will need to take melatonin daily over their entire lifetimes in order to remain entrained to the 24 h day. Left untreated, their free-running endocrine, metabolic, behavioral, and sleep/wake cycles can be almost as burdensome as not having vision.

  4. Clinical application of Chamomilla recutita in phlebitis: dose response curve study.

    Science.gov (United States)

    Reis, Paula Elaine Diniz Dos; Carvalho, Emilia Campos de; Bueno, Paula Carolina Pires; Bastos, Jairo Kenupp

    2011-01-01

    This experimental and dose-response curve study aimed to carry out the quality control of the Chamomilla recutita sample, as well as to estimate the ideal dose, for anti-inflammatory effect, of the extract of its capitula, in patients with phlebitis due to peripheral intravenous infusion of antineoplastic chemotherapy and to evaluate the toxicity of this extract in human beings. The therapeutic efficacy, concerning the anti-inflammatory potential, of different doses of Chamomilla recutita extract were analyzed and compared in 25 patients. The time of regression of phlebitis was shorter for groups with 2.5% concentration (mean=29.2h, standard deviation = 8.98) and 5% concentration (mean = 38.8h, standard deviation = 17.47). Local toxicity was almost not observed. This research contributes to the innovation of the nursing clinical practice, since it suggests an alternative for the treatment of phlebitis through the clinical use of phytotherapeutic drugs.

  5. Clinical evaluation of misonidazole for radiosensitizing effects

    Energy Technology Data Exchange (ETDEWEB)

    Mitsuhashi, Norio; Yonome, Ichiro; Niibe, Hideo (Gunma Univ., Maebashi (Japan). School of Medicine)

    1984-07-01

    Gunma Misonidazole Study Group has conducted an open clinical study to evaluate the radiosensitizing effects of misonidazole. Among the patients entered in this study, there were 119 patients with various local advanced or local recurrent radioresistant tumors. Of these, 29 patients had pulmonary cancer, 19 patients had glioblastoma, 10 patients had metastatic brain tumor, 31 patients had head and neck tumor, 16 patients had esophageal cancer and 14 patients had various other tumors. They were analyzed as to safety, effects on general condition besides radiosensitizing effects of misonidazole. The fractionation most often used was 1000 rad a week and a small dose of mis onidazole was given orally 4 hours before irradiation on treatment day s. The maximum total dose of misonidazole was 10 g/m/sup 2/. The plasma concentration of misonidazole was measured immediately before treatment. The mean value of plasma levels was 20.05 ..mu..g/ml. Accumulation of misonidazole in plasma was observed after its continuous administration. No severe irreversible neurotoxicites of misonidazole were observed, though 2 patients developed central nervous disorders and another 2 developed peripheral neuropathies. Radiosensitizing effect of misonidazole was not observed in 28% of the patients. But in the remaining 72%, there was a possibility of positive radiosensitizing effects of misonidazole. Prognosis was favarable in the patients with head and neck tumors on whom radiosensitizing effects of misonidazole were observed. Misonidazole had effects on initial tumor response to the treatment of pulmonary cancer, esophageal cancer and glioblastoma. Misonidazole is considered to be usefl cl inically, if it is combined with radiotherapy in the treatment of tumors that histologically have a great deal of anoxic components. But it should be emphasized that the development of more effective and less toxic radiosensitizer is necessary in clinical use.

  6. Quantitative aspects of informed consent: considering the dose response curve when estimating quantity of information.

    Science.gov (United States)

    Lynöe, N; Hoeyer, K

    2005-12-01

    Information is usually supposed to be a prerequisite for people making decisions on whether or not to participate in a clinical trial. Previously conducted studies and research ethics scandals indicate that participants have sometimes lacked important pieces of information. Over the past few decades the quantity of information believed to be adequate has increased significantly, and in some instances a new maxim seems to be in place: the more information, the better the ethics in terms of respecting a participant's autonomy. The authors hypothesise that the dose-response curve from pharmacology or toxicology serves as a model to illustrate that a large amount of written information does not equal optimality. Using the curve as a pedagogical analogy when teaching ethics to students in clinical sciences, and also in engaging in dialogue with research institutions, may promote reflection on how to adjust information in relation to the preferences of individual participants, thereby transgressing the maxim that more information means better ethics.

  7. Dose-response curve of a microfluidic magnetic bead-based surface coverage sandwich assay.

    Science.gov (United States)

    Cornaglia, Matteo; Trouillon, Raphaël; Tekin, H Cumhur; Lehnert, Thomas; Gijs, Martin A M

    2015-09-25

    Magnetic micro- and nanoparticles ('magnetic beads') have been used to advantage in many microfluidic devices for sensitive antigen (Ag) detection. Today, assays that use as read-out of the signal the number count of immobilized beads on a surface for quantification of a sample's analyte concentration have been among the most sensitive and have allowed protein detection lower than the fgmL(-1) concentration range. Recently, we have proposed in this category a magnetic bead surface coverage assay (Tekin et al., 2013 [1]), in which 'large' (2.8μm) antibody (Ab)-functionalized magnetic beads captured their Ag from a serum and these Ag-carrying beads were subsequently exposed to a surface pattern of fixed 'small' (1.0μm) Ab-coated magnetic beads. When the system was exposed to a magnetic induction field, the magnet dipole attractive interactions between the two bead types were used as a handle to approach both bead surfaces and assist with Ag-Ab immunocomplex formation, while unspecific binding (in absence of an Ag) of a large bead was reduced by exploiting viscous drag flow. The dose-response curve of this type of assay had two remarkable features: (i) its ability to detect an output signal (i.e. bead number count) for very low Ag concentrations, and (ii) an output signal of the assay that was non-linear with respect to Ag concentration. We explain here the observed dose-response curves and show that the type of interactions and the concept of our assay are in favour of detecting the lowest analyte concentrations (where typically either zero or one Ag is carried per large bead), while higher concentrations are less efficiently detected. We propose a random walk process for the Ag-carrying bead over the magnetic landscape of small beads and this model description explains the enhanced overall capture probability of this assay and its particular non-linear dose response curves.

  8. A Theoretical Model for the Hormetic Dose-response Curve for Anticancer Agents.

    Science.gov (United States)

    Yoshimasu, Tatsuya; Ohashi, Takuya; Oura, Shoji; Kokawa, Yozo; Kawago, Mitsumasa; Hirai, Yoshimitsu; Miyasaka, Miwako; Nishiguchi, Haruka; Kawashima, Sayoko; Yata, Yumi; Honda, Mariko; Fujimoto, Takahiro; Okamura, Yoshitaka

    2015-11-01

    In the present article, we quantitatively evaluated the dose-response relationship of hormetic reactions of anticancer agents in vitro. Serial dilutions of gemcitabine, cisplatin, 5-fluorouracil, vinorelbine, and paclitaxel were administered to the A549 non-small-cell lung cancer cell line. The bi-phasic sigmoidal curve with hormetic and cytotoxic effects is given by the formula y=(a-b/(1+exp(c(*)log(x)-d)))/(1+exp(e(*)log(x)-f)), that was used to perform a non-linear least square regression. The dose-responses of the five anticancer agents were fitted to this equation. Gemcitabine and 5-fluorouracil, which had the lowest ED50 for their hormetic reaction, had the most pronounced promotive effects out of the five anticancer agents tested. The hormetic reaction progressed exponentially with culturing time. Our theoretical model will be useful in predicting how hormetic reactions affect patients with malignant tumors.

  9. Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve.

    Science.gov (United States)

    Celik, Ilhan; Sürücü, Oguzkan; Dietz, Carsten; Heymach, John V; Force, Jeremy; Höschele, Iris; Becker, Christian M; Folkman, Judah; Kisker, Oliver

    2005-12-01

    We show here that recombinant endostatin protein has a biphasic effect on the inhibition of endothelial cell migration in vitro. In tumor-bearing animals, there is a similar biphasic effect on the inhibition of tumor growth and on circulating endothelial cells after once-daily s.c. injections. This biphasic effect is revealed as a U-shaped curve in which efficacy is optimal between very low and very high doses depending on the tumor type. This result may be applicable to other inhibitors of endothelial growth and to angiogenesis. Furthermore, these results have important implications for clinicians who administer angiogenesis inhibitors for cancer or other angiogenesis-dependent diseases. When these results are taken together with two previous reports of angiogenesis inhibitors with a U-shaped dose-response, they suggest that other regulators of endothelial growth may display a similar pattern.

  10. Influence of lung parenchymal destruction on the different indexes of the methacholine dose-response curve in COPD patients

    NARCIS (Netherlands)

    G.T. Verhoeven; A.F.M. Verbraak (Anton); S. Boere-van der Straat; H.C. Hoogsteden (Henk); J.M. Bogaard (Jan)

    2000-01-01

    textabstractSTUDY OBJECTIVES: The interpretation of nonspecific bronchial provocation dose-response curves in COPD is still a matter of debate. Bronchial hyperresponsiveness (BHR) in patients with COPD could be influenced by the destruction of the parenchyma and the

  11. Cytogenetics dosimetry: dose-response curve for low doses of X-ray; Dosimetria citogenetica: curva dosis-respuesta para bajas dosis de rayos-X

    Energy Technology Data Exchange (ETDEWEB)

    Lara, Virginia E. Noval; Pineda Bolivar, William R.; Riano, Victor M. Pabon, E-mail: venovall.15@hotmail.com, E-mail: wrpineda@misena.edu.co, E-mail: vmpabonr@udistrital.edu.co [Universidad Distrital Francisco Jose de Caldas (UD), Bogota (Colombia). Grupo de Investigacion en Ciencia y Tecnologia Nuclear; Ureana, Cecilia Crane, E-mail: cecicrane@yahoo.com [Instituto Nacional de Salud (INS), Bogota (Colombia). Laboratorio de Genetica

    2013-07-01

    The purpose of this study was to conduct a preliminary study for the standardization in the future, the dose-response curve for low doses of X-rays, through the analysis of in vitro cultures of peripheral blood samples of 3 men and 3 women occupationally not exposed to artificial sources of ionizing radiation, age 18-40 years, where possible nonsmokers.

  12. Quality control procedures for dose-response curve generation using nanoliter dispense technologies.

    Science.gov (United States)

    Quintero, Catherine; Rosenstein, Craig; Hughes, Bethany; Middleton, Richard; Kariv, Ilona

    2007-09-01

    With the advancement of high-throughput biomolecular screening techniques to the lead optimization stage, there is a critical need to quality control (QC) dose-response curves generated by robotic liquid handlers to ensure accurate affinity determinations. One challenge in evaluating the performance of liquid handlers is identifying and validating a robust method for testing dispense volumes across different instruments. Although traditional automated liquid handlers are still considered the standard platform in many laboratories, nanoliter dispensers are becoming more common and pose new challenges for routine quality control procedures. For example, standard gravimetric measurements are unreliable for testing the accuracy of nanoliter liquid dispenses. However, nanoliter dispensing technology allows for the conservation of compound, reduces compound carryover from well to well through discrete dispenses, and eliminates the need for intermediate compound dilution steps to achieve a low final DMSO assay concentration. Moreover, an intermediate dilution step in aqueous solution might result in compound precipitation at high concentrations. This study compared representative automation procedures done on a variety of liquid dispensers, including manual, traditional, and nanodispense volumes. The data confirmed the importance of establishing robust QC procedures for dose-response generation in addition to accuracy and precision determinations for each instrument, and they validated the use of nanoliter pipettors for dose-response testing. The results of this study also support the requirement for thorough mixing during serial compound dilutions prepared for high-throughput lead optimization strategies using traditional liquid handlers.

  13. Radiosensitivity of toxigenic Aspergillus isolated from spices and destruction of aflatoxins by gamma-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Kume, Tamikazu; Ito, Hitoshi; Ishigaki, Isao (Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment); Soedarman, Harsono (National Atomic Energy Agency, Jakarta (Indonesia). Centre for the Application of Isotopes and Radiation)

    1989-01-01

    Radiosensitivities of Aspergillus flavus var columnaris isolated from spices were investigated. The D{sub 10} values and induction doses were 267-293 Gy and 75-165 Gy in wet conditions, respectively. In dry conditions, the survival curves were exponential and D{sub 10} values were 538-600 Gy. The survival curves of standard strain of A. parasiticus IFO 30179 were similar both in wet and dry conditions. The necessary dose of 8 kGy for the destruction of these toxigenic Aspergillus was calculated from these values. Two of 11 strains of A. flavus var columnaris produced aflatoxins and the content of B{sub 1} was especially high. In the study of irradiation effect on aflatoxins produced on polished rice, aflatoxins G{sub 1} and B{sub 1} were more radiosensitive than G{sub 2} and B{sub 2}. However, these aflatoxins were very stable to radiation and the dose required for destruction was found to be more than 500 kGy. It is therefore concluded that the decontamination of molds by irradiation is necessary prior to their production of aflatoxins.

  14. Radiosensitivity of toxigenic Aspergillus isolated from spices and destruction of aflatoxins by gamma-irradiation

    Science.gov (United States)

    Kume, Tamikazu; Ito, Hitoshi; Soedarman, Harsono; Ishigaki, Isao

    Radiosensitivities of Aspergillus flavus var columnaris isolated from spices were investigated. The D10 values and induction doses were 267-293 Gy and 75-165 Gy in wet conditions, respectively. In dry conditions, the survival curves were exponential and D10 values were 538-600 Gy. The survival curves of standard strain of A. parasiticus IFO 30179 were similar both in wet and dry conditions. The necessary dose of 8 kGy for the destruction of these toxigenic Aspergillus was calculated from these values. Two of 11 strains of A. flavus var columnaris produced aflatoxins and the content of B 1 was especially high. In the study of irradiation effect on aflatoxins produced on polished rice, aflatoxins G 1 and B 1 were more radiosensitive than G 2 and B 2. However, these aflatoxins were very stable to radiation and the dose required for destruction was found to be more than 500 kGy. It is therfore concluded that the decontamination of molds by irradiation is necessary prior to their production of aflatoxins.

  15. 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.

  16. A method for inverse bifurcation of biochemical switches: inferring parameters from dose response curves.

    Science.gov (United States)

    Otero-Muras, Irene; Yordanov, Pencho; Stelling, Joerg

    2014-11-20

    Within cells, stimuli are transduced into cell responses by complex networks of biochemical reactions. In many cell decision processes the underlying networks behave as bistable switches, converting graded stimuli or inputs into all or none cell responses. Observing how systems respond to different perturbations, insight can be gained into the underlying molecular mechanisms by developing mathematical models. Emergent properties of systems, like bistability, can be exploited to this purpose. One of the main challenges in modeling intracellular processes, from signaling pathways to gene regulatory networks, is to deal with high structural and parametric uncertainty, due to the complexity of the systems and the difficulty to obtain experimental measurements. Formal methods that exploit structural properties of networks for parameter estimation can help to overcome these problems. We here propose a novel method to infer the kinetic parameters of bistable biochemical network models. Bistable systems typically show hysteretic dose response curves, in which the so called bifurcation points can be located experimentally. We exploit the fact that, at the bifurcation points, a condition for multistationarity derived in the context of the Chemical Reaction Network Theory must be fulfilled. Chemical Reaction Network Theory has attracted attention from the (systems) biology community since it connects the structure of biochemical reaction networks to qualitative properties of the corresponding model of ordinary differential equations. The inverse bifurcation method developed here allows determining the parameters that produce the expected behavior of the dose response curves and, in particular, the observed location of the bifurcation points given by experimental data. Our inverse bifurcation method exploits inherent structural properties of bistable switches in order to estimate kinetic parameters of bistable biochemical networks, opening a promising route for developments in

  17. Mathematical modeling improves EC50 estimations from classical dose-response curves.

    Science.gov (United States)

    Nyman, Elin; Lindgren, Isa; Lövfors, William; Lundengård, Karin; Cervin, Ida; Sjöström, Theresia Arbring; Altimiras, Jordi; Cedersund, Gunnar

    2015-03-01

    The β-adrenergic response is impaired in failing hearts. When studying β-adrenergic function in vitro, the half-maximal effective concentration (EC50 ) is an important measure of ligand response. We previously measured the in vitro contraction force response of chicken heart tissue to increasing concentrations of adrenaline, and observed a decreasing response at high concentrations. The classical interpretation of such data is to assume a maximal response before the decrease, and to fit a sigmoid curve to the remaining data to determine EC50 . Instead, we have applied a mathematical modeling approach to interpret the full dose-response curve in a new way. The developed model predicts a non-steady-state caused by a short resting time between increased concentrations of agonist, which affect the dose-response characterization. Therefore, an improved estimate of EC50 may be calculated using steady-state simulations of the model. The model-based estimation of EC50 is further refined using additional time-resolved data to decrease the uncertainty of the prediction. The resulting model-based EC50 (180-525 nm) is higher than the classically interpreted EC50 (46-191 nm). Mathematical modeling thus makes it possible to re-interpret previously obtained datasets, and to make accurate estimates of EC50 even when steady-state measurements are not experimentally feasible. The mathematical models described here have been submitted to the JWS Online Cellular Systems Modelling Database, and may be accessed at http://jjj.bio.vu.nl/database/nyman. © 2015 FEBS.

  18. Radiosensitivity of cultured human and mouse keratinocytes

    Energy Technology Data Exchange (ETDEWEB)

    Parkinson, E.K.; Hume, W.J.; Potten, C.S.

    1986-10-01

    Clonogenic survival assays after ..gamma..-radiation in vitro were performed on freshly isolated and subcultured keratinocytes from mouse skin, mouse tongue and human skin. Survival curves were constructed by fitting the data to a multi-target model of cell survival. When subcultured, keratinocytes from all sites produced survival curves which showed a reduced shoulder region and an increased D/sub 0/ when compared with their freshly isolated counterparts. Freshly isolated human skin keratinocytes were more radiosensitive than mouse keratinocytes from either skin or tongue.

  19. Heavy particle irradiation, neurochemistry and behavior: thresholds, dose-response curves and recovery of function

    Science.gov (United States)

    Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

    2004-01-01

    Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation-induced disruption of dopaminergic function affects a variety of behaviors that are dependent upon the integrity of this system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current report reviews the data relevant to the degree to which these characteristics are common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity.

  20. Heavy particle irradiation, neurochemistry and behavior: thresholds, dose-response curves and recovery of function

    Science.gov (United States)

    Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

    2004-01-01

    Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation-induced disruption of dopaminergic function affects a variety of behaviors that are dependent upon the integrity of this system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current report reviews the data relevant to the degree to which these characteristics are common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity. c2004 COSPAR. Published by Elsevier Ltd. All rights reserved.

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

    Institute of Scientific and Technical Information of China (English)

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

    2006-01-01

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

  2. [Prostate cancer boost using high-dose-rate brachytherapy: impact of the learning curve on the dosimetry].

    Science.gov (United States)

    Benhaïm, C; Chand, M-È; Gal, J; Hijazi, H; Gautier, M; Hannoun-Lévi, J-M

    2014-11-01

    To analyse the influence of the learning curve on dosimetric data for high-dose-rate brachytherapy prostate cancer boost. From February 2009 to May 2012, after a first course of external beam radiation therapy (46Gy/23 fractions), 124 patients underwent high-dose-rate brachytherapy boost using Plato™ (Nucletron, an Elekta company, Elekta AB, Stockholm, Sweden). The impact of the learning curve on the dosimetric quality of the prostate implant was assessed. The dosimetric data have been analysed: clinical target volume (CTV), D90 (dose to 90 % of CTV), D100, V100 (part on the CTV receiving 100 % of the dose), V150, V200 and DHI (dose non-homogeneity index). The doses delivered to 0.1, 1 and 2 cm(3) of the rectum and urethra were calculated. During the study period (39 months), a significant reduction of V150 (PD100 (P=0.3). This study confirms that the dosimetric quality of high-dose-rate brachytherapy prostate implant is significantly improved during the learning curve period. Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1980-07-01

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

  4. Dose-response curve slope helps predict therapeutic potency and breadth of HIV broadly neutralizing antibodies.

    Science.gov (United States)

    Webb, Nicholas E; Montefiori, David C; Lee, Benhur

    2015-09-29

    A new generation of HIV broadly neutralizing antibodies (bnAbs) with remarkable potency, breadth and epitope diversity has rejuvenated interest in immunotherapeutic strategies. Potencies defined by in vitro IC50 and IC80 values (50 and 80% inhibitory concentrations) figure prominently into the selection of clinical candidates; however, much higher therapeutic levels will be required to reduce multiple logs of virus and impede escape. Here we predict bnAb potency at therapeutic levels by analysing dose-response curve slopes, and show that slope is independent of IC50/IC80 and specifically relates to bnAb epitope class. With few exceptions, CD4-binding site and V3-glycan bnAbs exhibit slopes >1, indicative of higher expected therapeutic effectiveness, whereas V2-glycan, gp41 membrane-proximal external region (MPER) and gp120-gp41 bnAbs exhibit less favourable slopes <1. Our results indicate that slope is one major predictor of both potency and breadth for bnAbs at clinically relevant concentrations, and may better coordinate the relationship between bnAb epitope structure and therapeutic expectations.

  5. QSAR study on the non-monotonic dose-response curve of PCBs in chicken embryo hepatocyte bioassay

    Institute of Scientific and Technical Information of China (English)

    MU YunSong; ZHANG AiQian; GAO ChangAn; PENG SuFen; WANG LianSheng

    2009-01-01

    Endocrine disrupting chemicals (EDCs) in the natural environment exhibit a unique non-monotonic dose-response curve and it is impossible to select one simple index to characterize the bilogogical activity of these compounds. Quantitative structure-activity relationship (QSAR) study on non-monotonic dose-response curve has become a real challenge presently. In order to explore the possible mechanism for the non-monotonic dose-response curve of polychlorinated biphenyls con-geners (PCBs) in chicken embryo hepatocyte bioassay, AM1 method of ChemOffice was adopted to calculate necessary structure descriptors for PCBs, while the interactions between PCBs and simulated AhR ligand binding domain (LBD) were analyzed by using FlexX in SYBYL7.0. Different binding modes for PCBs have been distinguished not only from aligned conformation but also from free binding energy. Some QSAR models were established separately for both low and high doses ranges, revealing that receptor binding may predominate in the interference of the physiological function of cytochrome P4501A-P4501A in the low doses range. But with the higher doses range, the EROD suppression might he related to acute toxicity owing to molecular polarity or distribution of charges and consequently damage structure and function of chicken embryo hepatocyte.

  6. QSAR study on the non-monotonic dose-response curve of PCBs in chicken embryo hepatocyte bioassay

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Endocrine disrupting chemicals (EDCs) in the natural environment exhibit a unique non-monotonic dose-response curve and it is impossible to select one simple index to characterize the bilogogical activity of these compounds. Quantitative structure-activity relationship (QSAR) study on non-monotonic dose-response curve has become a real challenge presently. In order to explore the possible mechanism for the non-monotonic dose-response curve of polychlorinated biphenyls congeners (PCBs) in chicken embryo hepatocyte bioassay, AM1 method of ChemOffice was adopted to calculate necessary structure descriptors for PCBs, while the interactions between PCBs and simulated AhR ligand binding domain (LBD) were analyzed by using FlexX in SYBYL7.0. Different binding modes for PCBs have been distinguished not only from aligned conformation but also from free binding energy. Some QSAR models were established separately for both low and high doses ranges, revealing that receptor binding may predominate in the interference of the physiological function of cytochrome P4501A-P4501A in the low doses range. But with the higher doses range, the EROD suppression might be related to acute toxicity owing to molecular polarity or distribution of charges and consequently damage structure and function of chicken embryo hepatocyte.

  7. Establishment of Dose-response Curves for Dicentrics and Premature Chromosome Condensation for Radiological Emergency Preparedness in Thailand

    Science.gov (United States)

    Rungsimaphorn, Benchawan; Rerkamnuaychoke, Budsaba; Sudprasert, Wanwisa

    2016-01-01

    The in vitro dose calibration curves using conventional biological dosimetry – dicentric chromosome assay (DCA) and premature chromosome condensation (PCC) assay – were performed for the first time in Thailand for reconstruction of radiation dose in the exposed individuals. The peripheral blood lymphocyte samples from healthy donors were irradiated with 137Cs source at a dose rate of 0.652 Gy/min to doses of 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 5 Gy for DCA technique, and 5, 10, 15, 20, and 25 Gy for PCC technique. The blood samples were cultured and processed following the standard procedure as prescribed in the International Atomic Energy Agency report with slight modifications. The yield of dicentrics with dose from at least 1000 metaphases or 100 dicentrics was fitted to a linear quadratic model using Chromosome Aberration Calculation Software (CABAS, version 2.0) whereas those of PCC rings with dose from 100 rings was fitted to a linear quadratic equation at doses from 0 to 15 Gy. These curves will be useful for in vitro dose reconstruction and can support the preparedness for overexposure to radiation among public or occupational workers and eventual radiological accident in Thailand. PMID:28217284

  8. Short and long-term exposure of CNS cell lines to BPA-f a radiosensitizer for boron neutron capture therapy: safety dose evaluation by a battery of cytotoxicity tests.

    Science.gov (United States)

    De Simone, U; Manzo, L; Ferrari, C; Bakeine, J; Locatelli, C; Coccini, T

    2013-03-01

    Despite the current clinical use of boronophenylalanine-fructose (BPA-f), as radiosensitizer, in BNCT application for brain tumors, still remains to be determined the safety dose of this agent. We evaluated the potential risk of primary BPA-f toxicity before neutronic irradiation at different concentrations (0-100μgBeq/ml) after short- and long-term exposure (4-48h and 7-10 days), using a battery of tests (i.e. MTT assay, calcein-AM/Propidium Iodide staining, clonogenic test) in CNS cell models (D384 and SH-SY5Y), and non-neuronal primary human fibroblasts (F26). MTT data showed: (i) no cytotoxic effects after short-term exposure (4h) to any of BPA-f concentrations tested in all cell models; (ii) dose- and time-dependent mitochondrial activity impairment in D384 and SH-SY5Y cells only (with 60% and 40% cell death in D384 and SH-SY5Y, respectively, after 48h exposure to BPA-f 100μgBeq/ml). By Calcein-AM/PI staining, BPA-f treatment was specific toward SH-SY5Y cells only: a dose-dependent cell density reduction was observed, with a more pronounced effect after 48h exposure (15-40% at doses ranging 20-100μgBeq/ml). Clonogenic data revealed dose-dependent decrease of cell proliferative capacity in all cell lines, still the SH-SY5Y cells were the most sensitive ones: the lowest dose (20μgBeq/ml) produced 90% cell decrease. These results indicate dose- and time-dependent cytotoxic effects of BPA-f, with CNS cells showing a lower tolerance compared to fibroblasts. Long-term exposure to BPA-f compromised the proliferative capacity regardless of cell model type (cell sensitivity being SH-SY5Y>D384>F26). In short-time exposure, BPA-f exhibits a safe dosage up to 40μgBeq/ml for the viability of CNS cell lines. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Influence of lung parenchymal destruction on the different indexes of the methacholine dose-response curve in COPD patients

    NARCIS (Netherlands)

    G.T. Verhoeven; A.F.M. Verbraak (Anton); S. Boere-van der Straat; H.C. Hoogsteden (Henk); J.M. Bogaard (Jan)

    2000-01-01

    textabstractSTUDY OBJECTIVES: The interpretation of nonspecific bronchial provocation dose-response curves in COPD is still a matter of debate. Bronchial hyperresponsiveness (BHR) in patients with COPD could be influenced by the destruction of the parenchyma and the aug

  10. Fundamental investigations of natural and laboratory generated SAR dose response curves for quartz OSL in the high dose range

    DEFF Research Database (Denmark)

    Timar-Gabor, Alida; Constantin, Daniela; Buylaert, Jan-Pieter;

    2015-01-01

    SAR-OSL investigations on quartz from Romanian loess resulted in non concordant fine and coarse-grain ages for equivalent doses higher than ~100 Gy. The laboratory dose response for both grain sizes is well represented by a sum of two saturating exponential functions, fine and coarse grains chara...

  11. Isobolographic analysis of interaction between drugs with nonparallel dose-response relationship curves: a practical application.

    Science.gov (United States)

    Luszczki, Jarogniew J

    2007-04-01

    The objective of this study was to characterize the anticonvulsant and acute adverse-effect potentials of topiramate (TPM) and gabapentin (GBP)-two second-generation antiepileptic drugs administered alone and in combination in the maximal electroshock (MES)-induced seizures and chimney test in mice. The anticonvulsant and acute adverse effects of the combination of TPM with GBP at the fixed ratio of 1:1 were determined using the type I isobolographic analysis for nonparallel dose-response relationship curves (DRRCs). To ascertain any pharmacokinetic contribution to the observed interaction between TPM and GBP, total brain concentrations of both drugs were determined. The isobolographic analysis of interaction for TPM and GBP, whose DRRCs were not parallel in both MES and chimney tests, was accompanied with a presentation of all required calculations allowing the determination of lower and upper lines of additivity. The isobolographic analysis revealed that TPM combined with GBP at the fixed-ratio combination of 1:1 interacted supraadditively (synergistically) in terms of suppression of MES-induced seizures, and simultaneously, the combination produced additive interaction with respect to motor coordination impairment (adverse effects) in the chimney test. The evaluation of pharmacokinetic characteristics of interaction for the combination of TPM with GBP revealed that neither TPM nor GBP affected their total brain concentrations in experimental animals, and thus, the observed interaction in the MES test was pharmacodynamic in nature. In conclusion, the combination of TPM with GBP, because of supraadditivity in the MES test and additivity in terms of motor coordination impairment in the chimney test as well as lack of pharmacokinetic interactions between drugs, fulfilled the criterion of a favorable combination, worthy of recommendation in further clinical practice.

  12. Reply to Comment on ‘Implications on clinical scenario of gold nanoparticle radiosensitization in regards to photon energy, nanoparticle size, concentration and location’

    Science.gov (United States)

    Pignol, Jean-Philippe; Lechtman, Eli

    2012-01-01

    In a comment on a recent paper by Lechtman et al (2011 Phys. Med. Biol. 56 4631-47), McMahon critiques one of Lechtman's conclusion that gold nanoparticle radiosensitization may not be applicable to megavoltage radiotherapy. He refers to recently published experimental studies showing radiosensitization with 6 MV x-rays and low gold concentrations. However those published studies show conflicting results, presenting survival curves with a small cell death increased with gold and some with no difference. In regards to gold nanoparticle radiosensitization physical, chemical, pharmacological and biological constraints all interplay. There are plenty of experimental and theoretical data to confirm the strong dependence to the primary photon energy and gold concentration. The manuscript of Lechtman added the dependence to microscopic localization, analysing the spatial distribution and the quality of secondary electrons, as a major player in the feasibility of the technique. We agree that radiobiological dose modification factor should be considered, but it is unlikely that accounting for a maximum RBE of 2 can compensate for the drastic decrease of photoelectric events shifting from kV to MV. Lechtman calculated that to achieve similar radiosensitization for low energy beams and intra-cellular gold concentration of 0.5%, concentrations 300 times higher are required for 6 MV beams. To date it seems unlikely that concentration higher than 1% could be achieved such that it is unlikely that megavoltage would yield a measurable clinical effect.

  13. Dose quality control in stereotactic radiation therapy using radiosensitive gels; Controle de qualite dosimetrique en radiotherapie stereotaxique a l`aide de gels radiosensibles

    Energy Technology Data Exchange (ETDEWEB)

    Rousselle, I.; Rousseau, J. [Centre Hospitalier Universitaire, 59 - Lille (France). Institut de technologie medicale; Castelain, B.; Coche-Dequeant, B.; Sarrazin, T. [Centre de Lutte Contre le Cancer Oscar-Lambret, 59 - Lille (France)

    1998-03-01

    Typical dosimeters used in stereotactic radiation therapy such as ionization chambers, films, and thermoluminescent diodes, allow basic physical measurements. They are, however, neither well suited to discern small target volumes with high dose gradient, nor suitable for three-dimensional (3D) dose measurements. Gel dosimetry is becoming more and more interesting, owing to magnetic resonance imaging (MRI). It permits isocenter position planning verification of accuracy and the precision of the 3D dose mapping in the brain (when irradiated in realistic conditions), especially when several different targets are concerned. Many authors have assessed stereotactic radiation therapy quality control using different gels, and different irradiation procedures. This paper consists of the review of these different methods to assess quality control. Gel dosimetry cannot provide absolute dose measurements. However, gels can be used to check the 3D dose mapping with a high degree of detail. In our experiment, the difference between the stereotactic frame center and the isocenter is about 1 mm. The difference between the theoretical isodoses obtained by the treatment planning system and the experimental isodoses obtained by the MRI gray level calibration is also about 1 mm, the order of magnitude of the MRI pixel size. (authors)

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

    DEFF Research Database (Denmark)

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

    1997-01-01

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

  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. 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.

  17. Dose-response calibration curves of {sup 137}Cs gamma rays for dicentric chromosome aberrations in human lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Jo, Wol Soon; Oh, Su Jung; Jeong, Soo Kyun; Yang, Kwang Mo [Dept. of Research center, Dong Nam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of); Jeong, Min Ho [Dept. of Microbiology, Dong A University College of Medicine, Busan (Korea, Republic of)

    2012-11-15

    Recently, the increased threat of radiologically industrial accident such as radiation nondestructive inspection or destruction of nuclear accident by natural disaster such as Fukushima accident requires a greater capacity for cytogenetic biodosimetry, which is critical for clinical triage of potentially thousands of radiation-exposed individuals. Dicentric chromosome aberration analysis is the conventional means of assessing radiation exposure. Dose–response calibration curves for {sup 13}'7Cs gamma rays have been established for unstable chromosome aberrations in human peripheral blood lymphocytes in many laboratories of international biodosimetry network. In this study, therefore, we established dose– response calibration curves of our laboratory for {sup 137}Cs gamma raysaccording to the IAEA protocols for conducting the dicentric chromosome assay We established in vitro dose–response calibration curves for dicentric chromosome aberrations in human lymphocytes for{sup 13}'7Cs gamma rays in the 0 to 5 Gy range, using the maximum likelihood linear-quadratic model, Y = c+αD+βD2. The estimated coefficients of the fitted curves were within the 95% confidence intervals (CIs) and the curve fitting of dose–effect relationship data indicated a good fit to the linear-quadratic model. Hence, meaningful dose estimation from unknown sample can be determined accurately by using our laboratory’s calibration curve according to standard protocol.

  18. Dose-response curve for blood exposed to gamma-neutron mixed field by conventional cytogenetic method

    Energy Technology Data Exchange (ETDEWEB)

    Brandao, Jose Odinilson de C.; Souza, Priscilla L.G.; Santos, Joelan A.L.; Vilela, Eudice C.; Lima, Fabiana F., E-mail: jodinilson@cnen.gov.b, E-mail: fflima@cnen.gov.b, E-mail: jasantos@cnen.gov.b [Centro Regional de Ciencias Nucleares do Nordeste (CRCN-NE/CNEN-PE), Recife, PE (Brazil); Calixto, Merilane S.; Santos, Neide, E-mail: santos_neide@yahoo.com.b [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Genetica

    2009-07-01

    There is increasing concern about airline crew members (about one million worldwide) are exposed to measurable neutrons doses. Historically, cytogenetic biodosimetry assays have been based on quantifying asymmetrical chromosome alterations (dicentrics, centric rings and acentric fragments) in mytogen-stimulated T-lymphocytes in their first mitosis after radiation exposure. Increased levels of chromosome damage in peripheral blood lymphocytes are a sensitive indicator of radiation exposure and they are routinely exploited for assessing radiation absorbed dose after accidental or occupational exposure. Since radiological accidents are not common, not all nations feel that it is economically justified to maintain biodosimetry competence. However, dependable access to biological dosimetry capabilities is completely critical in event of an accident. In this paper the dose-response curve was measured for the induction of chromosomal alterations in peripheral blood lymphocytes after chronic exposure in vitro to neutron-gamma mixes field. Blood was obtained from one healthy donor and exposed to two neutron-gamma mixed field from sources {sup 241}AmBe (20 Ci) at the Neutron Calibration Laboratory (NCL-CRCN/NE-PE-Brazil). The evaluated absorbed doses were 0.2 Gy; 1.0 Gy and 2.5 Gy. The dicentric chromosomes were observed at metaphase, following colcemid accumulation and 1000 well-spread metaphase figures were analyzed for the presence of dicentrics by two experienced scorers after painted by giemsa 5%. Our preliminary results showed a linear dependence between radiations absorbed dose and dicentric chromosomes frequencies. Dose-response curve described in this paper will contribute to the construction of calibration curve that will be used in our laboratory for biological dosimetry. (author)

  19. Equivalent intraperitoneal doses of ibuprofen supplemented in drinking water or in diet: a behavioral and biochemical assay using antinociceptive and thromboxane inhibitory dose-response curves in mice.

    Science.gov (United States)

    Salama, Raghda A M; El Gayar, Nesreen H; Georgy, Sonia S; Hamza, May

    2016-01-01

    Background. Ibuprofen is used chronically in different animal models of inflammation by administration in drinking water or in diet due to its short half-life. Though this practice has been used for years, ibuprofen doses were never assayed against parenteral dose-response curves. This study aims at identifying the equivalent intraperitoneal (i.p.) doses of ibuprofen, when it is administered in drinking water or in diet. Methods. Bioassays were performed using formalin test and incisional pain model for antinociceptive efficacy and serum TXB2 for eicosanoid inhibitory activity. The dose-response curve of i.p. administered ibuprofen was constructed for each test using 50, 75, 100 and 200 mg/kg body weight (b.w.). The dose-response curves were constructed of phase 2a of the formalin test (the most sensitive phase to COX inhibitory agents), the area under the 'change in mechanical threshold'-time curve in the incisional pain model and serum TXB2 levels. The assayed ibuprofen concentrations administered in drinking water were 0.2, 0.35, 0.6 mg/ml and those administered in diet were 82, 263, 375 mg/kg diet. Results. The 3 concentrations applied in drinking water lay between 73.6 and 85.5 mg/kg b.w., i.p., in case of the formalin test; between 58.9 and 77.8 mg/kg b.w., i.p., in case of the incisional pain model; and between 71.8 and 125.8 mg/kg b.w., i.p., in case of serum TXB2 levels. The 3 concentrations administered in diet lay between 67.6 and 83.8 mg/kg b.w., i.p., in case of the formalin test; between 52.7 and 68.6 mg/kg b.w., i.p., in case of the incisional pain model; and between 63.6 and 92.5 mg/kg b.w., i.p., in case of serum TXB2 levels. Discussion. The increment in pharmacological effects of different doses of continuously administered ibuprofen in drinking water or diet do not parallel those of i.p. administered ibuprofen. It is therefore difficult to assume the equivalent parenteral daily doses based on mathematical calculations.

  20. Biological dosimetry of ionizing radiation: Evaluation of the dose with cytogenetic methodologies by the construction of calibration curves

    Science.gov (United States)

    Zafiropoulos, Demetre; Facco, E.; Sarchiapone, Lucia

    2016-09-01

    In case of a radiation accident, it is well known that in the absence of physical dosimetry biological dosimetry based on cytogenetic methods is a unique tool to estimate individual absorbed dose. Moreover, even when physical dosimetry indicates an overexposure, scoring chromosome aberrations (dicentrics and rings) in human peripheral blood lymphocytes (PBLs) at metaphase is presently the most widely used method to confirm dose assessment. The analysis of dicentrics and rings in PBLs after Giemsa staining of metaphase cells is considered the most valid assay for radiation injury. This work shows that applying the fluorescence in situ hybridization (FISH) technique, using telomeric/centromeric peptide nucleic acid (PNA) probes in metaphase chromosomes for radiation dosimetry, could become a fast scoring, reliable and precise method for biological dosimetry after accidental radiation exposures. In both in vitro methods described above, lymphocyte stimulation is needed, and this limits the application in radiation emergency medicine where speed is considered to be a high priority. Using premature chromosome condensation (PCC), irradiated human PBLs (non-stimulated) were fused with mitotic CHO cells, and the yield of excess PCC fragments in Giemsa stained cells was scored. To score dicentrics and rings under PCC conditions, the necessary centromere and telomere detection of the chromosomes was obtained using FISH and specific PNA probes. Of course, a prerequisite for dose assessment in all cases is a dose-effect calibration curve. This work illustrates the various methods used; dose response calibration curves, with 95% confidence limits used to estimate dose uncertainties, have been constructed for conventional metaphase analysis and FISH. We also compare the dose-response curve constructed after scoring of dicentrics and rings using PCC combined with FISH and PNA probes. Also reported are dose response curves showing scored dicentrics and rings per cell, combining

  1. 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

  2. Radiosensitive Severe Combined Immunodeficiency Disease

    OpenAIRE

    Dvorak, Christopher C.; Cowan, Morton J.

    2010-01-01

    Inherited defects in components of the non-homologous 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 traditionally utilized for conditioning prior to allogeneic hematopoietic cell transplantation (HCT). Known etiologies of radiosensit...

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

    Directory of Open Access Journals (Sweden)

    Brooks Colin

    2012-09-01

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

  4. Valganciclovir dosing using area under the curve calculations in pediatric solid organ transplant recipients.

    Science.gov (United States)

    Villeneuve, David; Brothers, Adam; Harvey, Eric; Kemna, Mariska; Law, Yuk; Nemeth, Thomas; Gantt, Soren

    2013-02-01

    Pediatric valganciclovir dosing recommendations have not been extensively validated for prevention or treatment for CMV infection. As such, we performed a pharmacokinetic study to compare different valganciclovir dosing regimens and the potential benefits of individualized dose adjustments in children following organ transplantation. Ganciclovir AUCs were calculated from four plasma drug levels in pediatric SOT recipients aged six months through three yr receiving valganciclovir suspension by mouth. Of the 28 ganciclovir AUC calculations performed, 11 (39%) were outside the therapeutic target range of 40-60 mcg h/L leading to a valganciclovir dose adjustment. Current manufacturer-recommended dosing based on BSA and CrCl was estimated to result in therapeutic AUCs in fewer patients than the simple weight-based formula used in our institution (4 vs. 13; p = 0.017). An AUC calculation using only the two- and five-h measurements was strongly correlated with the AUC using all four time measurements (R(2) = 0.846; p < 0.001). A simple weight-based dosing approach gives a higher probability for therapeutic AUCs compared to the manufacturer-recommended dosing in pediatric transplant patients aged six months through three yr with normal renal function. An AUC calculated using two sample times might allow for fewer blood draws in the future. © 2012 John Wiley & Sons A/S.

  5. Dose-response curve slope is a missing dimension in the analysis of HIV-1 drug resistance.

    Science.gov (United States)

    Sampah, Maame Efua S; Shen, Lin; Jilek, Benjamin L; Siliciano, Robert F

    2011-05-03

    HIV-1 drug resistance is a major clinical problem. Resistance is evaluated using in vitro assays measuring the fold change in IC(50) caused by resistance mutations. Antiretroviral drugs are used at concentrations above IC(50), however, and inhibition at clinical concentrations can only be predicted from IC(50) if the shape of the dose-response curve is also known. Curve shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m). Implicit in current analysis of resistance is the assumption that mutations shift dose-response curves to the right without affecting the slope. We show here that m is altered by resistance mutations. For reverse transcriptase and fusion inhibitors, single resistance mutations affect both slope and IC(50). For protease inhibitors, single mutations primarily affect slope. For integrase inhibitors, only IC(50) is affected. Thus, there are fundamental pharmacodynamic differences in resistance to different drug classes. Instantaneous inhibitory potential (IIP), the log inhibition of single-round infectivity at clinical concentrations, takes into account both slope and IC(50), and thus provides a direct measure of the reduction in susceptibility produced by mutations and the residual activity of drugs against resistant viruses. The standard measure, fold change in IC(50), does not correlate well with changes in IIP when mutations alter slope. These results challenge a fundamental assumption underlying current analysis of HIV-1 drug resistance and suggest that a more complete understanding of how resistance mutations reduce antiviral activity requires consideration of a previously ignored parameter, the dose-response curve slope.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-09-03

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

  7. 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

  8. Multi-detector computed tomography radiation doses in the follow ...

    African Journals Online (AJOL)

    2014-05-09

    May 9, 2014 ... more radiosensitive because of a higher rate of cell division in the former and radiosensitive. Page 1 of 4. Scan this QR code with your smart phone or mobile ... independent inspection bodies and dose parameters were.

  9. Silicon diodes as an alternative to diamond detectors for depth dose curves and profile measurements of photon and electron radiation

    Energy Technology Data Exchange (ETDEWEB)

    Scherf, Christian; Moog, Jussi; Licher, Joerg; Kara, Eugen; Roedel, Claus; Ramm, Ulla [Dept. of Radiotherapy and Oncology, Center of Radiology, Univ. Hospital, Frankfurt/Main (Germany); Peter, Christiane [Dept. of Radiotherapy and Oncology, Center of Radiology, Univ. Hospital, Frankfurt/Main (Germany); Inst. for Medical Physics and Radiation Protection, Advanced Technical Coll. Giessen-Friedberg (Germany); Zink, Klemens [Inst. for Medical Physics and Radiation Protection, Advanced Technical Coll. Giessen-Friedberg (Germany)

    2009-08-15

    Background: Depth dose curves and lateral dose profiles should correspond to relative dose to water in any measured point, what can be more or less satisfied with different detectors. Diamond as detector material has similar dosimetric properties like water. Silicon diodes and ionization chambers are also commonly used to acquire dose profiles. Material and Methods: The authors compared dose profiles measured in an MP3 water phantom with a diamond detector 60003, unshielded and shielded silicon diodes 60008 and 60012 and a 0.125-cm{sup 3} thimble chamber 233642 (PTW, Freiburg, Germany) for 6- and 25-MV photons. Electron beams of 6, 12 and 18 MeV were investigated with the diamond detector, the unshielded diode and a Markus chamber 23343. Results: The unshielded diode revealed relative dose differences at the water surface below +10% for 6-MV and +4% for 25-MV photons compared to the diamond data. These values decreased to less than 1% within the first millimeters of water depth. The shielded diode was only required to obtain correct data of the fall-off zones for photon beams larger than 10 x 10 cm{sup 2} because of important contributions of low-energy scattered photons. For electron radiation the largest relative dose difference of -2% was observed with the unshielded silicon diode for 6 MeV within the build-up zone. Spatial resolutions were always best with the small voluminous silicon diodes. Conclusion: Relative dose profiles obtained with the two silicon diodes have the same degree of accuracy as with the diamond detector. (orig.)

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-06-15

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

  11. Low blood lead level effects on intelligence: can a dose-response curve be determined from the epidemiological data?

    Science.gov (United States)

    Banner, W; Kahn, C M

    2014-02-01

    CONTEXT. Recent publications have graphically demonstrated a curvilinear relationship between measures of intelligence and blood lead levels at low concentrations (dose-response curves. METHODS. Random data based on varied distributions were constructed to simulate a previous study using a single, randomly generated covariate income (Inc) to demonstrate the impact of normally versus exponentially distributed data on the shape of the graph of intelligence quotient (IQ) versus blood lead. We also used an existing database of US blood lead levels and constructed a similar model of income and IQ using both assumptions of distribution for the intermediate variable income. RESULTS. When both lead and income are exponentially distributed, the graph of lead and IQ will be a curve. CONCLUSION. The apparent shape of a dose-response relationship from simulated epidemiological data is nonlinear when one variable and a covariate are exponentially distributed. A non-linear biological relationship should not be assumed and in fact may be the least likely explanation. The use of observational epidemiological data to discern a dose-response relationship between two variables may be misleading.

  12. Study of dose-response and radical decay curves of gamma irradiated norfloxacin using EPR spectroscopy

    Science.gov (United States)

    Sütçü, Kerem; Osmanoǧlu, Yunus Emre

    2017-02-01

    In this study, Electron Paramagnetic Resonance (EPR) spectra of unirradiated and γ-irradiated at doses of 1, 5, 10, 12 and 15 kGy norfloxacin (NOF) were investigated. Before irradiation no EPR signal were observed. After irradiation a weak singlet signal at g = 2.0039 were obtained at room temperature. In order to describe the variation of EPR signal intensity with absorbed radiation dose, several mathematical equations were tried. Increasing irradiation dose up to 15 kGy has increased the signal intensity of the central signal however, no significant changes were observed in g spectroscopic splitting factor. The stability of signal intensity of irradiated NOF was studied over a storage period of 200 days. According to analyses conducted, EPR spectroscopy can be used to distinguish irradiated and unirradiated samples from each other.

  13. Calculations of dose attenuation in slowly curving tunnel geometries at a high-energy proton accelerator

    CERN Document Server

    Vincke, Helmut H

    2003-01-01

    The CERN Neutrino beam to Gran Sasso (CNGS) project and the Large Hadron Collider (LHC) will receive 450 GeV/c protons extracted from the Super Proton Synchrotron (SPS). In the tunnels leading to the CNGS target and the LHC accelerator there is a 150 m straight section where a beam dump (TED) can be moved into the beam chamber, intercepting the proton beam. After the TED, the beam is routed into either the 700m slowly curving TT41 tunnel (CNGS) or the TI8 tunnel consisting of a 400 m straight section followed by a curved 1.5 km long tunnel (LHC). The curved tunnels have a radius of approximately 1 km. During tests a proton beam of 1.2 multiplied by 10**1**3 s**- **1 could be sent to the dump. The question posed was how close to the TED could access be allowed during dumping operations. Initial simulations using the FLUKA Monte-Carlo transport program were optimised assuming that the high-energy muon contribution dominates. Discrepancies with an analytically based calculation led to a revision of this optimisa...

  14. The Use of MTT Assay, In Vitro and Ex Vivo, to Predict the Radiosensitivity of Colorectal Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ji Eun; Kim, Mi Sook; Kang, Chang Mo; Shin, Hye Kyung; Choi, Chul Won; Seo, Young Seok; Ji, Young Hoon [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Jong Il [Seoul Women' s University College of Medicine, Seoul (Korea, Republic of)

    2008-09-15

    The measurement of radiosensitivity of individuals is useful in radiation therapy. Unfortunately, the measurement of radiation survival using a clonogenic assay, which is the established standard, can be difficult and time consuming. The aim of this study is to compare radiosensitivity results obtained from the MTT and clonogenic assays, and to evaluate whether the MTT assay can be used on clinical specimens. Materials and Methods: HCT-8, LoVo, CT-26, and WiDr were the colon cancer cell lines used for this study. The clonogenic assay was performed to obtain the cell survival curves and surviving fractions at a dose of 2 Gy (SF2) as the standard technique for radiosensitivity. Also, the MTT assay was performed for each of the cell lines (in vitro). To simulate clinical specimens, the cell lines were inoculated into nude mice, removed when the tumors reached 1 cm in diameter, and chopped. Next, the tumors were subjected to the same process involved with the MTT assay in vitro. The inhibition rates (IR) of 10 Gy or 20 Gy of irradiation for in vitro and ex vivo were calculated based on the optical density of the MTT assay, respectively. Results: According to SF2 and the cell survival curve, the HCT-8 and WiDr cell lines were more resistant to radiation than LoVo and CT-26 (p<0.05). The IR was measured by in vitro. The MTT assay IR was 17.3%, 21%, 30% and 56.5% for the WiDr, HCT-8, LoVo and CT-26 cell lines, respectively. In addition, the IR measured ex vivo by the MTT assay was 23.5%, 26%, 38% and 53% in the HCT-8, WiDr, LoVo and CT-26 tumors, respectively. Conclusion: The radiosensitivity measured by the MTT assay was correlated with the measures obtained from the clonogenic assay. This result highlights the possibility that the MTT assay could be used in clinical specimens for individual radiosensitivity assays.

  15. A sex-specific dose-response curve for testosterone: could excessive testosterone limit sexual interaction in women?

    Science.gov (United States)

    Krapf, Jill M; Simon, James A

    2017-04-01

    Testosterone treatment increases sexual desire and well-being in women with hypoactive sexual desire disorder; however, many studies have shown only modest benefits limited to moderate doses. Unlike men, available data indicate women show a bell-shaped dose-response curve for testosterone, wherein a threshold dosage of testosterone leads to desirable sexual function effects, but exceeding this threshold results in a lack of further positive sexual effects or may have a negative impact. Emotional and physical side-effects of excess testosterone, including aggression and virilization, may counteract the modest benefits on sexual interaction, providing a possible explanation for a threshold dose of testosterone in women. In this commentary, we will review and critically analyze data supporting a curvilinear dose-response relationship between testosterone treatment and sexual activity in women with low libido, and also explore possible explanations for this observed relationship. Understanding optimal dosing of testosterone unique to women may bring us one step closer to overcoming regulatory barriers in treating female sexual dysfunction.

  16. [Study on the effect of grape seed proanthocyanidins on increasing the radiosensitivity for X-ray].

    Science.gov (United States)

    Pan, Xiao-jing; Wang, Min; Wang, Xue-xi; Liu, Bin; Zhang, Hong

    2012-02-01

    To investigate the effect of Grape Seed Proanthocyanidins (GSPs) on enhancing the radiosensitivity of human hepatic carcinoma cell line HepG2, human cervical cancer cell line Hela and human leukemia cell line K562 for X-ray in vitro. The killing effect of GSPs combined with X-ray on cells was evaluated by SRB and clone formation assay. The GSPs had obvious cytotoxicity on three cell lines in a dose-dependent and time-dependent manners. However, inhibition rate of different cell line were quite different, the strongest one was human leukemia K562 cells and the others were weak. The sensitization ranges calculated by univariate analysis were 6.25-12.5 microg/mL for human leukemia K562 cells. Sensitization enhancement ratio was 1.94 using curve fitting method for K562 cells. GSPs can obviously enhance the radiosensitivity of cancer cells in vitro. The mechanism of sensitization effect may be related to the effects of GSPs on oxygen balance and cell cycle.

  17. Learning curve of MRI-based planning for high-dose-rate brachytherapy for prostate cancer

    DEFF Research Database (Denmark)

    Buus, Simon; Rylander, Susanne; Hokland, Steffen

    2016-01-01

    –D as treatment planning time, and D to E as treatment delivery time. Dose-volume parameters were retrieved from the dose planning system. Results from the first 21 patients were compared with the last 21 patients. Results Total procedure time, operating room time, MRI procedure time, and treatment planning time...... decreased significantly from average 7.6 to 5.3 hours (p delivery time remained unchanged at 0.5 hours. Clinical target volume prostate+3mmD90 fulfilled planning aim in 92% of procedures...

  18. Validation of dose-response curve of CRCN-NE - Regional Center for Nuclear Sciences from Northeast Brazil for {sup 60}Co: preliminary results; Validacao da curva dose-resposta do CRCN-NE para {sup 60}Co: resultados preliminares

    Energy Technology Data Exchange (ETDEWEB)

    Mendonca, Julyanne C.G.; Mendes, Mariana E.; Hwang, Suy F.; Lima, Fabiana F. [Centro Regional de Ciencias Nucleares do Nordeste (CRCN-NE/CNEN-PE), Recife, PE (Brazil); Santos, Neide, E-mail: july_cgm@yahoo.com.br [Universidade Federal de Pernambuco (CCB/UFPE), Recife, PE (Brazil). Departamento de Genetica

    2014-07-01

    The cytogenetic study has the chromosomal alterations as biomarkers in absorbed dose estimation by the body of individuals involved in exposure to ionizing radiation by interpreting a dose response calibration curve. Since the development of the technique to the analysis of data, you can see protocol characteristics, leading the International Atomic Energy Agency indicate that any laboratory with intention to carry out biological dosimetry establish their own calibration curves. The Biological Dosimetry Laboratory of the Centro Regional de Ciencias Nucleares (CRCN-NE/CNEN), Brazil, recently established the calibration curve related to gamma radiation ({sup 60}Co). Thus, this work aimed to start the validation of this calibration curve from samples of three different blood donors which were irradiated with an absorbed known single dose of 1 Gy. Samples were exposed to {sup 60}Co source (Glaucoma 220) located in the Department of Nuclear Energy (DEN/UFPE). After fixation with methanol and acetic acid and 5% Giemsa staining, the frequency of chromosomal alterations (dicentric chromosomes, acentric rings and fragments) were established from reading of 500 metaphases per sample and doses were estimated using Dose Estimate program. The results showed that, using the dose-response curve calibration for dicentrics, the dose absorbed estimated for the three individuals ranged from 0.891 - 1,089Gy, taking into account the range of confidence of 95%. By using the dose-response curve for dicentrics added to rings and for the same interval of confidence the doses ranged from 0,849 - 1,081Gy. Thus, the estimative encompassed known absorbed dose the three individuals in confidence interval of 95%. These preliminary results seems to demonstrate that dicentric dose-response curves and dicentrics plus rings established by CRCN-NE / CNEN are valid for dose estimation in exposed individuals. This validation will continue with samples from different individuals at different doses.

  19. Testing of the radiosensitivity of human malignant tumor cells in culture

    Energy Technology Data Exchange (ETDEWEB)

    Schoenfelder, M.; Neumeister, K.; Jahns, J.; Kamprad, F. (Karl-Marx-Universitaet, Leipzig (German Democratic Republic). Chirurgische Klinik; Bezirkskrankenhaus Karl-Marx-Stadt (German Democratic Republic); Karl-Marx-Universitaet, Leipzig (German Democratic Republic). Radiologische Klinik)

    1984-01-01

    Primary cell cultures of human malignant tumors were irradiated with X-ray doses of 1-30 Gy. Their radiosensitivity has been examined for 3 weeks postirradiation concerning morphological aspects. The investigations were carried out on 43 tumors of different histology. In 26 cases the results of the radiosensitivity test in the tumor cell culture were compared with the results of the radiotherapy of the adequate patients, 6-8 years postirradiation. In 17 patients the in vitro results correlated with the conventional clinical experience as to the radiosensitivity of the corresponding tumor.

  20. Mathematical Modeling of Allelopathy. III. A Model for Curve-Fitting Allelochemical Dose Responses

    OpenAIRE

    Liu, Li; An, Min; Johnson, Ian R.; Lovett, John V.

    2003-01-01

    Bioassay techniques are often used to study the effects of allelochemicals on plant processes, and it is generally observed that the processes are stimulated at low allelochemical concentrations and inhibited as the concentrations increase. A simple empirical model is presented to analyze this type of response. The stimulation-inhibition properties of allelochemical-dose responses can be described by the parameters in the model. The indices, p% reductions, are calculated to assess the alleloc...

  1. Hormonal status can modify radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Ricoul, M.; Sabatier, L.; Dutrillaux, B. [CEA Fontenay-aux-Roses, 92 (France). Dept. de Radiobiologie et de Radiopathologie

    1997-03-01

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

  2. 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.

  3. Hypoxic radiosensitizers: substituted styryl derivatives.

    Science.gov (United States)

    Nudelman, A; Falb, E; Odesa, Y; Shmueli-Broide, N

    1994-10-01

    A number of novel styryl epoxides, N-substituted-styryl-ethanolamines, N-mono and N,N'-bis-(2-hydroxyethyl)-cinnamamides--analogues to the known radiosensitizers RSU-1069, pimonidazole and etanidazole--display selective hypoxic radiosensitizing activity. The styryl group, especially when substituted by electron withdrawing groups, was found to be bioisosteric to the nitroimidazolyl functionality. The most active derivative 2-(2'-nitrophenyl)ethen-1-yl-oxirane 8a displayed a sensitizer enhancement ratio (SER) of 5 relative to misonidazole.

  4. A Monte Carlo-based model of gold nanoparticle radiosensitization

    Science.gov (United States)

    Lechtman, Eli Solomon

    The goal of radiotherapy is to operate within the therapeutic window - delivering doses of ionizing radiation to achieve locoregional tumour control, while minimizing normal tissue toxicity. A greater therapeutic ratio can be achieved by utilizing radiosensitizing agents designed to enhance the effects of radiation at the tumour. Gold nanoparticles (AuNP) represent a novel radiosensitizer with unique and attractive properties. AuNPs enhance local photon interactions, thereby converting photons into localized damaging electrons. Experimental reports of AuNP radiosensitization reveal this enhancement effect to be highly sensitive to irradiation source energy, cell line, and AuNP size, concentration and intracellular localization. This thesis explored the physics and some of the underlying mechanisms behind AuNP radiosensitization. A Monte Carlo simulation approach was developed to investigate the enhanced photoelectric absorption within AuNPs, and to characterize the escaping energy and range of the photoelectric products. Simulations revealed a 10 3 fold increase in the rate of photoelectric absorption using low-energy brachytherapy sources compared to megavolt sources. For low-energy sources, AuNPs released electrons with ranges of only a few microns in the surrounding tissue. For higher energy sources, longer ranged photoelectric products travelled orders of magnitude farther. A novel radiobiological model called the AuNP radiosensitization predictive (ARP) model was developed based on the unique nanoscale energy deposition pattern around AuNPs. The ARP model incorporated detailed Monte Carlo simulations with experimentally determined parameters to predict AuNP radiosensitization. This model compared well to in vitro experiments involving two cancer cell lines (PC-3 and SK-BR-3), two AuNP sizes (5 and 30 nm) and two source energies (100 and 300 kVp). The ARP model was then used to explore the effects of AuNP intracellular localization using 1.9 and 100 nm Au

  5. Mathematical Modeling of Allelopathy. III. A Model for Curve-Fitting Allelochemical Dose Responses

    Science.gov (United States)

    Liu, De Li; An, Min; Johnson, Ian R.; Lovett, John V.

    2003-01-01

    Bioassay techniques are often used to study the effects of allelochemicals on plant processes, and it is generally observed that the processes are stimulated at low allelochemical concentrations and inhibited as the concentrations increase. A simple empirical model is presented to analyze this type of response. The stimulation-inhibition properties of allelochemical-dose responses can be described by the parameters in the model. The indices, p% reductions, are calculated to assess the allelochemical effects. The model is compared with experimental data for the response of lettuce seedling growth to Centaurepensin, the olfactory response of weevil larvae to α-terpineol, and the responses of annual ryegrass (Lolium multiflorum Lam.), creeping red fescue (Festuca rubra L., cv. Ensylva), Kentucky bluegrass (Poa pratensis L., cv. Kenblue), perennial ryegrass (L. perenne L., cv. Manhattan), and Rebel tall fescue (F. arundinacea Schreb) seedling growth to leachates of Rebel and Kentucky 31 tall fescue. The results show that the model gives a good description to observations and can be used to fit a wide range of dose responses. Assessments of the effects of leachates of Rebel and Kentucky 31 tall fescue clearly differentiate the properties of the allelopathic sources and the relative sensitivities of indicators such as the length of root and leaf. PMID:19330111

  6. Mathematical Modeling of Allelopathy. III. A Model for Curve-Fitting Allelochemical Dose Responses.

    Science.gov (United States)

    Liu, De Li; An, Min; Johnson, Ian R; Lovett, John V

    2003-01-01

    Bioassay techniques are often used to study the effects of allelochemicals on plant processes, and it is generally observed that the processes are stimulated at low allelochemical concentrations and inhibited as the concentrations increase. A simple empirical model is presented to analyze this type of response. The stimulation-inhibition properties of allelochemical-dose responses can be described by the parameters in the model. The indices, p% reductions, are calculated to assess the allelochemical effects. The model is compared with experimental data for the response of lettuce seedling growth to Centaurepensin, the olfactory response of weevil larvae to alpha-terpineol, and the responses of annual ryegrass (Lolium multiflorum Lam.), creeping red fescue (Festuca rubra L., cv. Ensylva), Kentucky bluegrass (Poa pratensis L., cv. Kenblue), perennial ryegrass (L. perenne L., cv. Manhattan), and Rebel tall fescue (F. arundinacea Schreb) seedling growth to leachates of Rebel and Kentucky 31 tall fescue. The results show that the model gives a good description to observations and can be used to fit a wide range of dose responses. Assessments of the effects of leachates of Rebel and Kentucky 31 tall fescue clearly differentiate the properties of the allelopathic sources and the relative sensitivities of indicators such as the length of root and leaf.

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

    LENUS (Irish Health Repository)

    Baeyens, A

    2002-12-02

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

  8. 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...

  9. Implementation of a dose-response curve for γ-radiation in the Portuguese population by use of the chromosomal aberration assay.

    Science.gov (United States)

    Martins, V; Antunes, A C; Monteiro Gil, O

    2013-01-20

    An in vitro dose-response curve following exposure to γ-radiation was determined at the IST/ITN, by use of the chromosomal aberration assay. This is the first study of this kind carried out among the Portuguese population. Un-irradiated and γ-irradiated peripheral blood lymphocytes from 16 healthy donors were cultured. A total of 22,395 metaphases were analyzed for frequency and distribution of dicentrics and centric rings, as a function of the radiation dose. The dose-response data for dicentrics and dicentrics plus centric rings were fitted by use of a linear-quadratic model: Y(dic)=(0.0011±0.0006)+(0.0105±0.0035)D+(0.0480±0.0019)D(2) and Y(dic+rings)=(0.0011±0.0006)+(0.0095±0.0036)D+(0.0536±0.0020)D(2). Also, calibration curves related to age and gender were determined, but no significant differences were found. Following the establishment of the dose-response curves, a validation experiment was carried out with three individuals. Real and estimated doses, obtained with the dose-response curves, were in agreement. These results give us confidence to apply both dose-response calibration curves in future biological dosimetry requirements.

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

    Institute of Scientific and Technical Information of China (English)

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

    2005-01-01

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

  11. Radio-sensitization by Piper longumine of human breast adenoma MDA-MB-231 cells in vitro.

    Science.gov (United States)

    Yao, Jian-Xin; Yao, Zhi-Feng; Li, Zhan-Feng; Liu, Yong-Biao

    2014-01-01

    The current study investigated the effects of Piper longumine on radio-sensitization of human breast cancer MDA-MB-231 cells and underlying mechanisms. Human breast cancer MDA-MB-231 cells were cultured in vitro and those in logarithmic growth phase were selected for experiments divided into four groups: control, X-ray exposed, Piper longumine, and Piper longumine combined with X-rays. Conogenic assays were performed to determine the radio-sensitizing effects. Cell survival curves were fitted by single-hit multi-target model and then the survival fraction (SF), average lethal dose (D0), quasi-threshold dose (Dq) and sensitive enhancement ratio (SER) were calculated. Cell apoptosis was analyzed by flow cytometry (FCM).Western blot assays were employed for expression of apoptosis-related proteins (Bc1-2 and Bax) after treatment with Piper longumine and/or X-ray radiation. The intracellular reactive oxygen species (ROS) level was detected by FCM with a DCFH-DA probe. The cloning formation capacity was decreased in the group of piperlongumine plus radiation, which displayed the values of SF2, D0, Dq significantly lower than those of radiation alone group and the sensitive enhancement ratio (SER) of D0 was1.22 and 1.29, respectively. The cell apoptosis rate was increased by the combination treatment of Piper longumine and radiation. Piper longumine increased the radiation-induced intracellular levels of ROS. Compared with the control group and individual group, the combination group demonstrated significantly decreased expression of Bcl-2 with increased Bax. Piper longumine at a non-cytotoxic concentration can enhance the radio-sensitivity of MDA- MB-231cells, which may be related to its regulation of apoptosis-related protein expression and the increase of intracellular ROS level, thus increasing radiation-induced apoptosis.

  12. Increased chromosome radiosensitivity during pregnancy

    Energy Technology Data Exchange (ETDEWEB)

    Ricoul, Michelle; Sabatier, Laure; Dutrillaux, Bernard [Commissariat a l`Energie Atomique, Laboratoire de Radiobiologie et Oncologie, DRR, DSV, Fontenay aux roses (France)

    1997-03-04

    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.

  13. Radiosensitive Severe Combined Immunodeficiency Disease

    Science.gov (United States)

    Dvorak, Christopher C.; Cowan, Morton J.

    2009-01-01

    Synopsis Inherited defects in components of the non-homologous 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 traditionally utilized for conditioning prior to allogeneic hematopoietic cell transplantation (HCT). Known etiologies of radiosensitive SCID include deficiencies of Artemis, DNA Ligase IV, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and Cernunnos-XLF, all of which have been treated with HCT. Because of their sensitivity to certain forms of chemotherapy, the approach to donor selection and type of conditioning regimen utilized for a radiosensitive SCID patient requires careful consideration. Significantly more research needs to be done in order to determine the long-term outcomes of radiosensitive SCID patients following HCT, as well as to discover novel non-toxic approaches to HCT that might benefit those with intrinsic radio- and chemo-sensitivity, as well as potentially all patients undergoing an HCT. PMID:20113890

  14. Impact of learning curve and technical changes on dosimetry in low-dose brachytherapy for prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Le Fur, E. [CHU Brest (France). Radiation Therapy Dept.; Universite de Bretagne Occidentale, Brest (France). Faculte de Medecine et des Sciences de la Sante; Malhaire, J.P.; Baverez, D.; Schlurmann, F. [CHU Brest (France). Radiation Therapy Dept.; Delage, F.; Perrouin-Verbe, M.A. [CHU Brest (France). Urology Dept.; Guerif, S. [University Hospital La Miletrie, Poitiers (France). Radiation Therapy Dept.; Poitiers Univ. (France); Fournier, G.; Valeri, A. [CHU Brest (France). Urology Dept.; Universite de Bretagne Occidentale, Brest (France). Faculte de Medecine et des Sciences de la Sante; Universite Europeenne de Bretagne, Rennes (France); APHP, Hopital Tenon, Paris (France). CeRe.PP; Pradier, O. [CHU Brest (France). Radiation Therapy Dept.; Universite de Bretagne Occidentale, Brest (France). Faculte de Medecine et des Sciences de la Sante; Universite Europeenne de Bretagne, Rennes (France); CHU Brest (France). LaTIM, INSERM U650

    2012-12-15

    Purpose: To assess the impact of experience and technical changes on peri- and postimplantation (1 month later) dosimetry for permanent prostate brachytherapy (PPB). Patients and methods: From July 2003 to May 2010, 150 prostate cancer patients underwent low-dose, loose-seed I{sup 125} PPB as monotherapy with intraoperative planning. Patients were divided into three groups - P1 (n = 64), P2 (n = 45), P3 (n = 41) - according to the technical changes that occurred during the study period: use of an automatic stepper at the beginning of P2 and a high-frequency ultrasound probe in P3. Peri- and postimplantation dosimetric parameters (on day 30) were reported: D90 (dose received by 90% of prostate volume), V100 and V150 (prostate volume receiving, respectively, 100% and 150% of the prescribed dose), D2 cc and D0.1 cc (doses received by 2 cc and 0.1 cc of the rectum), R100 (rectum volume that received 100% of the prescribed dose), and D10 and D30 (doses received by 10% and 30% of the urethra, only during peri-implantation). Results: We observed a decrease in the number of needles and seeds used over time. The mean peri-implantation D90 was 187.52 Gy without a significant difference between the three periods (p = 0.48). The postimplantation D90, V100, and V150 parameters were, respectively, 168.3 Gy, 91.9%, and 55% with no significant difference between the three periods. The peri-implantation and postimplantation D0.1 cc and R100 significantly decreased over time; on day 30: D0.1 cc P1 = 223.1 Gy vs. D0.1 cc P3 = 190.4 Gy (p = 8.10- 5) and R100 P1 = 1.06 cc vs. R100 P3 = 0.53 cc (p = 0.0008). Conclusion: We observed a learning curve for the implantation parameters, which led to a significant decrease in the rectal doses without having any impact on the prostate dosimetric parameters. (orig.)

  15. Dose-response curve of associative plasticity in human motor cortex and interactions with motor practice.

    Science.gov (United States)

    Elahi, Behzad; Hutchison, William D; Daskalakis, Z Jeff; Gunraj, Carolyn; Chen, Robert

    2014-02-01

    Associative plasticity is hypothesized to be an important neurophysiological correlate of memory formation and learning with potentials for applications in neurorehabilitation and for the development of new electrophysiological measures to study disorders of cortical plasticity. We hypothesized that the magnitude of the paired associative stimulation (PAS)-induced long-term potentiation (LTP)-like effect depends on the number of pairs in the PAS protocol. We also hypothesized that homeostatic interaction of PAS with subsequent motor learning is related to the magnitude of the PAS-induced LTP-like effect. We studied 10 healthy subjects. In experiment 1a, subjects received 90 (PAS90), 180 (PAS180), or 270 (PAS270) pairs of stimuli, followed by a dynamic motor practice (DMP) 1 h after the end of the PAS protocols. In experiment 1b, the DMP preceded the PAS protocol. In experiment 2, the time course of PAS270 was studied. We found that PAS270 resulted in greater increase in motor evoked potential (MEP) amplitude compared with protocols with fewer pairs of stimuli. Moreover, the interaction between PAS protocols with motor learning differed depending on the number of stimulus pairs used to induce PAS. While DMP alone increased MEP amplitudes, DMP during the LTP-like effects induced by PAS270 led to a long-term depression (LTD)-like effect (homeostatic interaction). This homeostatic interaction did not occur after PAS90 and PAS180. In conclusion, we found a dose-dependent effect of the number of stimulus pairs used in the PAS protocol on cortical plasticity. Homeostatic interaction between PAS and DMP was observed only after PAS270.

  16. An empirical formula to obtain tissue-phantom ratios from percentage depth-dose curves for small fields

    Science.gov (United States)

    Ding, George X.; Krauss, Rob

    2013-07-01

    For small photon fields, accurate values of a tissue-phantom ratio (TPR) are difficult to obtain either by direct measurement or by the conventional method of converting from measured percentage depth doses (%dd). This study aims to develop an empirical method to accurately obtain TPRs from %dd curves for small radiosurgery beams. The Monte Carlo simulation codes BEAMnrc/DOSXYZnrc were used to simulate the accelerator head and small, collimated fields including the circular cone accessory. The Monte Carlo directly calculated TPR values as a function of depth were compared with TPRs converted from %dd curves in a water phantom for field sizes ranging from 4 mm diameter to 10 × 10 cm2 fields. Direct measurements of TPRs were performed with the detector remaining fixed at a SAD of 100 cm and increasing the detector depth by adding water. The %dd curves were measured at 100 cm SSD in a 50 × 50 × 50 cm3 water tank. Using the Monte Carlo values, we developed an empirical formula to obtain TPRs from %dd and validated its accuracy. The conventional method of obtaining TPRs from %dd underestimate TPR by 3.4% and 0.6% at a depth 1.5 cm and overestimate TPR by 6.4% and 1.7% at a depth of 25 cm for 4 mm and 30 mm diameter circular fields, respectively. The empirical formula is derived from realistic Monte Carlo simulations using field sizes ranging from 4 to 30 mm and depth ranging from 1.5 to 25 cm. TPRs calculated using this function deviate from TPRs directly calculated from Monte Carlo by less than 0.5%. The accuracy of this empirical formula is validated against the directly measured TPRs in water. The developed empirical method has the potential to greatly simply the work in obtaining TPRs from measured %dd curves for small fields. By using this developed empirical formula the uncertainties between directly measured TPRs and converted TPRs from measured %dd curves are within 1%.

  17. Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life

    Directory of Open Access Journals (Sweden)

    Antonio W. Zuardi

    2017-05-01

    Full Text Available The purpose of this study was to investigate whether the anxiolytic effect of cannabidiol (CBD in humans follows the same pattern of an inverted U-shaped dose-effect curve observed in many animal studies. Sixty healthy subjects of both sexes aged between 18 and 35 years were randomly assigned to five groups that received placebo, clonazepam (1 mg, and CBD (100, 300, and 900 mg. The subjects were underwent a test of public speaking in a real situation (TPSRS where each subject had to speak in front of a group formed by the remaining participants. Each subject completed the anxiety and sedation factors of the Visual Analog Mood Scale and had their blood pressure and heart rate recorded. These measures were obtained in five experimental sessions with 12 volunteers each. Each session had four steps at the following times (minutes after administration of the drug/placebo, as time 0: -5 (baseline, 80 (pre-test, 153 (speech, and 216 (post-speech. Repeated-measures analyses of variance showed that the TPSRS increased the subjective measures of anxiety, heart rate, and blood pressure. Student-Newman-Keuls test comparisons among the groups in each phase showed significant attenuation in anxiety scores relative to the placebo group in the group treated with clonazepam during the speech phase, and in the clonazepam and CBD 300 mg groups in the post-speech phase. Clonazepam was more sedative than CBD 300 and 900 mg and induced a smaller increase in systolic and diastolic blood pressure than CBD 300 mg. The results confirmed that the acute administration of CBD induced anxiolytic effects with a dose-dependent inverted U-shaped curve in healthy subjects, since the subjective anxiety measures were reduced with CBD 300 mg, but not with CBD 100 and 900 mg, in the post-speech phase.

  18. Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life.

    Science.gov (United States)

    Zuardi, Antonio W; Rodrigues, Natália P; Silva, Angélica L; Bernardo, Sandra A; Hallak, Jaime E C; Guimarães, Francisco S; Crippa, José A S

    2017-01-01

    The purpose of this study was to investigate whether the anxiolytic effect of cannabidiol (CBD) in humans follows the same pattern of an inverted U-shaped dose-effect curve observed in many animal studies. Sixty healthy subjects of both sexes aged between 18 and 35 years were randomly assigned to five groups that received placebo, clonazepam (1 mg), and CBD (100, 300, and 900 mg). The subjects were underwent a test of public speaking in a real situation (TPSRS) where each subject had to speak in front of a group formed by the remaining participants. Each subject completed the anxiety and sedation factors of the Visual Analog Mood Scale and had their blood pressure and heart rate recorded. These measures were obtained in five experimental sessions with 12 volunteers each. Each session had four steps at the following times (minutes) after administration of the drug/placebo, as time 0: -5 (baseline), 80 (pre-test), 153 (speech), and 216 (post-speech). Repeated-measures analyses of variance showed that the TPSRS increased the subjective measures of anxiety, heart rate, and blood pressure. Student-Newman-Keuls test comparisons among the groups in each phase showed significant attenuation in anxiety scores relative to the placebo group in the group treated with clonazepam during the speech phase, and in the clonazepam and CBD 300 mg groups in the post-speech phase. Clonazepam was more sedative than CBD 300 and 900 mg and induced a smaller increase in systolic and diastolic blood pressure than CBD 300 mg. The results confirmed that the acute administration of CBD induced anxiolytic effects with a dose-dependent inverted U-shaped curve in healthy subjects, since the subjective anxiety measures were reduced with CBD 300 mg, but not with CBD 100 and 900 mg, in the post-speech phase.

  19. Radiosensitization: enhancing the radiation inactivation of foodborne bacteria

    Science.gov (United States)

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

    2004-09-01

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

  20. Radiosensitization: enhancing the radiation inactivation of foodborne bacteria

    Energy Technology Data Exchange (ETDEWEB)

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

    2004-10-01

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

  1. Dose response curve of induction of MN in lymphocytes for energies Cs-137; Curva dosis respuesta de induccion de micronucleos en linfocitos para las energias Cs-137

    Energy Technology Data Exchange (ETDEWEB)

    Serna Berna, A.; Alcaraz, M.; Acevedo, C.; Vicente, V.; Fuente, I. de la; Canteras, M.

    2006-07-01

    The determination of the dose-response curve is a crucial step to use the Micronucleus assay in Lymphocytes as a biological dosimeters. The most widely used fitting function is the linear-quadratic function. The coefficients are fitted by calibration data provided by irradiations of blood from healthy donors. In our case we performed the calibration curve corresponding to gamma radiation from Cesium-137 (660 keV). Doses ranged from 0 to 16 Gy. The fitting procedure used was the iteratively re weighted least square algorithm implemented in a Matlab routine. The results of the analysis of our data show that the dose-effect curve does not follow a linear-quadratic curve at high radiation doses, diminishing the quadratic parameters as dose increases. This can be interpreted as a micronucleus saturation effect beyond a certain dose level. We conclude that the MN assay with lymphocytes can be well characterized as a biological dosimeters up to a maximum dose of 4.5 Gy. (Author)

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

    Directory of Open Access Journals (Sweden)

    Kim Han

    2012-07-01

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

  3. Calculation the Received dose by gonads arising from some common diagnostic radiography

    Directory of Open Access Journals (Sweden)

    Hassan Zarghani

    2017-08-01

    Conclusion: One of the ways for patient and gonadal dose reduction is to use appropriate shields for radiosensitive organs such as gonads. Hence its recommended to use appropriate shields for gonads because of their high radiosensitivity.

  4. Modification of radiosensitivity by the so-called tissue recovery stimulator, 1; Radiosensitizing effects of solcoseryl

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Ashok; Kimura, Hiroshi; Aoyama, Takashi (Shiga University of Medical Science, Otsu (Japan)); Sugahara, Tsutomu

    1992-12-01

    The effect of solcoseryl on the growth, radiosensitization and ability of V79 cells to recover from X-ray-induced damage has been observed. Solcoseryl at 0.8 mg/ml was the optimal concentration for the stimulation of cell growth. Increased sensitivity to X-irradiation was found in the shoulder region of V79 cells treated before and after irradiation with solcoseryl (0.8 mg/ml). The Dq and extrapolation number (n) decreased. Solcoseryl treatment apparently dose not reduce split dose recovery or inhibit the repair of potentially lethal damage. Flow cytofluorometry studies of the cell cycle distribution and mitotic index show that solcoseryl inhibits the expression of radiation-induced cell arrest in the G[sub 2] phase of the cell cycle. Although this action increases radiation sensitization, additional mechanisms probably exist. (author).

  5. Predictive effect of γH2AX expression on the radiosensitivity of glioma

    Directory of Open Access Journals (Sweden)

    Jun-wei WANG

    2014-03-01

    Full Text Available Objective To observe the expression changes of γH2AX in high-grade glioma cell lines (U87, U251 and LN229 and to investigate the relationship between the expression of γ H2AX and the radiosensitivity of high-grade glioma cells in vitro.  Methods The radiosensitivity of glioma U251, U87 and LN229 cell lines were measured by clone forming assay. Afte X-ray irradiation of different doses (0, 2, 4, 6, 8 and 10 Gy, the clone forming rates of 3 cell lines were measured, and cell survival curves were drawn. The DNA double-strand break (DSB damage of 3 cell lines were determined by Western blotting assay. Results For glioma U251, U87 and LN229 cell lines, the survival fraction and clone forming rate were gradually decreased with the increase of Χ-ray radiation dose, and the radiotherapy sensitization enhancement ratio (SER of U87 cells was slightly higher compared with LN229, U251 cells (P = 0.000, for all. In the Western blotting assay, the kinetics of the expression of γH2AX protein after irradiation was featured by increase and decay. The γH2AX expression of U87, LN229 and U251 cells after irradiation reached the peak value at 2 h, 1 h and 1 h respectively (P = 0.000, 0.000, 0.015. There was positive correlation between SER and γH2AX attenuation speed (r = 0.733, P = 0.025, as well as between SER and degree of increasing (r = 0.672, P = 0.047.  Conclusions The phosphorylated histone γH2AX is expected to become a powerful tool to monitor DNA DSB and to predict the radiosensitivity in high-grade glioma nradiotherapy. doi: 10.3969/j.issn.1672-6731.2014.03.015

  6. How much is enough? Modulation of dose-response curve for steroid receptor-regulated gene expression by changing concentrations of transcription factor.

    Science.gov (United States)

    Simons, S Stoney

    2006-01-01

    The position of the dose-response curve for steroid-regulated gene expression determines how much variation in response will accompany the normal physiological changes in circulating steroid. Over the last several years, it has become clear that the concentration of steroid hormone required for half-maximal induction or repression by a given receptor-steroid complex, which is normally called the EC50, is not constant for all responsive genes. Thus, the position of the dose-response curve can change so that a single concentration of steroid produces very different percentages of maximal activity. This, in turn, allows for the differential expression of genes by a common steroid hormone concentration during development, differentiation, and homeostasis. Here we review the variety of factors that influence the EC50 and position of the dose-response curve for steroid hormone receptors, discuss what is known about the mechanisms, and highlight promising areas for future research.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-07-01

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

  8. Ganetespib radiosensitization for liver cancer therapy

    Science.gov (United States)

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

    2016-01-01

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

  9. 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...

  10. A rat model of unilateral hindpaw burn injury: slowly developing rightwards shift of the morphine dose-response curve.

    Science.gov (United States)

    Wang, Shuxing; Lim, Grewo; Yang, Liling; Zeng, Qing; Sung, Backil; Jeevendra Martyn, J A; Mao, Jianren

    2005-07-01

    Management of pain after burn injury is an unresolved clinical issue. In a rat model of hindpaw burn injury, we examined the effects of systemic morphine on nociceptive behaviors following injury. Injury was induced by immersing the dorsal part of one hindpaw into a hot water bath (85 degrees C) for 4, 7, or 12 s under pentobarbital anesthesia. Mechanical allodynia to von Frey filament stimulation and thermal hyperalgesia to radiant heat were assessed. Burn injury induced by the 12-s (but not 4-, or 7-s) hot water immersion resulted in reliable and lasting mechanical allodynia and thermal hyperalgesia evident by day 1. In addition, there was an upregulation of protein kinase Cgamma and a progressive downregulation of mu-opioid receptors within the spinal cord dorsal horn ipsilateral to injury as revealed by immunohistochemistry and Western blot. In both injured and sham rats, the anti-nociceptive effects of subcutaneous morphine were examined on post-injury days 7 and 14. While the morphine AD50 dose was comparable on day 7 between burn (1.61 mg/kg) and control (1.7 mg/kg) rats, the morphine dose-response curve was shifted to the right in burn-injured rats (4.6 mg/kg) on post-injury day 14 as compared with both the injured rats on post-injury day 7 and sham rats on day 14 (1.72 mg/kg). These data indicate that hindpaw burn injury reliably produces persistent mechanical allodynia and thermal hyperalgesia and that the reduced efficacy of morphine anti-nociception in chronic burn injury may be in part due to a downregulation of spinal mu-opioid receptors.

  11. (Depth-dose curves of the beta reference fields (147)Pm, (85)Kr and (90)Sr/(90)Y produced by the beta secondary standard BSS2.

    Science.gov (United States)

    Brunzendorf, Jens

    2012-08-01

    The most common reference fields in beta dosimetry are the ISO 6980 series 1 radiation fields produced by the beta secondary standard BSS2 and its predecessor BSS. These reference fields require sealed beta radiation sources ((147)Pm, (85)Kr or (90)Sr/(90)Y) in combination with a source-specific beam-flattening filter, and are defined only at a given distance from the source. Every radiation sources shipped with the BSS2 is sold with a calibration certificate of the Physikalisch-Technische Bundesanstalt. The calibration workflow also comprises regular depth-dose measurements. This work publishes complete depth-dose curves of the series 1 sources (147)Pm, (85)Kr and (90)Sr/(90)Y in ICRU tissue up to a depth of 11 mm,when all electrons are stopped. For this purpose, the individual depth-dose curves of all BSS2 sources calibrated so far have been determined, i.e. the complete datasets of all BSS2 beta sources have been re-evaluated. It includes 191 depth-dose curves of 116 different sources comprising more than 2200 data points in total. Appropriate analytical representations of the nuclide-specific depth-dose curves are provided for the first time.

  12. Neuropathy of nitroimidazole radiosensitizers: clinical and pathological description

    Energy Technology Data Exchange (ETDEWEB)

    Wasserman, T.H.; Nelson, J.S.; VonGerichten, D.

    1984-09-01

    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.

  13. Radiosensitivity of A. ochraceus, A. flavus, A. niger, A. parasiticus and A. carbonarius in CYA medium and on grains of rice, oat, wheat and peanuts

    Energy Technology Data Exchange (ETDEWEB)

    Borges, Valeria Barbosa [Universidade Federal Fluminense, Niteroi, RJ (Brazil). Faculdade de Veterinaria. Dept. de Tecnologia de Alimentos]. E-mail: niveam@uol.com.br; Vital, Helio de Carvalho; Hernandes, Nilber Kenup [Centro Tecnologico do Exercito, Rio de Janeiro, RJ (Brazil). Div. de Defesa Quimica, Biologica e Nuclear]. E-mail: vital@ctex.eb.br; Rosa, Carlos Alberto da Rocha [Universidade Federal Rural do Rio de Janeiro (UFRRJ), Seropedica, RJ (Brazil). Inst. de Veterinaria. Dept. de Microbiologia e Imunologia Veterinaria]. E-mail: shalako@ufrrj.br

    2007-07-01

    Irradiation is regarded as an efficient process to delay fungi growth in foods. However information on the resistance of toxigenic molds to gamma radiation is still scarce in the literature. This work investigated the radiosensitivity of five species of Aspergillus spp., namely: A. ochraceus, A. flavus, A. niger, A. parasiticus and A. carbonarius grown and irradiated in CYA medium, peanuts and on grains of rice, oat and wheat. After inoculation the colonies were stored for five days at 25 deg C and gamma irradiated with doses ranging from 0 to 5.5 kGy. Six days later the colonies were analyzed for post-irradiation growth. Survival curves were then determined as linear functions of the absorbed doses. Regardless of the substrates, the radiosensitivities of the five species have been grouped in three different levels. Expressed in terms of the parameters D{sub 50} and Do (the doses needed to reduce the number of active colonies by 50% and 100%, respectively), those groups are: D{sub 50} = 2.2 kGy and D0 = 3.2 kGy for A. ochraceus and A. carbonarius; D{sub 50} = 2.5 kGy and D0 = 4.1 kGy for A. niger and A. flavus; and D{sub 50} = 3.1 kGy and D0 = 4.7 kGy for A. parasiticus. (author)

  14. Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs.

    Science.gov (United States)

    Shen, Lin; Peterson, Susan; Sedaghat, Ahmad R; McMahon, Moira A; Callender, Marc; Zhang, Haili; Zhou, Yan; Pitt, Eleanor; Anderson, Karen S; Acosta, Edward P; Siliciano, Robert F

    2008-07-01

    Highly active antiretroviral therapy (HAART) can control HIV-1 replication, but suboptimal treatment allows for the evolution of resistance and rebound viremia. A comparative measure of antiviral activity under clinically relevant conditions would guide drug development and the selection of regimens that maximally suppress replication. Here we show that current measures of antiviral activity, including IC(50) and inhibitory quotient, neglect a key dimension, the dose-response curve slope. Using infectivity assays with wide dynamic range, we show that this slope has noteworthy effects on antiviral activity. Slope values are class specific for antiviral drugs and define intrinsic limitations on antiviral activity for some classes. Nucleoside reverse transcriptase inhibitors and integrase inhibitors have slopes of approximately 1, characteristic of noncooperative reactions, whereas non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors unexpectedly show slopes >1. Instantaneous inhibitory potential (IIP), the log reduction in single-round infectivity at clinical drug concentrations, is strongly influenced by slope and varies by >8 logs for anti-HIV drugs. IIP provides a more accurate measure of antiviral activity and in general correlates with clinical outcomes. Only agents with slopes >1 achieve high-level inhibition of single-round infectivity, a finding with profound implications for drug and vaccine development.

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

    Directory of Open Access Journals (Sweden)

    F Seif

    2008-04-01

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

  16. Calibration Curve for Dicentric Chromosomes Induced in Human Blood Lymphocytes Exposed to Gamma Rays at a Dose Rate of 12.5 mGy/s.

    Science.gov (United States)

    Que, Tran; Duy, Pham Ngoc; Luyen, Bui Thi Kim

    2016-01-01

    To develop a calibration curve for induction of dicentric chromosomes by radiation, we have used a 60Co gamma-ray source with dose rate of 12.5 mGy/s. Whole blood from 15 healthy donors was collected. Whole blood from each donor was divided equally into 8 parts for exposing to supposedly physical doses 0, 0.30, 0.50, 1.00, 1.50, 2.00, 3.00 and 4.00 Gy for a independent calibration curve. Whole blood from 15 donors was used to calibrate dose - effect and statistical for general calibration curve. Using Poisson test (U-test) for the distribution of dicentric chromosomes in the metaphases to determine the uniformity of the radiation field. The average from 15 independent calibration curves of linear correlated coefficient was determined to be r (y, d) = 0.5136 ± 0.0038. The model equation derived is y = aD + bD(2) + C. The calibration equation of dose-effect was y = 1.01D + 4.43D(2) + 0.56.

  17. Combining in vitro embryotoxicity data with physiologically based kinetic (PBK) modelling to define in vivo dose-response curves for developmental toxicity of phenol in rat and human

    NARCIS (Netherlands)

    Strikwold, M.; Spenkelink, B.; Woutersen, R.A.; Rietjens, I.M.C.M.; Punt, A.

    2013-01-01

    In vitro assays are often used for the hazard characterisation of compounds, but their application for quantitative risk assessment purposes is limited. This is because in vitro assays cannot provide a complete in vivo dose-response curve from which a point of departure (PoD) for risk assessment can

  18. Biological effects in lymphocytes irradiated with {sup 99m}Tc: determination of the curve dose-response; Efeitos biologicos em linfocitos irradiados com {sup 99m}Tc: determinacao da curva dose-resposta

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira, Romero Marcilio Barros Matias de

    2002-08-01

    Biological dosimetry estimates the absorbed dose taking into account changes in biological parameters. The most used biological indicator of an exposition to ionizing radiation is the quantification of chromosomal aberrations of lymphocytes from irradiated individuals. The curves of dose versus induced biological effects, obtained through bionalyses, are used in used in retrospective evaluations of the dose, mainly in the case of accidents. In this research, a simple model for electrons and photons transports was idealized to simulate the irradiation of lymphocytes with {sup 99m} Tc, representing a system used for irradiation of blood cells. The objective of the work was to establish a curve of dose versus frequencies of chromosomal aberrations in lymphocytes of human blood. For the irradiation of blood samples micro spheres of human serum of albumin (HSAM) market with {sup 99m} Tc were used, allowing the irradiation of blood with different administered activities of {sup 99m} Tc, making possible the study the cytogenetical effects as a function of such activities. The conditions of irradiation in vivo using HSAM spheres marked with {sup 99m} Tc were simulated with MCNP 4C (Monte Carlo N-Particle) code to obtain the dose-response curve. Soft tissue composition was employed to simulate blood tissue and the analyses of the curve of dose versus biological effect showed a linear quadratic response of the unstable chromosomal aberrations. As a result, the response of dose versus chromosomal aberrations of blood irradiation with {sup 99m} Tc was best fitted by the curve Y=(8,99 {+-}2,06) x 1-{sup -4} + (1,24 {+-}0,62) x 10{sup -2} D + (5,67 {+-} 0,64) x 10{sup -2} D{sup 2}. (author)

  19. Outliers on the dose-response curve: how to minimize this problem using therapeutic drug monitoring, an underutilized tool in psychiatry.

    Science.gov (United States)

    Preskorn, Sheldon H

    2010-05-01

    This column continues the discussion of outliers on the dose-response curve begun in earlier columns. It focuses on therapeutic drug monitoring (TDM) as an underutilized tool in psychiatry to minimize this problem. The scientific rationale for dose adjustment based on TDM is presented and its efficiency is contrasted with dose adjustment based on clinical assessment of response. In current practice, the use of TDM with psychiatric drugs is generally restricted to drugs with narrow therapeutic windows or drugs imported into psychiatry from neurology where TDM is more commonly used. Examples of each of these types of drugs are cited.

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

    Directory of Open Access Journals (Sweden)

    Yu Qian

    2015-03-01

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

  1. Modification of radiosensitivity by the so-called tissue recovery stimulator. I. Radiosensitizing effects of solcoseryl.

    Science.gov (United States)

    Kumar, A; Kimura, H; Aoyama, T; Sugahara, T

    1992-12-01

    The effect of solcoseryl on the growth, radiosensitization and ability of V79 cells to recover from X-ray-induced damage has been observed. Solcoseryl at 0.8 mg/ml was the optimal concentration for the stimulation of cell growth. Increased sensitivity to X-irradiation was found in the shoulder region of V79 cells treated before and after irradiation with solcoseryl (0.8 mg/ml). The Dq and extrapolation number (n) decreased. Solcoseryl treatment apparently does not reduce split dose recovery or inhibit the repair of potentially lethal damage. Flow cytofluorometry studies of the cell cycle distribution and mitotic index show that solcoseryl inhibits the expression of radiation-induced cell arrest in the G2 phase of the cell cycle. Although this action increases radiation sensitization, additional mechanisms probably exist.

  2. Radiosensitization of non-small cell lung cancer by kaempferol.

    Science.gov (United States)

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

    2015-11-01

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

  3. Interpretation of the margin of exposure for genotoxic carcinogens - elicitation of expert knowledge about the form of the dose response curve at human relevant exposures.

    Science.gov (United States)

    Boobis, Alan; Flari, Villie; Gosling, John Paul; Hart, Andy; Craig, Peter; Rushton, Lesley; Idahosa-Taylor, Ehi

    2013-07-01

    The general approach to risk assessment of genotoxic carcinogens has been to advise reduction of exposure to "as low as reasonably achievable/practicable" (ALARA/P). However, whilst this remains the preferred risk management option, it does not provide guidance on the urgency or extent of risk management actions necessary. To address this, the "Margin of Exposure" (MOE) approach has been proposed. The MOE is the ratio between the point of departure for carcinogenesis and estimated human exposure. However, interpretation of the MOE requires implicit or explicit consideration of the shape of the dose-response curve at human relevant exposures. In a structured elicitation exercise, we captured expert opinion on available scientific evidence for low dose-response relationships for genotoxic carcinogens. This allowed assessment of: available evidence for the nature of dose-response relationships at human relevant exposures; the generality of judgments about such dose-response relationships; uncertainties affecting judgments on the nature of such dose-response relationships; and whether this last should differ for different classes of genotoxic carcinogens. Elicitation results reflected the variability in experts' views on the form of the dose-response curve for low dose exposure and major sources of uncertainty affecting the assumption of a linear relationship.

  4. Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer.

    Science.gov (United States)

    Du, Juan; Cieslak, John A; Welsh, Jessemae L; Sibenaller, Zita A; Allen, Bryan G; Wagner, Brett A; Kalen, Amanda L; Doskey, Claire M; Strother, Robert K; Button, Anna M; Mott, Sarah L; Smith, Brian; Tsai, Susan; Mezhir, James; Goswami, Prabhat C; Spitz, Douglas R; Buettner, Garry R; Cullen, Joseph J

    2015-08-15

    The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.

  5. Dose-response curve of EBT, EBT2, and EBT3 radiochromic films to synchrotron-produced monochromatic x-ray beams

    CERN Document Server

    Brown, Thomas A D; Alvarez, Diane; Matthews, Kenneth L; Ham, Kyungmin; Dugas, Joseph P; 10.1118/1.4767770

    2012-01-01

    This work investigates the dose-response curves of GAFCHROMIC EBT, EBT2, and EBT3 radiochromic films using synchrotron-produced monochromatic x-ray beams. EBT2 film is being utilized for dose verification in photoactivated Auger electron therapy at the Louisiana State University CAMD synchrotron facility. Monochromatic beams of 25, 30, and 35 keV were generated on the tomography beamline at CAMD. Ion chamber depth-dose measurements were used to determine the dose delivered to films irradiated at depths from 0.7 to 8.5 cm in a 10x10x10-cm3 PMMA phantom. AAPM TG-61 protocol was applied to convert measured ionization into dose. Films were digitized using an Epson 1680 Professional flatbed scanner and analyzed using the net optical density (NOD) derived from the red channel. A dose-response curve was obtained at 35 keV for EBT film, and at 25, 30, and 35 keV for EBT2 and EBT3 films. Calibrations of films for 4 MV x-rays were obtained for comparison using a radiotherapy accelerator at Mary Bird Perkins Cancer Cent...

  6. Low Dose Radiation Response Curves, Networks and Pathways in Human Lymphoblastoid Cells Exposed from 1 to 10 cGy of Acute Gamma Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Wyrobek, A. J.; Manohar, C. F.; Nelson, D. O.; Furtado, M. R.; Bhattacharya, M. S.; Marchetti, F.; Coleman, M.A.

    2011-04-18

    We investigated the low dose dependency of the transcriptional response of human cells to characterize the shape and biological functions associated with the dose response curve and to identify common and conserved functions of low dose expressed genes across cells and tissues. Human lymphoblastoid (HL) cells from two unrelated individuals were exposed to graded doses of radiation spanning the range of 1-10 cGy were analyzed by transcriptome profiling, qPCR and bioinformatics, in comparison to sham irradiated samples. A set of {approx}80 genes showed consistent responses in both cell lines; these genes were associated with homeostasis mechanisms (e.g., membrane signaling, molecule transport), subcellular locations (e.g., Golgi, and endoplasmic reticulum), and involved diverse signal transduction pathways. The majority of radiation-modulated genes had plateau-like responses across 1-10 cGy, some with suggestive evidence that transcription was modulated at doses below 1 cGy. MYC, FOS and TP53 were the major network nodes of the low-dose response in HL cells. Comparison our low dose expression findings in HL cells with those of prior studies in mouse brain after whole body exposure, in human keratinocyte cultures, and in endothelial cells cultures, indicates that certain components of the low dose radiation response are broadly conserved across cell types and tissues, independent of proliferation status.

  7. 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

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

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    The aim of the present investigation is to determine initial G2-chromosome aberrations and to validate whether the G2-chromosome aberrations can predict the cellular clonogenic survival in human tumor cell lines. Cell lines of human ovary carcinoma cells (HO8910) and human hepatoma cells (HepG2) were irradiated with a range of doses and assessed both for initial G2-chromosome aberrations and for cell survival after γ-irradiation. The initial G2-chromosome aberrations were measured by counting the number of G2-chromatid breaks after irradiation, detected by the premature chromosome condensation technique, and the G2-assay method. Cell survival was documented by a colony formation assay. A linear-quadratic survival curve was observed in both cell lines. The dose-response results show that the numbers of G2-chromatid breaks increase with the increase in dose in the two cell lines. At higher doses (higher than 4 Gy) of irradiation, the number of G2-chromatid breaks for the G2-assay method cannot be determined because too few cells reach mitosis, and hence their detection is difficult. A good correlation is found between the clonogenic survival and the radiation-induced initial G2-chromatid breaks per cell (r=0.9616). The present results suggest that the premature chromosome condensation technique may be useful for determining chromatid breaks in G2 cells, and the number of initial G2-chromatid breaks holds promise for predicting the radiosensitivity of tumor cells.

  9. Establishing cytogenetic biodosimetry laboratory in Saudi Arabia and producing preliminary calibration curve of dicentric chromosomes as biomarker for medical dose estimation in response to radiation emergencies.

    Science.gov (United States)

    Al-Hadyan, Khaled; Elewisy, Sara; Moftah, Belal; Shoukri, Mohamed; Alzahrany, Awad; Alsbeih, Ghazi

    2014-12-01

    In cases of public or occupational radiation overexposure and eventual radiological accidents, it is important to provide dose assessment, medical triage, diagnoses and treatment to victims. Cytogenetic bio-dosimetry based on scoring of dicentric chromosomal aberrations assay (DCA) is the "gold standard" biotechnology technique for estimating medically relevant radiation doses. Under the auspices of the National Science, Technology and Innovation Plan in Saudi Arabia, we have set up a biodosimetry laboratory and produced a national standard dose-response calibration curve for DCA, pre-required to estimate the doses received. For this, the basic cytogenetic DCA technique needed to be established. Peripheral blood lymphocytes were collected from four healthy volunteers and irradiated with radiation doses between 0 and 5 Gy of 320 keV X-rays. Then, lymphocytes were PHA stimulated, Colcemid division arrested and stained cytogenetic slides were prepared. The Metafer4 system (MetaSystem) was used for automatic and manually assisted metaphase finding and scoring of dicentric chromosomes. Results were fit to the linear-quadratic dose-effect model according to the IAEA EPR-Biodosimetry-2011 report. The resulting manually assisted dose-response calibration curve (Y = 0.0017 + 0.026 × D + 0.081 × D(2)) was in the range of those described in other populations. Although the automated scoring over-and-under estimates DCA at low (2 Gy) doses, respectively, it showed potential for use in triage mode to segregate between victims with potential risk to develop acute radiotoxicity syndromes. In conclusion, we have successfully established the first biodosimetry laboratory in the region and have produced a preliminary national dose-response calibration curve. The laboratory can now contribute to the national preparedness plan in response to eventual radiation emergencies in addition to providing information for decision makers and public health officials who assess the

  10. Clinical experiences with the radiosensitizer Misonidazol

    Energy Technology Data Exchange (ETDEWEB)

    Bamberg, M.; Scherer, C.; Tamulevicius, P.; Streffer, C.

    1981-08-01

    The principle of action of sensitizers with electron affinity is explained and the development of these radiosensitizing substances up to the clinical of Misonidazol (MIS; Ro-07-0582) is shown. With special regard to the pharmacokinetic action of this substance, the therapeutic effects of MIS were examined in ten patients with brain tumors of high malignancy (400 mg/m/sup 2/) and four patients with oesophageal carcinomas (1 g/m/sup 2/), all these patients having reached the clinical phase III. Four other patients with recurrent brain tumors received a dose of 1 g/m/sup 2/ of MIS before each irradiation. Apart from slight neurotoxic and gastrointestinal side effects, the applicated doses of MIS were generally well tolerated. Only in one case a generalized maculopapular exanthema developed which regressed completely within few days. No correlation could be found between the subjective side effects and the plasma values determined by means of high pressure liquid chromatography (HPLC). After one to four hours following oral application, the maximum plasma concentrations were measured, the half-life (T 1/2) varying in all patients between five and ten hours. It was not possible to demonstrate an influence of dexamethasone on the plasma concentration of half-life of MIS in the brain tumor patients. The cerebrospinal fluid concentrations of MIS which may be used as an index for the concentrations in brain tumors, are closely correlated with the corresponding plasma values. There was no correlation between MIS concentrations in plasma and saliva, so that the determination of MIS in the saliva cannot be recommended as a routine method for control examinations.

  11. Numb/Notch signaling pathway modulation enhances human pancreatic cancer cell radiosensitivity.

    Science.gov (United States)

    Bi, Yi-Liang; Min, Min; Shen, Wei; Liu, Yan

    2016-11-01

    The present study aims to evaluate whether repression of the Numb/Notch signaling pathway affects the radiosensitivity of human pancreatic cancer cell lines. Different doses of X-rays (0, 2, 3, 4, and 5 Gy) were applied to the PANC-1, SW1990, and MIA PaCa-2 human pancreatic cancer cell lines, and the Numb/Notch pathway inhibitor DAPT was added at different doses (0, 1, 3, and 5 μmol/l). MTT assay, colony formation assay, flow cytometry, scratch assay, and Transwell experiments were performed, and qRT-PCR and Western blot were conducted for the detection of Numb expression. Tumorigenicity assay in nude mice was carried out to verify the influence of blocker of the Numb/Notch signaling pathway on the radiosensitivity of xenograft tumors. The MTT assay, colony formation assay and flow cytometry experiments revealed that proliferation decreased as radiation dose increased. The viability of PANC-1 cells at 5 Gy, SW 1990 cells at 4 Gy and 5 Gy, and MIA PaCa-2 cells at 2-5 Gy was significantly lower than that of non-irradiated cells (all P cancer cells is associated with X-ray radiation and that inhibition of the Numb/Notch signaling pathway can enhance radiosensitivity, suggesting that inhibition of the Numb/Notch signaling pathway may serve as a potential target for clinical improvement of the radiosensitivity of pancreatic cancer.

  12. Effects of solcoseryl to the radiosensitivity of the cells

    Energy Technology Data Exchange (ETDEWEB)

    Kimura, H.; Ikebuchi, M.; Otsu, Y.; Aoyama, T. (Shiga Univ. of Medical Science, Otsu (Japan)); Morimoto, K.

    1981-07-01

    CHO cells derived from chinese hamster were used to study effects of solcoseryl to the radiosensitivity. Radiosensitivity of the cells was decreased by solcoseryl both under low and normal oxygen pressure. Addition of solcoseryl before or after irradiation was effective to decrease the radiosensitivity. Proliferation of the cells was not effected by solcoseryl, suggesting that the decrease of the radiosensitivity was not due to the injuries of the cell proliferation or disturbance of the cell cycle. When a deconjugating agent coexisted, the radiosensitivity was not further affected by the addition of solcoseryl, which suggested that there is a common mechanism to modify radiosensitivity between solcoseryl and deconjugating agents.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1994-06-01

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

  14. Calibration curve to establish the exposure dose at Co{sup 60} gamma radiation; Curva de calibracion para establecer dosis de exposicion a radiacion gamma de Co{sup 60}

    Energy Technology Data Exchange (ETDEWEB)

    Guerrero C, C.; Brena V, M. [Departamento de Biologia, Instituto Nacional de Investigaciones Nucleares, A.P. 18-1027, Mexico D.F. (Mexico)

    2000-07-01

    The biological dosimetry is an adequate method for the dose determination in cases of overexposure to ionizing radiation or doubt of the dose obtained by physical methods. It is based in the aberrations analysis produced in the chromosomes. The behavior of leisure in chromosomes is of dose-response type and it has been generated curves in distinct laboratories. Next is presented the curve for gamma radiation produced in the National Institute of Nuclear Research (ININ) laboratory. (Author)

  15. The suitable dose range for the calibration of EBT2 film by the PDD method with a comparison of two curve fitting algorithms

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Liyun, E-mail: cliyun2000@gmail.com [Department of Medical Imaging and Radiological Sciences, I-Shou University, Kaohsiung, Taiwan (China); Ho, Sheng-Yow [Department of Radiation Oncology, Chi Mei Medical Center, Liouying, Tainan, Taiwan (China); Lee, Tsair-Fwu [Medical Physics and Informatics Laboratory, Department of Electronics Engineering, National Kaohsiung University of Applied Sciences, Kaohsiung, Taiwan (China); Yeh, Shyh-An [Department of Medical Imaging and Radiological Sciences, I-Shou University, Kaohsiung, Taiwan (China); Department of Radiation Oncology, E-Da Hospital, Kaohsiung, Taiwan (China); Ding, Hueisch-Jy [Department of Medical Imaging and Radiological Sciences, I-Shou University, Kaohsiung, Taiwan (China); Chen, Pang-Yu, E-mail: pangyuchen@yahoo.com.tw [Department of Radiation Oncology, Sinlau Christian Hospital, Tainan, Taiwan (China)

    2015-03-21

    EBT2 film is a convenient dosimetry quality-assurance (QA) tool with high 2D dosimetry resolution and a self-development property for use in verifications of radiation therapy treatment planning and special projects; however, the user will suffer from a relatively higher degree of uncertainty (more than ±6% by Hartmann et al. [29]), and the trouble of cutting one piece of film into small pieces and then reintegrating them each time. To prevent this tedious cutting work, and save calibration time and budget, a dose range analysis is presented in this study for EBT2 film calibration using the Percentage–Depth–Dose (PDD) method. Different combinations of the three dose ranges, 9–26 cGy, 33–97 cGy and 109–320 cGy, with two types of curve fitting algorithms, film pixel values and net optical densities converting into doses, were tested and compared. With the lowest error and acceptable inaccuracy of less than 3 cGy for the clinical dose range (9–320 cGy), a single film calibrated by the net optical density algorithm with the dose range 109–320 cGy was suggested for routine calibration.

  16. Dose-response curve of EBT, EBT2, and EBT3 radiochromic films to synchrotron-produced monochromatic x-ray beams

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Thomas A. D.; Hogstrom, Kenneth R.; Alvarez, Diane; Matthews, Kenneth L. II; Ham, Kyungmin; Dugas, Joseph P. [Mary Bird Perkins Cancer Center, 4950 Essen Lane, Baton Rouge, Louisiana 70809 and Department of Physics and Astronomy, Louisiana State University and A and M College, 202 Nicholson Hall, Baton Rouge, Louisiana 70803 (United States); Department of Physics and Astronomy, Louisiana State University and A and M College, 202 Nicholson Hall, Baton Rouge, Louisiana 70803 (United States); Center for Advanced Microstructures and Devices, Louisiana State University and A and M College, 6980 Jefferson Highway, Baton Rouge, Louisiana 70806 (United States); Mary Bird Perkins Cancer Center, 4950 Essen Lane, Baton Rouge, Louisiana 70809 and Department of Physics and Astronomy, Louisiana State University and A and M College, 202 Nicholson Hall, Baton Rouge, Louisiana 70803 (United States)

    2012-12-15

    Purpose: This work investigates the dose-response curves of GAFCHROMIC{sup Registered-Sign} EBT, EBT2, and EBT3 radiochromic films using synchrotron-produced monochromatic x-ray beams. EBT2 film is being utilized for dose verification in photoactivated Auger electron therapy at the Louisiana State University Center for Advanced Microstructures and Devices (CAMD) synchrotron facility. Methods: Monochromatic beams of 25, 30, and 35 keV were generated on the tomography beamline at CAMD. Ion chamber depth-dose measurements were used to determine the dose delivered to films irradiated at depths from 0.7 to 8.5 cm in a 10 Multiplication-Sign 10 Multiplication-Sign 10-cm{sup 3} polymethylmethacrylate phantom. AAPM TG-61 protocol was applied to convert measured ionization into dose. Films were digitized using an Epson 1680 Professional flatbed scanner and analyzed using the net optical density (NOD) derived from the red channel. A dose-response curve was obtained at 35 keV for EBT film, and at 25, 30, and 35 keV for EBT2 and EBT3 films. Calibrations of films for 4 MV x-rays were obtained for comparison using a radiotherapy accelerator at Mary Bird Perkins Cancer Center. Results: The sensitivity (NOD per unit dose) of EBT film at 35 keV relative to that for 4-MV x-rays was 0.73 and 0.76 for doses 50 and 100 cGy, respectively. The sensitivity of EBT2 film at 25, 30, and 35 keV relative to that for 4-MV x-rays varied from 1.09-1.07, 1.23-1.17, and 1.27-1.19 for doses 50-200 cGy, respectively. For EBT3 film the relative sensitivity was within 3% of unity for all three monochromatic x-ray beams. Conclusions: EBT and EBT2 film sensitivity showed strong energy dependence over an energy range of 25 keV-4 MV, although this dependence becomes weaker for larger doses. EBT3 film shows weak energy dependence, indicating that it would be a better dosimeter for kV x-ray beams where beam hardening effects can result in large changes in the effective energy.

  17. Behaviors of the percentage depth dose curves along the beam axis of a phantom filled with different clinical PTO objects, a Monte Carlo Geant4 study

    Science.gov (United States)

    EL Bakkali, Jaafar; EL Bardouni, Tarek; Safavi, Seyedmostafa; Mohammed, Maged; Saeed, Mroan

    2016-08-01

    The aim of this work is to assess the capabilities of Monte Carlo Geant4 code to reproduce the real percentage depth dose (PDD) curves generated in phantoms which mimic three important clinical treatment situations that include lung slab, bone slab, bone-lung slab geometries. It is hoped that this work will lead us to a better understanding of dose distributions in an inhomogeneous medium, and to identify any limitations of dose calculation algorithm implemented in the Geant4 code. For this purpose, the PDD dosimetric functions associated to the three clinical situations described above, were compared to one produced in a homogeneous water phantom. Our results show, firstly, that the Geant4 simulation shows potential mistakes on the shape of the calculated PDD curve of the first physical test object (PTO), and it is obviously not able to successfully predict dose values in regions near to the boundaries between two different materials. This is, surely due to the electron transport algorithm and it is well-known as the artifacts at interface phenomenon. To deal with this issue, we have added and optimized the StepMax parameter to the dose calculation program; consequently the artifacts due to the electron transport were quasi disappeared. However, the Geant4 simulation becomes painfully slow when we attempt to completely resolve the electron artifact problems by considering a smaller value of an electron StepMax parameter. After electron transport optimization, our results demonstrate the medium-level capabilities of the Geant4 code to modeling dose distribution in clinical PTO objects.

  18. Radiosensitization by the novel DNA intercalating agent vosaroxin

    Directory of Open Access Journals (Sweden)

    Gordon Ira K

    2012-02-01

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

  19. Agarose overlay selectively improves macrocolony formation and radiosensitivity assessment in primary fibroblasts.

    Science.gov (United States)

    Chandna, Sudhir; Dagur, Raghubendra Singh; Mathur, Ankit; Natarajan, Adayapalam Tyagarajan; Harms-Ringdahl, Mats; Haghdoost, Siamak

    2014-05-01

    Primary fibroblasts are not suitable for in vitro macrocolony assay due to their inability to form distinct colonies. Here we present a modification of agarose overlay that yielded extensive improvement in their colony formation and assessment of radiosensitivity. Macrocolony formation was assessed in primary human fibroblasts VH10 and HDFn with or without overlay using 0.5% agarose in growth medium at 24 h post-seeding. Malignant human cell lines (A549, U87) and transformed non-malignant fibroblasts (AA8 hamster, MRC5 human) were used for comparison. Agarose overlay caused significant improvement marked by early appearance (one week) of distinct colonies with high cell density and multifold higher plating efficiency than conventional macrocolony assay in VH10 and HDFn human fibroblasts. Compared to conventional assay or feeder cell supplementation, agarose overlay resulted in broader cell morphology due to improved adherence, and yielded more compact colonies. Gamma-radiation dose-response survival curves could be successfully generated for both fibroblast cell lines using this method, which yielded no such effects in the transformed/malignant cell lines tested. This easy and inexpensive 'agarose overlay technique' significantly and selectively improves the fibroblast plating efficiency, thus considerably reducing time and effort to greatly benefit the survival studies on primary fibroblasts.

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

    Energy Technology Data Exchange (ETDEWEB)

    Agoni, Lorenzo [Department of Pathology, Albert Einstein College of Medicine, Bronx, New York (United States); Basu, Indranil [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Gupta, Seema [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Biophysics Research Institute of America, North Miami Beach, Florida (United States); Alfieri, Alan [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Gambino, Angela [Department of Gynecologic Oncology, University of Brescia, Brescia (Italy); Goldberg, Gary L. [Department of Gynecologic Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Reddy, E. Premkumar [Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York (United States); Guha, Chandan, E-mail: cguha@montefiore.org [Department of Pathology, Albert Einstein College of Medicine, Bronx, New York (United States); Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States)

    2014-04-01

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

  1. Hyperthermic radiosensitization : mode of action and clinical relevance

    NARCIS (Netherlands)

    Kampinga, HH; Dikomey, E

    2001-01-01

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

  2. For whom the bell (curve) tolls: cortisol rapidly affects memory retrieval by an inverted U-shaped dose-response relationship.

    Science.gov (United States)

    Schilling, Thomas M; Kölsch, Monika; Larra, Mauro F; Zech, Carina M; Blumenthal, Terry D; Frings, Christian; Schächinger, Hartmut

    2013-09-01

    Stress and cortisol are generally considered to impair declarative memory retrieval, although opposite results have also been reported. Dose-dependent effects and differences between genomic and non-genomic cortisol effects are possible reasons for these discrepancies. The aim of the current experiment was to assess the non-genomic effects of escalating doses of intravenous cortisol on cued recall of socially relevant information in humans. 40 participants (age range 20-30 years; 20 females) learned associations between male faces with a neutral facial expression and descriptions of either positive or negative social behaviors and were tested one week later in a cued recall paradigm. Escalating doses of cortisol (0, 3, 6, 12, 24 mg) were administered 8 min before testing according to a between-subjects design. An inverted U-shaped dose-response relationship between salivary cortisol levels and recall performance was observed, with moderate elevation of salivary cortisol resulting in the best recall performance. This is the first study in humans demonstrating that cortisol rapidly modulates declarative memory retrieval via a dose-dependent, non-genomic mechanism that follows an inverted U-shaped curve. Our result further emphasizes the importance of fast cortisol effects for human cognition.

  3. Equivalent intraperitoneal doses of ibuprofen supplemented in drinking water or in diet: a behavioral and biochemical assay using antinociceptive and thromboxane inhibitory dose–response curves in mice

    Directory of Open Access Journals (Sweden)

    Raghda A.M. Salama

    2016-07-01

    Full Text Available Background. Ibuprofen is used chronically in different animal models of inflammation by administration in drinking water or in diet due to its short half-life. Though this practice has been used for years, ibuprofen doses were never assayed against parenteral dose–response curves. This study aims at identifying the equivalent intraperitoneal (i.p. doses of ibuprofen, when it is administered in drinking water or in diet. Methods. Bioassays were performed using formalin test and incisional pain model for antinociceptive efficacy and serum TXB2 for eicosanoid inhibitory activity. The dose–response curve of i.p. administered ibuprofen was constructed for each test using 50, 75, 100 and 200 mg/kg body weight (b.w.. The dose–response curves were constructed of phase 2a of the formalin test (the most sensitive phase to COX inhibitory agents, the area under the ‘change in mechanical threshold’-time curve in the incisional pain model and serum TXB2 levels. The assayed ibuprofen concentrations administered in drinking water were 0.2, 0.35, 0.6 mg/ml and those administered in diet were 82, 263, 375 mg/kg diet. Results. The 3 concentrations applied in drinking water lay between 73.6 and 85.5 mg/kg b.w., i.p., in case of the formalin test; between 58.9 and 77.8 mg/kg b.w., i.p., in case of the incisional pain model; and between 71.8 and 125.8 mg/kg b.w., i.p., in case of serum TXB2 levels. The 3 concentrations administered in diet lay between 67.6 and 83.8 mg/kg b.w., i.p., in case of the formalin test; between 52.7 and 68.6 mg/kg b.w., i.p., in case of the incisional pain model; and between 63.6 and 92.5 mg/kg b.w., i.p., in case of serum TXB2 levels. Discussion. The increment in pharmacological effects of different doses of continuously administered ibuprofen in drinking water or diet do not parallel those of i.p. administered ibuprofen. It is therefore difficult to assume the equivalent parenteral daily doses based on mathematical calculations.

  4. 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)

  5. Radiosensitivity of glial progenitor cells of the perinatal and adult rat optic nerve studied by an in vitro clonogenic assay

    Energy Technology Data Exchange (ETDEWEB)

    Maazen, R.W.M. van der; Verhagen, I.; Kleiboer, B.J.; Kogel, A.J. van der (Nijmegen University (Netherlands). Institute of Radiotherapy)

    1991-04-01

    The cellular basis of radiation-induced demyelination and white matter necrosis of the central nervous system (CNS), is poorly understood. Glial cells responsible for myelination in the CNS might be the target cells of this type of damage. Glial cells with stem cell properties derived from the perinatal and adult rat CNS can be cultured in vitro. These cells are able to differentiate into oligodendrocytes or type-2 astrocytes (O-2A) depending on the culture conditions. Growth factors produced by monolayers of type-1 astrocytes inhibit premature differentiation of O-2A progenitor cells and allow colony formation. A method which employs these monolayers of type-1 astrocytes to culture O-2A progenitor cells has been adapted to allow the analysis of colonies of surviving cells after X-irradiation. In vitro survival curves were obtained for glial progenitor cells derived from perinatal and adult optic nerves. The intrinsic radiosensitivity of perinatal and adult O-2A progenitor cells showed a large difference. Perinatal O-2A progenitor cells are quite radiosensitive, in contrast to adult O-2A progenitor cells. For both cell types an inverse relationship was found between the dose and the size of colonies derived from surviving cells. Surviving O-2A progenitor cells maintain their ability to differentiate into oligo-dendrocytes or type-2 astrocytes. This system to assess radiation-induced damage to glial progenitor cells in vitro systems to have a great potential in unraveling the cellular basis of radiation-induced demyelinating syndromes of the CNS. (author). 28 refs.; 4 figs.; 1 tab.

  6. Combining in vitro embryotoxicity data with physiologically based kinetic (PBK) modelling to define in vivo dose-response curves for developmental toxicity of phenol in rat and human.

    Science.gov (United States)

    Strikwold, Marije; Spenkelink, Bert; Woutersen, Ruud A; Rietjens, Ivonne M C M; Punt, Ans

    2013-09-01

    In vitro assays are often used for the hazard characterisation of compounds, but their application for quantitative risk assessment purposes is limited. This is because in vitro assays cannot provide a complete in vivo dose-response curve from which a point of departure (PoD) for risk assessment can be derived, like the no observed adverse effect level (NOAEL) or the 95 % lower confidence limit of the benchmark dose (BMDL). To overcome this constraint, the present study combined in vitro data with a physiologically based kinetic (PBK) model applying reverse dosimetry. To this end, embryotoxicity of phenol was evaluated in vitro using the embryonic stem cell test (EST), revealing a concentration-dependent inhibition of differentiation into beating cardiomyocytes. In addition, a PBK model was developed on the basis of in vitro and in silico data and data available from the literature only. After evaluating the PBK model performance, effective concentrations (ECx) obtained with the EST served as an input for in vivo plasma concentrations in the PBK model. Applying PBK-based reverse dosimetry provided in vivo external effective dose levels (EDx) from which an in vivo dose-response curve and a PoD for risk assessment were derived. The predicted PoD lies within the variation of the NOAELs obtained from in vivo developmental toxicity data from the literature. In conclusion, the present study showed that it was possible to accurately predict a PoD for the risk assessment of phenol using in vitro toxicity data combined with reverse PBK modelling.

  7. Cardiovascular effects of indapamide in hypertensive patients with or without renal failure. A dose-response curve.

    Science.gov (United States)

    Leenen, F H; Smith, D L; Farkas, R M; Boer, W H; Reeves, R A; Marquez-Julio, A

    1988-01-29

    Fifteen patients with mild-to-moderate hypertension (10 with normal and five with decreased renal function) were studied after treatment with placebo and low (1 mg), intermediate (2.5 mg), and high (5.0 mg per day) doses of indapamide, each for four weeks. Six patients--five with normal renal function--were classified as nonresponders (decrease in diastolic blood pressure less than 5 mm Hg). The remaining nine patients had dose-related decreases in blood pressure. Patients with or without renal failure showed similar decreases in blood pressure. Blood pressure reduction was associated with a significant decrease in cardiac index in the responders at the highest dose, related to a decrease in left ventricular end-diastolic dimension and stroke volume, whereas heart rate did not increase. This apparent decrease in venous return was associated with a significant decrease in body weight but not plasma volume in the responders. Indapamide did not change plasma norepinephrine levels, but decreased pressor responsiveness to exogenous norepinephrine. Responders had lower initial plasma renin activity and a smaller absolute increase in plasma renin activity while receiving indapamide, whereas angiotensin II pressor responsiveness was decreased more. The results presented indicate that the blood pressure lowering effect of indapamide in the present patient population is observed with or without renal failure and is associated with a decrease in pressor reactivity. In nonresponders, compensatory mechanisms (e.g., renin) may negate the antihypertensive effect of indapamide.

  8. Cellular and molecular mechanisms affecting tumour radiosensitivity : An in vitro study

    Science.gov (United States)

    Power, Olive Mary

    The response of tumour cells in vitro to ionising radiation can, to a certain extent, predict the response of tumours to various radiotherapy treatment modalities. This thesis considers some of the factors known to be involved in the radiation response of human tumour cells in vitro. These parameters include radiation-induced cell-cycle perturbations, apoptosis and DNA damage repair. A panel of eight human tumour cell lines with markedly differing radiosensitivities were assessed in order to determine the key factors governing their radiation response. A wide range of doses spanning both the low dose region (0-2 Gy and 0-5 Gy) and the clinically relevant region (1-4 Gy) were used to determine whether differences in responses could distinguish cells which were radiosensitive or resistant. Ionising radiation produced a cell cycle delay in all cell lines in one or both of the cellular checkpoints. A Gl/S delay was detected in those cell lines that expressed wild-type p53, and the duration of this delay appeared to be directly related to the level of constitutive protein. p53 protein stabilisation was observed after 4 h, even at doses of 0-2 Gy, although a Gl/S delay was only detectable at higher doses. There was no direct relationship between p53 status and survival although wild-type p53 expression was more prevalent in the radiosensitive cell lines (3/4 sensitives are wild-type versus 2/4 resistants). A G2/M delay could only be detected at doses of > 1 Gy. This delay appeared to be dose independent in the resistant cell lines, suggesting a threshold dose of IGy, above which no further effect is observed. A radiation-induced reduction of cyclin B1 protein was observed in all cell lines implicating this protein in the induction of a G2/M delay. The duration of G2/M delay was significantly longer in the radiosensitive cell lines at 4 Gy (7-20 h versus 4-6 h at 4 Gy). The proportion of cells that exited the G2/M block and re-entered GO/G1 phase was also significantly

  9. Is there association between handedness and radiosensitivity in breast cancer women?

    Science.gov (United States)

    Khosravifarsani, Meysam; Monfared, Ali Shabestani; Elahimanesh, Farideh; Borzoueisileh, Sajad; Hajian-Tilaki, Karimollah; Seyfizadeh, Nayer; Amiri, Mehrangiz

    2012-12-01

    Radiosensitivity is a biological response to radiation. This response depends on many factors such as radiation factors as well as biological system factors. It is shown that identical doses of radiation for the treatment of Cancer patients produce different biological responses that are assumed to be depend on different specifications of the biological systems. However, by elimination of these factors, people may still show different biological responses such as acute and low responses to radiotherapy in similar doses of radiation. Some reports indicate that breast cancer, immune diseases including autoimmune diseases such as lupus, Myasthenia Gravies and even the rate of allergy are more frequent in left-handed compared to right-handed individuals. The main goal of the present study is determination of radiosensitivity in left-handed compared to right-handed in breast cancer women by cytogenetic assay. Peripheral venous blood samples (10 ml) of 30 breast cancer women (10 left- and 20 right-handed) were divided into two identical parts. One part is exposed to 2 Gy Co-60 gamma rays, and the second part is considered as non-exposed controls. Lymphocytes were cultured in standard media, and cytokinesis blocked to score micronuclei in bi-nucleated cells. The frequency of micronuclei in 1,000 cells in each sample is considered as the rate of radiosensitivity and was compared in left- and right-handed breast cancer women by appropriate statistical analysis. Results showed that radiosensitivity index in left-handers is higher than right-handers also mean frequency of MN in exposed group of left-handers compare to right-handers is elevated. It seems that left-handed breast cancer women are more radiosensitive than right-handed. More investigations on right- and left-handed healthy people are ongoing in our laboratory.

  10. 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.

  11. Oligo dements Se, Zn, Mn Plus Lachesin Muta as Radioprotectors of Normal Tissues and Radiosensitizers 9 p.

    Energy Technology Data Exchange (ETDEWEB)

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

    2004-07-01

    The in vitro effect of O-LM on radiosensitivity of different human cell lines and the in vivo tolerance to high doses of ionizing radiation induced by the combination of Se, Zm and Mn plus Lachesis muta (O-LM) was evaluated. Sprague-Dawley rats received whole-body irradiation with a single dose (2 to 15 Gy) employing a ''137Cs source of 189 TB{sub q} (7.7 Gy/min). A half of rats received daily se O-LM starting 10 days before irradiation. these animals receiving 8, 10, and 12mGy showed significantly higher survival versus controls (p<0.0001, 0.003 and 0.0083, respectively). ''30LD{sub 5}0 value for O-LM treated rats was 9,6 Gy vs. 5.8 Gy for controls (p<0.0001). the protective effect of O-LM was also in vivo evaluated on small intestine and bone marrow of nude mice irradiated with a single whole-body dose of 10 Gy. Mice were sacrificed 5 days after irradiation. Mice receiving se daily O-LM starting 90 days before irradiation, showed better villous and crypts conservation, lack of oedema and vascular damage in comparison to controls. Bone marrows of treated animals showed grade I-II aplasia instead of grade III aplasia in control ones. For in vitro studies, MDA-231 cells (human breast carcinoma) and HBL-100 (normal mammary epithelium) were irradiated with 0-10 Gy employing the same source. Cell cultures were treated with O-Lm for 24 hs previous and up to 24 hs post-irradiation. Number of colonies over 50 cells where counted after 10 days. Cell surviving curves indicated that O-LM produced a significant decrease (p<0.001) in survival of transformed cells while no difference was observed in normal HBL-100. These results demonstrated a protective effect on normal tissues exerted by O-LM for in vivo high doses of ionizing irradiation and a significant increase in radiosensitivity ono the transformed MDA-231cells but not in normal HBL-100 cells. (Author) 11 refs.

  12. 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.

  13. Radiosensitivity of tumor cells. Oncogenes and apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Peltenburg, L. T. C. [Leiden Univ., Leiden (Netherlands). Dept. of Clinical Oncology

    2000-12-01

    The success of treatment of cancer patients by radiotherapy largely depends on tumor radiosensitivity. Several molecular factors that determine the sensitivity of tumor cells to ionizing radiation have been identified during the last couple of years. Some of these factors are known as oncogenes and tumor suppressor genes. This review focuses on the influence of some of these molecular factors on a major determinant of radiosensitivity: i. e. programmed cell death or apoptosis. The crucial molecular step in ionizing radiation-induced apoptosis is the release of mitochondrial cytochrome c into the cell's cytosol. The ways the tumor suppressor protein p53, as well as the oncogenes ras and raf, c-myc and Bcl-2 can influence this process at different stages are presented. As will be discussed, the result of activation of an oncoprotein on tumor radiosensitivity depends on its mechanism of action and on the presence of other (oncogenic) factors, since complex interactions among many molecular factors determine the delicate balance between cell proliferation and cell death. The ongoing identification and characterization of factors influencing apoptosis will eventually make it possible to predict tumor radiosensitivity and thereby improve cancer treatment.

  14. On the mechanism of salivary gland radiosensitivity

    NARCIS (Netherlands)

    Konings, AWT; Coppes, RP; Vissink, A

    2005-01-01

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

  15. A New Drug Combinatory Effect Prediction Algorithm on the Cancer Cell Based on Gene Expression and Dose-Response Curve.

    Science.gov (United States)

    Goswami, C Pankaj; Cheng, L; Alexander, P S; Singal, A; Li, L

    2015-02-01

    Gene expression data before and after treatment with an individual drug and the IC20 of dose-response data were utilized to predict two drugs' interaction effects on a diffuse large B-cell lymphoma (DLBCL) cancer cell. A novel drug interaction scoring algorithm was developed to account for either synergistic or antagonistic effects between drug combinations. Different core gene selection schemes were investigated, which included the whole gene set, the drug-sensitive gene set, the drug-sensitive minus drug-resistant gene set, and the known drug target gene set. The prediction scores were compared with the observed drug interaction data at 6, 12, and 24 hours with a probability concordance (PC) index. The test result shows the concordance between observed and predicted drug interaction ranking reaches a PC index of 0.605. The scoring reliability and efficiency was further confirmed in five drug interaction studies published in the GEO database.

  16. The use of in vitro toxicity data and physiologically based kinetic modeling to predict dose-response curves for in vivo developmental toxicity of glycol ethers in rat and man.

    Science.gov (United States)

    Louisse, Jochem; de Jong, Esther; van de Sandt, Johannes J M; Blaauboer, Bas J; Woutersen, Ruud A; Piersma, Aldert H; Rietjens, Ivonne M C M; Verwei, Miriam

    2010-12-01

    At present, regulatory assessment of systemic toxicity is almost solely carried out using animal models. The European Commission's REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration-response curves for specific target cells, whereas in vivo dose-response curves are regularly used for human risk assessment. The present study shows an approach to predict in vivo dose-response curves for developmental toxicity by combining in vitro toxicity data and in silico kinetic modeling. A physiologically based kinetic (PBK) model was developed, describing the kinetics of four glycol ethers and their embryotoxic alkoxyacetic acid metabolites in rat and man. In vitro toxicity data of these metabolites derived in the embryonic stem cell test were used as input in the PBK model to extrapolate in vitro concentration-response curves to predicted in vivo dose-response curves for developmental toxicity of the parent glycol ethers in rat and man. The predicted dose-response curves for rat were found to be in concordance with the embryotoxic dose levels measured in reported in vivo rat studies. Therefore, predicted dose-response curves for rat could be used to set a point of departure for deriving safe exposure limits in human risk assessment. Combining the in vitro toxicity data with a human PBK model allows the prediction of dose-response curves for human developmental toxicity. This approach could therefore provide a means to reduce the need for animal testing in human risk assessment practices.

  17. 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

  18. Dose-dependent effect of 17 beta-estradiol determined by growth curves and flow cytometric DNA analysis of a human breast carcinoma (T61) grown in nude mice

    DEFF Research Database (Denmark)

    Brünner, N; Spang-Thomsen, M; Vindeløv, L

    1985-01-01

    of the treatment was evaluated using growth curves and flow cytometric DNA analysis. The treatment induced a dose-dependent growth delay and dose-dependent changes in the cell cycle distribution. The cell cycle changes comprised a decrease in the G1 phase, an accumulation of cells in the S phase, and an increasing...

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

    OpenAIRE

    Khosravifarsani, Meysam; Monfared, Ali Shabestani; Akhavan-Niaki, Haleh; Moslemi, Dariush; Hajian-Tilaki, Karimollah; Elahimanesh, Farideh; Borzoueisileh, Sajad; Seyfizadeh, Nayer; Amiri, Mehrangiz

    2012-01-01

    Background Radiosensitivity is an inheriting trait that mainly depends on genetic factors. it is well known in similar dose of ionizing radiation and identical biological characteristics 9–10 percent of normal population have higher radiation response. Some reports indicate that distribution of breast cancer, immune diseases including autoimmune diseases as example lupus, Myasthenia Gravies and even the rate of allergy are more frequent in left handed individuals compared to right handed indi...

  20. SU-E-T-562: Scanned Percent Depth Dose Curve Discrepancy for Photon Beams with Physical Wedge in Place (Varian IX) Using Different Sensitive Volume Ion Chambers

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, H; Sarkar, V; Rassiah-Szegedi, P; Huang, Y; Szegedi, M; Huang, L; Salter, B [University Utah, Salt Lake City, UT (United States)

    2014-06-01

    Purpose: To investigate and report the discrepancy of scanned percent depth dose (PDD) for photon beams with physical wedge in place when using ion chambers with different sensitive volumes. Methods/Materials: PDD curves of open fields and physical wedged fields (15, 30, 45, and 60 degree wedge) were scanned for photon beams (6MV and 10MV, Varian iX) with field size of 5x5 and 10x10 cm using three common scanning chambers with different sensitive volumes - PTW30013 (0.6cm3), PTW23323 (0.1cm3) and Exradin A16 (0.007cm3). The scanning system software used was OmniPro version 6.2, and the scanning water tank was the Scanditronix Wellhoffer RFA 300.The PDD curves from the three chambers were compared. Results: Scanned PDD curves of the same energy beams for open fields were almost identical between three chambers, but the wedged fields showed non-trivial differences. The largest differences were observed between chamber PTW30013 and Exradin A16. The differences increased as physical wedge angle increased. The differences also increased with depth, and were more pronounced for 6MV beam. Similar patterns were shown for both 5x5 and 10x10 cm field sizes. For open fields, all PDD values agreed with each other within 1% at 10cm depth and within 1.62% at 20 cm depth. For wedged fields, the difference of PDD values between PTW30013 and A16 reached 4.09% at 10cm depth, and 5.97% at 20 cm depth for 6MV with 60 degree physical wedge. Conclusion: We observed a significant difference in scanned PDD curves of photon beams with physical wedge in place obtained when using different sensitive volume ion chambers. The PDD curves scanned with the smallest sensitive volume ion chamber showed significant difference from larger chamber results, beyond 10cm depth. We believe this to be caused by varying response to beam hardening by the wedges.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-07-01

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

  2. In vitro radiosensitization by oxaliplatin and 5-fluorouracil in a human colon cancer cell line

    Energy Technology Data Exchange (ETDEWEB)

    Kjellstroem, Johan; Kjellen, Elisabeth; Johnsson, Anders [Univ. Hospital, Lund (Sweden). Dept. of Oncology

    2005-10-01

    The current study was designed to compare the radiosensitizing effects of oxaliplatin and 5-fluorouracil (5FU) in a human colon cancer cell line. A human colon cancer cell line (S1) was treated with various doses of oxaliplatin, 5FU, radiation, and combinations thereof. Various clinically used schedules were mimicked. 5FU was either incubated during 1 h ('bolus') or 24 h ('continuous infusion'). When combining oxaliplatin and 5FU, an isobologram analysis revealed synergistic effects, regardless of 5FU schedule. The IC{sub 10} and IC{sub 50}-doses for the drugs where then combined with radiotherapy. With equitoxic drug doses (IC{sub 50}), radiosensitization was observed in the following order: oxaliplatin>5FU 24 h>5FU 1 h exposure. The degree of potentiation corresponded to approximately 0.8 Gy, 0.7 Gy, and 0.2 Gy, respectively. In this experimental setting, oxaliplatin seemed to be a better radiosensitizer than 5FU, and longer incubation time with 5FU was better than short exposure.

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

    Energy Technology Data Exchange (ETDEWEB)

    Kobayashi, Jindo; Wagatuma, Kaoru

    1987-02-01

    In irradiated mouse hematopoietic tissue, there is a group of cells which can proliferate and form macroscopic colonies. In the spleen, the colonies formed in this manner are discrete and easy to count. In order to look into a difference of radiosensitivity between male and female and the mechanisms of the modification, such as protective agent and hormones on radiosensitivity, the spleen colony forming (SCF) is used as an indicator of reactions in the x-rays irradiated mice. A linear decrease was found in SCF depended on x-rays dose. From the colony forming after irradiation the male was more radiosensitive than female. AET protected from the injury depended on the radiation dose in male mice, but in female mice, protection effects were not observed. Gonatropin showed protective effects for radiation injury on high dose irradiation both in male and female mice. Adrenaline showed similar effects as Gonatropin. Insuline showed a negative effects of protection on 400 R irradiation, while on 600 R irradiation, protective effects were observed.

  4. The potential value of the neutral comet assay and the expression of genes associated with DNA damage in assessing the radiosensitivity of tumor cells.

    Science.gov (United States)

    Jayakumar, Sundarraj; Bhilwade, Hari N; Pandey, Badri N; Sandur, Santosh K; Chaubey, Ramesh C

    2012-10-09

    The assessment of tumor radiosensitivity would be particularly useful in optimizing the radiation dose during radiotherapy. Therefore, the degree of correlation between radiation-induced DNA damage, as measured by the alkaline and the neutral comet assays, and the clonogenic survival of different human tumor cells was studied. Further, tumor radiosensitivity was compared with the expression of genes associated with the cellular response to radiation damage. Five different human tumor cell lines were chosen and the radiosensitivity of these cells was established by clonogenic assay. Alkaline and neutral comet assays were performed in γ-irradiated cells (2-8Gy; either acute or fractionated). Quantitative PCR was performed to evaluate the expression of DNA damage response genes in control and irradiated cells. The relative radiosensitivity of the cell lines assessed by the extent of DNA damage (neutral comet assay) immediately after irradiation (4Gy or 6Gy) was in agreement with radiosensitivity pattern obtained by the clonogenic assay. The survival fraction of irradiated cells showed a better correlation with the magnitude of DNA damage measured by the neutral comet assay (r=-0.9; Pcomet assay (r=-0.73; Pcomet assay was better than alkaline comet assay for assessment of radiosensitivities of tumor cells after acute or fractionated doses of irradiation.

  5. Prediction of human cell radiosensitivity: Comparison of clonogenic assay with chromosome aberrations scored using premature chromosome condensation with fluorescence in situ hybridization

    Energy Technology Data Exchange (ETDEWEB)

    Sasai, K.; Evans, J.W.; Kovacs, M.S. [Stanford Univ. School of Medicine, CA (United States)] [and others

    1994-12-01

    The purpose of the present investigation was to determine whether chromosome aberrations scored by premature chromosome condensation (PCC) and fluorescence in situ hybridization (FISH) can predict the radiosensitivity of human cell lines, thereby providing a possible means of assessing the in situ radiosensitivity of normal tissues and the radiocurability of individual human cancers. We used four cells lines of different radiosensitivity: normal human fibroblasts (AG1522), ataxia-telangiectasia fibroblasts (AT2052), a human fibrosarcoma cell line (HT1080), and a human melanoma cell line (melanoma 903). These were irradiated in plateau phase with a range of doses and assessed both for clonogenic cell survival and for aberrations in a single chromosome (number 4) immediately after, and 24 h after irradiation. The initial number of breaks in chromosome 4 was proportional to irradiation dose and was identical for all the different human cell lines, irrespective of radiosensitivity. On the other hand, the number of chromosome 4 breaks remaining 24 h after irradiation reflected the radiosensitivity of the cells such that the relationship between residual chromosome aberrations and cell survival was the same for the different cell lines. These results suggest that the scoring of chromosome aberrations in interphase using FISH with PCC holds considerable promise for predicting the radiosensitivity of normal and tumor tissues in situ. 28 refs., 4 figs.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-11-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-07-01

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

  8. ESR dosimetry of fossil enamel: some comments about measurement precision, long-term signal fading and dose-response curve fitting.

    Science.gov (United States)

    Duval, M; Guilarte Moreno, V; Grün, R

    2013-12-01

    This work deals with the specific studies of three main sources of uncertainty in electron spin resonance (ESR) dosimetry/dating of fossil tooth enamel: (1) the precision of the ESR measurements, (2) the long-term signal fading the selection of the fitting function. They show a different influence on the equivalent dose (D(E)) estimates. Repeated ESR measurements were performed on 17 different samples: results show a mean coefficient of variation of the ESR intensities of 1.20 ± 0.23 %, inducing a mean relative variability of 3.05 ± 2.29 % in the D(E) values. ESR signal fading over 5 y was also observed: its magnitude seems to be quite sample dependant but is nevertheless especially important for the most irradiated aliquots. This fading has an apparent random effect on the D(E) estimates. Finally, the authors provide new insights and recommendations about the fitting of ESR dose-response curves of fossil enamel with a double saturating exponential (DSE) function. The potential of a new variation of the DSE was also explored. Results of this study also show that the choice of the fitting function is of major importance, maybe more than the other sources previously mentioned, in order to get accurate final D(E) values.

  9. J-curve relation between daytime nap duration and type 2 diabetes or metabolic syndrome: A dose-response meta-analysis.

    Science.gov (United States)

    Yamada, Tomohide; Shojima, Nobuhiro; Yamauchi, Toshimasa; Kadowaki, Takashi

    2016-12-02

    Adequate sleep is important for good health, but it is not always easy to achieve because of social factors. Daytime napping is widely prevalent around the world. We performed a meta-analysis to investigate the association between napping (or excessive daytime sleepiness: EDS) and the risk of type 2 diabetes or metabolic syndrome, and to quantify the potential dose-response relation using cubic spline models. Electronic databases were searched for articles published up to 2016, with 288,883 Asian and Western subjects. Pooled analysis revealed that a long nap (≥60 min/day) and EDS were each significantly associated with an increased risk of type 2 diabetes versus no nap or no EDS (odds ratio 1.46 (95% CI 1.23-1.74, p Dose-response meta-analysis showed a J-curve relation between nap time and the risk of diabetes or metabolic syndrome, with no effect of napping up to about 40 minutes/day, followed by a sharp increase in risk at longer nap times. In summary, longer napping is associated with an increased risk of metabolic disease. Further studies are needed to confirm the benefit of a short nap.

  10. 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.

  11. Immunodeficiency, radiosensitivity, and the XCIND syndrome.

    Science.gov (United States)

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

    2007-01-01

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

  12. Gold nanoparticles and electroporation impose both separate and synergistic radiosensitizing effects in HT-29 tumor cells: an in vitro study

    Directory of Open Access Journals (Sweden)

    Rezaee Z

    2017-02-01

    Full Text Available Zohre Rezaee,1,2 Ali Yadollahpour,1,2 Vahid Bayati,1 Fereshteh Negad Dehbashi1 1Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Avhaz, Iran; 2Department of Medical Physics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran Background and objective: Radiation therapy (RT is the gold standard treatment for more than half of known tumors. Despite recent improvements in RT efficiency, the side effects of ionizing radiation (IR in normal tissues are a dose-limiting factor that restricts higher doses in tumor treatment. One approach to enhance the efficiency of RT is the application of radiosensitizers to selectively increase the dose at the tumor site. Gold nanoparticles (GNPs and electroporation (EP have shown good potential as radiosensitizers for RT. This study aims to investigate the sensitizing effects of EP, GNPs, and combined GNPs-EP on the dose enhancement factor (DEF for 6 MV photon energy. Methods: Radiosensitizing effects of EP, GNPs, and combinations of GNPs-EP were comparatively investigated in vitro for intestinal colon cancer (HT-29 and Chinese hamster ovary (CHO cell lines by MTT assay and colony formation assay at 6 MV photon energy in six groups: IR (control group, GNPs+IR, GNPs (24 h+IR, EP+IR, GNPs+EP+IR, and GNPs (24 h+EP+IR. Results: Treatment of both cell lines with EP, GNPs, and combined GNPs-EP significantly enhanced the response of cells to irradiation. However, the HT-29 showed higher DEF values for all groups. In addition, the DEF value for HT-29 cells for GNPs+IR, GNPs (24 h+IR, EP+IR, GNPs+EP+IR, and GNPs (24 h+EP+IR was, respectively, 1.17, 1.47, 1.36, 2.61, and 2.89, indicating synergistic radiosensitizing effect for the GNPs (24 h+EP+IR group. Furthermore, the synergistic effect was observed just for HT-29 tumor cell lines. Conclusion: Combined GNPs-EP protocols induced synergistic radiosensitizing effect in HT-29 cells, and the effect is also

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

    Science.gov (United States)

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

    1987-01-01

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

  14. Mysteries of LiF TLD response following high ionisation density irradiation: nanodosimetry and track structure theory, dose response and glow curve shapes.

    Science.gov (United States)

    Horowitz, Y; Fuks, E; Datz, H; Oster, L; Livingstone, J; Rosenfeld, A

    2011-06-01

    Three outstanding effects of ionisation density on the thermoluminescence (TL) mechanisms giving rise to the glow peaks of LiF:Mg,Ti (TLD-100) are currently under investigation: (1) the dependence of the heavy charged particle (HCP) relative efficiency with increasing ionisation density and the effectiveness of its modelling by track structure theory (TST), (2) the behaviour of the TL efficiency, f(D), as a function of photon energy and dose. These studies are intended to promote the development of a firm theoretical basis for the evaluation of relative TL efficiencies to assist in their application in mixed radiation fields. And (3) the shape of composite peak 5 in the glow curve for various HCP types and energies and following high-dose electron irradiation, i.e. the ratio of the intensity of peak 5a to peak 5. Peak 5a is a low-temperature satellite of peak 5 arising from electron-hole capture in a spatially correlated trapping centre/luminescent centre (TC/LC) complex that has been suggested to possess a potential as a solid-state nanodosemeter due to the preferential electron/hole population of the TC/LC at high ionisation density. It is concluded that (1) the predictions of TST are very strongly dependent on the choice of photon energy used in the determination of f(D); (2) modified TST employing calculated values of f(D) at 2 keV is in agreement with 5-MeV alpha particle experimental results for composite peak 5 but underestimates the 1.5-MeV proton relative efficiencies. Both the proton and alpha particle relative TL efficiencies of the high-temperature TL (HTTL) peaks 7 and 8 are underestimated by an order of magnitude suggesting that the HTTL efficiencies are affected by other factors in addition to radial electron dose; (3) the dose-response supralinearity of peaks 7 and 8 change rapidly with photon energy: this behaviour is explained in the framework of the unified interaction model as due to a very strong dependence on photon energy of the relative

  15. Neutron-photon mixed field dosimetry by TLD-700 glow curve analysis and its implementation in dose monitoring for Boron Neutron Capture Therapy (BNCT) treatments

    Energy Technology Data Exchange (ETDEWEB)

    Boggio, E. F.; Longhino, J. M. [Centro Atomico Bariloche, Departamento de Fisica de Reactores y Radiaciones / CNEA, Av. E. Bustillo Km 9.5, R8402AGP San Carlos de Bariloche (Argentina); Andres, P. A., E-mail: efboggio@cab.cnea.gov.ar [Centro Atomico Bariloche, Division Proteccion Radiologica / CNEA, Av. E. Bustillo Km 9.5, R8402AGP San Carlos de Bariloche (Argentina)

    2015-10-15

    BNCT is a cancerous cells selective, non-conventional radiotherapy modality to treat malignant tumors such as glioblastoma, melanoma and recurrent head and neck cancer. It consists of a two-step procedure: first, the patient is injected with a tumor localizing drug containing a non-radioactive isotope (Boron-10) with high slow neutron capture cross-section. In a second step, the patient is irradiated with neutrons, which are absorbed by the Boron-10 agent with the subsequently nuclear reaction B- 10(n,a)Li-7, thereby resulting in dose at cellular level due to the high-Let particles. The neutron fields suitable for BNCT are characterized by high neutron fluxes and low gamma dose. Determination of each component is not an easy task, especially when the volume of measurement is quite small or inaccessible for a miniature ionization chamber, for example. A method of measuring the photon and slow neutron dose(mainly by N-14 and B-10) from the glow curve (GC) analysis of a single {sup 7}LiF thermoluminescence detector is evaluated. This method was suggested by the group headed by Dr. Grazia Gambarini. The dosemeters used were TLD-600 ({sup 6}LiF:Mg,Ti with 95.6% {sup 6}Li) and TLD-700 ({sup 7}LiF:Mg,Ti with 99.9% {sup 7}LiF) from Harshaw. Photon dose measurement using the GC analysis method with TLD-700 in mixed fields requires the relation of the two main peaks of a TLD-600 GC shape obtained from an exposition to the same neutron field, and a photon calibrated GC with TLD-700. The requirements for slow neutron dose measurements are similar. In order to properly apply the GC analysis method at the Ra-6 Research Reactor BNCT facility, measurements were carried out in a standard water phantom, fully characterized on the BNCT beam by conventional techniques (activation detectors and paired ionization chambers technique). Next, the method was implemented in whole body dose monitoring of a patient undergoing a BNCT treatment, using a Bo MAb (Bottle Manikin Absorption) phantom

  16. 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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-12-15

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

  18. Radiosensitizing effect of intratumoral interleukin-12 gene electrotransfer in murine sarcoma

    Directory of Open Access Journals (Sweden)

    Sedlar Ales

    2013-01-01

    Full Text Available Abstract Background Interleukin-12 (IL-12 based radiosensitization is an effective way of tumor treatment. Local cytokine production, without systemic shedding, might provide clinical benefit in radiation treatment of sarcomas. Therefore, the aim was to stimulate intratumoral IL-12 production by gene electrotransfer of plasmid coding for mouse IL-12 (mIL-12 into the tumors, in order to explore its radiosensitizing effect after single or multiple intratumoral gene electrotransfer. Methods Solid SA-1 fibrosarcoma tumors, on the back of A/J mice, were treated intratumorally by mIL-12 gene electrotransfer and 24 h later irradiated with a single dose. Treatment effectiveness was measured by tumor growth delay and local tumor control assay (TCD50 assay. With respect to therapeutic index, skin reaction in the radiation field was scored. The tumor and serum concentrations of cytokines mIL-12 and mouse interferon γ (mIFNγ were measured. Besides single, also multiple intratumoral mIL-12 gene electrotransfer before and after tumor irradiation was evaluated. Results Single intratumoral mIL-12 gene electrotransfer resulted in increased intratumoral but not serum mIL-12 and mIFNγ concentrations, and had good antitumor (7.1% tumor cures and radiosensitizing effect (21.4% tumor cures. Combined treatment resulted in the radiation dose-modifying factor of 2.16. Multiple mIL-12 gene electrotransfer had an even more pronounced antitumor (50% tumor cures and radiosensitizing (86.7% tumor cures effect. Conclusions Single or multiple intratumoral mIL-12 gene electrotransfer resulted in increased intratumoral mIL-12 and mIFNγ cytokine level, and may provide an efficient treatment modality for soft tissue sarcoma as single or adjuvant therapy to tumor irradiation.

  19. 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.

  20. Determination of the survival curve of the cell irradiated with low dose rate neutrons; Determinacao da curva de sobrevivencia de celulas irradiadas com neutrons a baixa taxa de dose

    Energy Technology Data Exchange (ETDEWEB)

    Mendes, Bruno M.; Freitas, Marcelo H.A. de; Campos, Tarcisio P.R. [Minas Gerais Univ., Belo Horizonte, MG (Brazil). Dept. de Engenharia Nuclear; Silva, Luciana M.; Dias, Consuelo L.F. [Fundacao Ezequiel Dias, Belo Horizonte, MG (Brazil). Dept. de Pesquisa. Lab. de Bioquimica

    2000-07-01

    The effect of the radiation in tissue and cells are a theme of extreme importance and that is receiving large attention more and more now. This work purposes to evaluate the deleterious effects of the neutrons radiation at low dose rate in lineages of human cancerous cells through the analysis of survival curves. Deleterious effects due to radiation of low dose rate (3.8 mSv/hr) were observed in cells of the lineage HeLa S3. Previous studies, in lineage HN5 of tongue carcinoma, showed survive level to 0.2Sv of 80%, compatible to the value of 88,57% 0.4 Sv obtained for HeLa S3. In a close future, with the molecular biology characterization of a great number or possibly all cancer types (that will be accelerated largely with the conclusion of the human genome project), studies like this, can be much more specific, and could determine the efficiency of the neutrons or any other radiation type for each one of those types. Those data would have of great value for the medicine and they would help to plan the treatments better. (author)

  1. Mapping of iso exposure curves generated by conventional mobile radiodiagnostic equipment and dose in hospitalized patients; Mapeamento de curvas de isoexposicao geradas por equipamentos de radiodiagnostico moveis convencionais e dose em pacientes hospitalizados

    Energy Technology Data Exchange (ETDEWEB)

    Hoff, Gabriela; Fischer, Andreia Caroline Fischer da Silveira; Accurso, Andre, E-mail: andreia.silveira.001@acad.pucrs.b, E-mail: andre.accurso@acad.pucrs.b [Pontificia Universidade Catolica do Rio Grande do Sul (PUC/RS), Porto Alegre, RS (Brazil). Grupo de Experimentacao e Simulacacao Computacional em Fisica Medica; Andrade, Jose Rodrigo Mendes, E-mail: jose.andrade@santacasa.tche.b [Irmandade da Santa Casa de Misericordia de Porto Alegre, RS (Brazil). Servico de Atencao a Saude e Qualidade de Vida; Bacelar, Alexandre, E-mail: abacelar@hcpa.ufrgs.b [Hospital de Clinicas de Porto Alegre, RS (Brazil). Setor de Fisica Medica e Radioprotecao

    2011-10-26

    This paper intended to measure iso expositions curves in areas of mobile equipment use. It was selected: a Shimadzu mobile equipment and two Siemens equipment, being used a non-anthropomorphic scatterer. The exposure measurements in mesh of 4.20 x 4.20 cubic centimeters, at a half-height of the simulator and steps of 30 cm, were used by using the radiographic techniques: 100 k Vp and 63 m As (Shimadzu) and 96 k Vp and 40 m As (Siemens). For estimation of environmental equivalent dose, during 12 months, were considered: 3.55 m As/examination and 44.5 procedures/month (adults): and 3.16 m As/examination and 20.1 procedures/month (pediatrics). It was observed that only the values in the distance of 60 cm presented over the maximum limit of environment equivalent dose defined for Free Area (0.5 mSv/year). The points collected at 2.1 m from the primary beam center, have shown to be always 12% of referred limit, shown to be a safe distance for the hospitalized patients

  2. Curvas dose-resposta em espécies de plantas daninhas com o uso do herbicida glyphosate(1 Dose-response curves in weed species with the use of herbicide glyphosate

    Directory of Open Access Journals (Sweden)

    André Luiz de Souza Lacerda

    2004-01-01

    . The herbicide glyphosate, inhibitor of the enzyme EPSPs, was used at rate 0.0; 11.3; 22.5; 45; 90; 180; 360; 720 and 1440 g.ha-1 a.i. Curves of dose-response were made by the adjustment of the equation of the collected data of green biomass using the log-logistic model: Y = C+D-C / 1 + Exp{b[log(x-log(RC50]}, calculated by the no linear statistical model through the SAS statistical program. After the determination of the dose-response curves for the species mentioned above the Bidens pilosa was considered the most susceptible weed to glyphosate, showing the houvest RC50 (31.86 g.ha-1 a.i.. The species Tridax procumbens, Digitaria insularis, Spermacoce latifolia, Ipomoea grandifolia and Commelina benghalensis obtained RC50 equal to 58.40; 128.50; 250.44; 615.49 and > 1440.00 g.ha-1 a.i., respectively, what means that the necessary amount of herbicide to reduce in 50% the green biomass was 1.83; 4.03; 7.86; 19.31 and >359.56 times higher in relation the Bidens pilosa.

  3. α-Solanine Modulates the Radiosensitivity of Esophageal Cancer Cells by Inducing MicroRNA 138 Expression

    Directory of Open Access Journals (Sweden)

    Yuanyuan Wang

    2016-08-01

    Full Text Available Background: Esophageal cancer (EC is one of the most common malignant tumors in the world. Due to difficulties with performing the operation, most patients choose to have palliative treatment instead. Radiotherapy is one of the main palliative treatments of EC. However, the clinical efficacy of radiotherapy is not satisfactory α-Solanine is a bioactive component of steroidal glycoalkaloids which has been demonstrated to exhibit anti-metastasis activity in different cancers. In the present study, we determined the effect of α-solanine on the radiosensitivity of EC cells and priliminarily explored the underlying molecular mechanisms. Methods: Cell Counting Kit-8 (CCK-8 assay was conducted to found the cytotoxic effect of α-solanine on EC cells. CCK-8 assay and colony-forming survival assays were performed to explore the effect of α-solanine on cell viability and proliferation of EC cells after irradiation. Immunofluorescence and comet assays were used to detect the effect of α-solanine on DNA repair capacity of EC cells after irradiation. The flow cytometry (FCM and Hoechst/PI staining were conductd to study the effect of α-solanine on apoptosis of EC cells after irradiation. Results: The cytotoxic effect of α-solanine to EC cells was dose-dependent. The results of CCK-8, colony-forming survival assay, immunofluorescence, comet assay, FCM and Hoechst/PI staining showed that α-solanine could enhance the radiosensitivity of EC cells. α-Solanine could downregulate Survivin expression level by upregulating miR-138 expression in EC cells. Upregulation of miR-138 and knock down Survivin both enhanced the radiosensitivity of EC cells. Moreover, Survivin could restore the effect of α-solanine and miR-138 on radiosensitivity of EC cells. Conclusions: α-solanine could enhance the radiosensitivity of esophageal cancer cells by inducing microRNA-138 expression, and probably be an effective radiosensitizer in treating EC.

  4. Dual-function 2-nitroimidazoles as hypoxic cell radiosensitizers and bioreductive cytotoxins: In vivo evaluation in KHT murine sarcomas

    Energy Technology Data Exchange (ETDEWEB)

    Cole, S.; Stratford, I.J.; Adams, G.E.; Fielden, E.M.; Jenkins, T.C. (Medical Research Council, Didcot, Oxon (England))

    1990-10-01

    The efficacies of a series of potential prodrugs of RSU-1069 and its alkyl-aziridine analogues were assessed. These 1-(2-haloethylamino)-3-(2-nitro-1-imidazolyl)-2-propanol compounds were designed to cyclize in vivo to generate 2-nitro-imidazoles with aziridine (RSU-1069) or alkyl-substituted aziridine (RSU-1164, RB-7040, or RSU-1150) functions. Maximum tolerated single, intraperitoneal doses (MTD) were determined in C3H/He mice bearing subcutaneous KHT sarcomas, and a drug dose-response relationship for radiosensitization was established for each compound administered at the optimum time (45-60 min) before local irradiation of tumors with a 10-Gy dose of X-rays. The potentials of the compounds as bioreductive cytotoxins were studied by administering them immediately after irradiation. Tumor cell survival was measured 18-24 h after treatment in an in vitro soft agar clonogenic assay. Results of toxicity, radiosensitization, and bioreductive cytotoxicity assays for each of the prodrugs (RB-6171, RB-6172, RB-6173, RB-6174, and RB-6175) of the alkyl-substituted aziridines were entirely consistent with complete conversion to their respective target compounds. For example, RB-6171 (the prodrug form of RSU-1164) was only about four times less efficient than RSU-1069 as a radiosensitizer and bioreductive cytotoxin but had an MTD 7.5 times higher. In contrast, prodrugs of RSU-1069 (RB-6144 and RB-6145) were two- to threefold less toxic than their expected product. RB-6144 was a poor radiosensitizer and bioreductive agent compared with RSU-1069 and was similar to RB-6170, a nonalkylating nitroimidazole. This is consistent with the observation that there is limited conversion of RB-6144 to RSU-1069 in vitro. However, radiosensitization and bioreductive cytotoxicity produced by RB-6145 were only slightly less than the effects produced by RSU-1069.

  5. End-joining deficiency and radiosensitization induced by gemcitabine

    NARCIS (Netherlands)

    van Putten, JWG; Groea, HJM; Smid, K; Peters, GJ; Kampinga, HH

    2001-01-01

    The mechanism of radiosensitization by gemcitabine (2',2'-dinuoro-2'-deoxycytidine, dFdC) is not exactly known. We investigated the possible role of inhibition of the repair of DNA double-strand breaks by dFdC by measuring the extent of radiosensitization in different cell lines deficient and

  6. Interactions of tiagabine with ethosuximide in the mouse pentylenetetrazole-induced seizure model: an isobolographic analysis for non-parallel dose-response relationship curves.

    Science.gov (United States)

    Luszczki, Jarogniew J

    2008-11-01

    The aim of this study was to characterize the interaction between tiagabine (TGB) and ethosuximide (ETS), two antiepileptic drugs, in pentylenetetrazole (PTZ)-induced clonic seizures in mice using isobolographic analysis. The nature of the interaction between the drugs administered in combination was ascertained by estimating plasma and brain concentrations of ETS and TGB using fluorescence polarization immunoassay (FPIA) and high-performance liquid chromatography (HPLC). The results indicated that both drugs produced clear anticonvulsant effects against PTZ-induced clonic seizures in mice, but that their dose-response relationship curves (DRRCs) were not parallel, consequently necessitating the isobolographic analysis for non-parallel DRRCs. The isobolographic analysis revealed that the combination of TGB with ETS at the fixed-ratio of 1:1 exerted an additive interaction against PTZ-induced clonic seizures in mice. FPIA documented that TGB significantly elevated brain ETS concentrations (by 64%), while having no effect on plasma ETS concentrations in experimental animals. In contrast, ETS had no significant impact on plasma and brain concentrations of TGB in mice, as measured by HPLC. It can be concluded that the additive interaction between TGB and ETS at the fixed-ratio of 1:1 in the PTZ test was complicated by a significant pharmacokinetic increase in total brain ETS concentrations. At present, there are no recommendations to use this drug combination in epileptic patients.

  7. TU-F-CAMPUS-T-03: Enhancing the Tumor Specific Radiosensitization Using Molecular Targeted Gold Nanorods

    Energy Technology Data Exchange (ETDEWEB)

    Diagaradjane, P [M.D. Anderson Cancer Center, Houston, TX (United States); Deorukhkar, A; Sankaranarayanapillai, M; Singh, P [The UT MD Anderson Cancer Center, Houston, TX (United States); Manohar, N; Tailor, R; Cho, S [UT MD Anderson Cancer Center, Houston, TX (United States); Goodrich, G [Nanospectra Biosciences Inc, Houston, TX (United States); Krishnan, S [The University of Texas MD Anderson Cancer Center, Houston, TX (United States)

    2015-06-15

    Purpose: Gold nanoparticle (GNP) mediated radiosensitization has gained significant attention in recent years. However, the widely used passive targeting strategy requires high concentration of GNPs to induce the desired therapeutic effect, thus dampening the enthusiasm for clinical translation. The purpose of this study is to utilize a molecular targeting strategy to minimize the concentration of GNPs injected while simultaneously enhancing the tumor specific radiosensitization for an improved therapeutic outcome. Methods: Cetuximab (antibody specific to the epidermal growth factor receptor that is over-expressed in tumors) conjugated gold nanorods (cGNRs) was used for the tumor targeting. The binding affinity, internalization, and in vitro radiosensitization were evaluated using dark field microscopy, transmission electron microscopy, and clonogenic cell survival assay, respectively. In vivo biodistribution in tumor (HCT116-colorectal cancer cells) bearing mice were quantified using inductively coupled plasma mass spectrometry. In vivo radiosensitization potential was tested using 250-kVp x-rays and clinically relevant 6-MV radiation beams. Results: cGNRs displayed excellent cell-surface binding and internalization (∼31,000 vs 12,000/cell) when compared to unconjugated GNRs (pGNRs). In vitro, the dose enhancement factor at 10% survival (DEF10) was estimated as 1.06 and 1.17, respectively for both 250-kVp and 6-MV beams. In vivo biodistribution analysis revealed enhanced uptake of cGNRs in tumor (1.3 µg/g of tumor tissue), which is ∼1000-fold less than the reported values using passive targeting strategy. Nonetheless, significant radiosensitization was observed in vivo with cGNRs when compared to pGNRs, when irradiated with 250-kVp (tumor volume doubling time 35 days vs 25 days; p=0.002) and 6 MV (17 days vs 13 days; p=0.0052) beams. Conclusion: The enhanced radiosensitization effect observed with very low intratumoral concentrations of gold and megavoltage x

  8. SU-E-J-122: The CBCT Dose Calculation Using a Patient Specific CBCT Number to Mass Density Conversion Curve Based On a Novel Image Registration and Organ Mapping Method in Head-And-Neck Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, J [University of Maryland School of Medicine, Bel Air, MD (United States); Lasio, G; Chen, S; Zhang, B; Langen, K; Prado, K; D’Souza, W [University of Maryland School of Medicine, Baltimore, MD (United States); Yi, B [Univ. of Maryland School Of Medicine, Baltimore, MD (United States); Huang, J [University of Texas at Arlington, Arlington, TX (United States)

    2015-06-15

    Purpose: To develop a CBCT HU correction method using a patient specific HU to mass density conversion curve based on a novel image registration and organ mapping method for head-and-neck radiation therapy. Methods: There are three steps to generate a patient specific CBCT HU to mass density conversion curve. First, we developed a novel robust image registration method based on sparseness analysis to register the planning CT (PCT) and the CBCT. Second, a novel organ mapping method was developed to transfer the organs at risk (OAR) contours from the PCT to the CBCT and corresponding mean HU values of each OAR were measured in both the PCT and CBCT volumes. Third, a set of PCT and CBCT HU to mass density conversion curves were created based on the mean HU values of OARs and the corresponding mass density of the OAR in the PCT. Then, we compared our proposed conversion curve with the traditional Catphan phantom based CBCT HU to mass density calibration curve. Both curves were input into the treatment planning system (TPS) for dose calculation. Last, the PTV and OAR doses, DVH and dose distributions of CBCT plans are compared to the original treatment plan. Results: One head-and-neck cases which contained a pair of PCT and CBCT was used. The dose differences between the PCT and CBCT plans using the proposed method are −1.33% for the mean PTV, 0.06% for PTV D95%, and −0.56% for the left neck. The dose differences between plans of PCT and CBCT corrected using the CATPhan based method are −4.39% for mean PTV, 4.07% for PTV D95%, and −2.01% for the left neck. Conclusion: The proposed CBCT HU correction method achieves better agreement with the original treatment plan compared to the traditional CATPhan based calibration method.

  9. 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

  10. 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)

  11. 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.

  12. 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.

  13. 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

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

    Science.gov (United States)

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

    1988-03-01

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

  15. Radiosensitizing Effect of P2X7 Receptor Antagonist on Melanoma in vitro and in vivo.

    Science.gov (United States)

    Tanamachi, Keisuke; Nishino, Keisuke; Mori, Natsuki; Suzuki, Toshihiro; Tanuma, Sei-Ichi; Abe, Ryo; Tsukimoto, Mitsutoshi

    2017-03-24

    Melanoma is highly malignant, and generally exhibits radioresistance, responding poorly to radiation therapy. We previously reported that activation of P2X7, P2Y6, and P2Y12 receptors is involved in the DNA damage response after γ-irradiation of human lung adenocarcinoma A549 cells. However, it is not clear whether these receptors are also involved in the case of melanoma cells, although P2X7 receptor is highly expressed in various cancers, including melanoma. Here, we show that P2X7 receptor antagonist enhances radiation-induced cytotoxicity in B16 melanoma cells in vitro and in vivo. We confirmed that these cells express P2X7 receptor mRNA and exhibit P2X7 receptor-mediated activities, such as ATP-induced pore formation and cytotoxicity. We further examined the radiosensitizing effect of P2X7 receptor antagonist Brilliant Blue G (BBG) in vitro by colony formation assay of B16 cells. γ-Irradiation dose-dependently reduced cell survival, and pretreatment with BBG enhanced the radiation-induced cytotoxicity. BBG pretreatment also decreased the number of DNA repair foci in nuclei, supporting involvement of P2X7 receptor in the DNA damage response. Finally, we investigated the radiosensitizing effect of BBG on B16 melanoma cells inoculated into the hind footpad of C57BL/6 mice. Neither 1 Gy γ-irradiation alone nor BBG alone suppressed the increase of tumor volume, but the combination of irradiation and BBG significantly suppressed tumor growth. Our results suggest that P2X7 receptor antagonist BBG has a radiosensitizing effect in melanoma in vitro and in vivo. BBG, which is used as a food coloring agent, appears to be a promising candidate as a radiosensitizer.

  16. The in vivo radiosensitizing effect of gold nanoparticles based MRI contrast agents.

    Science.gov (United States)

    Miladi, Imen; Alric, Christophe; Dufort, Sandrine; Mowat, Pierre; Dutour, Aurélie; Mandon, Céline; Laurent, Gautier; Bräuer-Krisch, Elke; Herath, Nirmitha; Coll, Jean-Luc; Dutreix, Marie; Lux, François; Bazzi, Rana; Billotey, Claire; Janier, Marc; Perriat, Pascal; Le Duc, Géraldine; Roux, Stéphane; Tillement, Olivier

    2014-03-26

    Owing to the high atomic number (Z) of gold element, the gold nanoparticles appear as very promising radiosensitizing agents. This character can be exploited for improving the selectivity of radiotherapy. However, such an improvement is possible only if irradiation is performed when the gold content is high in the tumor and low in the surrounding healthy tissue. As a result, the beneficial action of irradiation (the eradication of the tumor) should occur while the deleterious side effects of radiotherapy should be limited by sparing the healthy tissue. The location of the radiosensitizers is therefore required to initiate the radiotherapy. Designing gold nanoparticles for monitoring their distribution by magnetic resonance imaging (MRI) is an asset due to the high resolution of MRI which permits the accurate location of particles and therefore the determination of the optimal time for the irradiation. We recently demonstrated that ultrasmall gold nanoparticles coated by gadolinium chelates (Au@DTDTPA-Gd) can be followed up by MRI after intravenous injection. Herein, Au@DTDTPA and Au@DTDTPA-Gd were prepared in order to evaluate their potential for radiosensitization. Comet assays and in vivo experiments suggest that these particles appear well suited for improving the selectivity of the radiotherapy. The dose which is used for inducing similar levels of DNA alteration is divided by two when cells are incubated with the gold nanoparticles prior to the irradiation. Moreover, the increase in the lifespan of tumor bearing rats is more important when the irradiation is performed after the injection of the gold nanoparticles. In the case of treatment of rats with a brain tumor (9L gliosarcoma, a radio-resistant tumor in a radiosensitive organ), the delay between the intravenous injection and the irradiation was determined by MRI.

  17. Radiosensitization mechanism of riboflavin in vitro

    Institute of Scientific and Technical Information of China (English)

    LIU; Guanshu(刘官树); LU; Changyuan(陆长元); YAO; Side(姚思德); ZHAO; Fang(赵芳); LI; Yu; (李雨); MENG; Xiangshun(孟祥顺); GAO; Jianguo(高建国); CAI; Jianming; (蔡建明); ZHANG; Liming(张黎明); CHEN; Zhilong(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.

  18. Actual questions raised by nanoparticle radiosensitization

    Science.gov (United States)

    Brun, Emilie; Sicard-Roselli, Cécile

    2016-11-01

    Radiosensitization by metallic nanoparticles (NP) has been explored for more than a decade with promising results in vitro and in cellulo reported in a vast number of publications. Yet, few clinical trials are on-going. This could be related to the lack of selectivity of NP leading to massive quantities to be injected to observe an effect but also to the higher degree of complexity than first thought leading to an absence of consensus probably caused by the lack of standardization in pre-clinical studies. Given the wide panel of NP used, in terms of core nature, size, coating, not to mention of cell lines and irradiation modalities, cross-comparison of data is not a walk in the park. But only a thorough examination could help identifying the key parameters and the possible mechanisms involved. This step is crucial as it should provide guidance for designing the most efficient combination NP/radiation and rationally establishing clinical protocols. In this review, we will combine and confront cellular radiosensitization results with in vitro and numerical experiments in order to give the more recent vision of this complex phenomenon. We decided to address a few hot topics such as the influence of the incident radiation energy, the localization of NP or the so-called ;biological; effect. We will highlight that among the barriers to break down, some are not restricted to the ;nano; community: an incontestable support could be offered by the ;radiation; community in the broadest sense.

  19. Effect of iron salt counter ion in dose-response curves for inactivation of Fusarium solani in water through solar driven Fenton-like processes

    Science.gov (United States)

    Aurioles-López, Verónica; Polo-López, M. Inmaculada; Fernández-Ibáñez, Pilar; López-Malo, Aurelio; Bandala, Erick R.

    2016-02-01

    The inactivation of Fusarium solani in water was assessed by solar driven Fenton-like processes using three different iron salts: ferric acetylacetonate (Fe(acac)3), ferric chloride (FeCl3) and ferrous sulfate (FeSO4). The experimental conditions tested were [Fe] ≈ 5 mg L-1, [H2O2] ≈ 10 mg L-1 and [Fe] ≈ 10 mg L-1; [H2O2] ≈ 20 mg L-1 mild and high, respectively, and pH 3.0 and 5.0, under solar radiation. The highest inactivation rates were observed at high reaction conditions for the three iron salts tested at pH 5.0 with less than 3.0 kJ L-1 of accumulate energy (QUV) to achieve over 99.9% of F. solani inactivation. Fe(acac)3 was the best iron salt to accomplishing F. solani inactivation. The modified Fermi equation was used to fix the experimental inactivation, data showed it was helpful for modeling the process, adequately describing dose-response curves. Inactivation process using FeSO4 at pH 3.0 was modeled fairly with r2 = 0.98 and 0.99 (mild and high concentration, respectively). Fe(acac)3, FeCl3 and FeSO4 at high concentration (i.e. [Fe] ≈ 10 mg L-1; [H2O2] ≈ 20 mg L-1) and pH 5.0 showed the highest fitting values (r2 = 0.99). Iron salt type showed a remarkable influence on the Fenton-like inactivation process.

  20. Mapping of isoexposure curves for evaluation of equivalent environmental doses for radiodiagnostic mobile equipment; Mapeamento de curvas de isoexposicao para avaliacao de equivalente de dose ambiente para equipamentos moveis de radiodiagnostico

    Energy Technology Data Exchange (ETDEWEB)

    Bacelar, Alexandre, E-mail: abacelar@hcpa.ufrgs.b [Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS (Brazil). Hospital de Clinicas. Setor de Fisica Medica e Radioprotecao; Andrade, Jose Rodrigo Mendes, E-mail: jose.andrade@santacasa.tche.b [Irmandade da Santa Casa de Misericordia de Porto Alegre, RS (Brazil). Servico de Atencao a Saude e Qualidade de Vida; Fischer, Andreia Caroline Fischer da Silveira; Accurso, Andre; Hoff, Gabriela, E-mail: andreia.silveira.001@acad.pucrs.b, E-mail: andre.accurso@acad.pucrs.b [Pontificia Univ. Catolica do Rio Grande do Sul (PUC/RS), Porto Alegre, RS (Brazil). Grupo de Experimentacao e Simulacao Computacional em Fisica Medica

    2011-10-26

    This paper generates iso exposure curves in areas where the mobile radiodiagnostic equipment are used for evaluation of iso kerma map and the environment equivalent dose (H{sup *}(d)). It was used a Shimadzu mobile equipment and two Siemens, with non anthropomorphic scatter. The exposure was measured in a mesh of 4.20 x 4.20 square meter in steps of 30 cm, at half height from the scatterer. The calculation of H{sup *}(d) were estimated for a worker present in all the procedures in a period of 11 months, being considered 3.55 m As/examination and 44.5 procedures/month (adult UTI) and 3.16 m As/examination and 20.1 procedure/month (pediatric UTI), and 3.16 m As/examination and 20.1 procedure/month (pediatric UTI). It was observed that there exist points where the H{sup *}(d) was over the limit established for the free area inside the radius of 30 cm from the central beam of radiation in the case of pediatric UTI and 60 cm for adult UTI. The points localized 2.1 m from the center presented values lower than 25% of those limit

  1. Establishment of radiation dose-response curve based on in vitro irradiation of peripheral blood samples by X-ray%离体人外周血血X射线照射后剂量效应曲线的建立

    Institute of Scientific and Technical Information of China (English)

    李广伟; 李峰生

    2012-01-01

    目的 建立准确估算受辐射照射者辐射剂量的方法.方法 采用X射线照射离体人外周血,一步法培养外周血淋巴细胞56 h后收获制片,检测染色体"双着丝粒(dic)+环(r)"畸变率,拟合剂量效应曲线.结果 畸变率随照射剂量增加而增加,存在明显的剂量效应,剂量效应曲线回归方程为y=0.020 8x2+0.102 8x-0.024 8,r2=0.995 3(P<0.05).结论 通过建立X射线照射离体人外周血后的剂量效应曲线,能准确估算受照辐射剂量.%Objective To establish the method of estimating accurately radiation dose of the individuals exposed to ionizing-radi-ation. Methods The blood samples in vitro were irradiated by X-ray,then cultured using one-step method for 56 hours. According to the chromosomal aberration rate(including dicentric chromosome and ring) , radiation dose-response curve was fitted. Results The chromosomal aberration rate induced by the different radiation doses increased along with the increase of radiation dose, and there was an apparent dose-response relationship,the radiation dose-response curve regression equation:y=0. 020 8x2+0. 102 8x-0. 024 8. Conclusion The dose of the individual exposed to ionizing-radiation could be estimated accurately according to the radiation dose-response curve that might be fitted by the blood samples in vitro irradiated by X-ray.

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

    Science.gov (United States)

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

    2014-09-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-09-03

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

  4. Curvas de dose-resposta para avaliação do controle de fluxos de emergência de plantas daninhas pelo herbicida imazapic Dose-response curves to evaluate the control of weed emergence fluxes by imazapic

    Directory of Open Access Journals (Sweden)

    S.J.P. Carvalho

    2005-09-01

    Full Text Available O objetivo deste trabalho foi avaliar o controle de dois fluxos de emergência das plantas daninhas capim-marmelada (Brachiaria plantaginea e capim-colchão (Digitaria horizontalis pelo herbicida imazapic, aplicado em condição de pré-emergência, por meio de curvas de dose-resposta. O delineamento experimental foi o de blocos ao acaso, com quatro repetições; cada parcela constou de um vaso de 3 L de capacidade, preenchido com solo argiloso, acrescido de sementes de capim-marmelada e capim-colchão. Sendo D a dose recomendada do imazapic (140 g ha-1, os tratamentos foram: 4D, 2D, D, 1/2D, 1/4D, 1/8D, 1/16D e ausência do herbicida. Foram realizadas avaliações visuais de controle aos 30 e 60 dias após a infestação (DAI e de massa seca aos 60 DAI. Após a colheita da biomassa resultante do primeiro fluxo de emergência presente nas parcelas, os vasos foram novamente semeados com as plantas daninhas e foram realizadas novas avaliações de controle aos 30 e 60 dias após reinfestação (DAR e de massa seca aos 60 DAR. A partir dos resultados obtidos, pode-se afirmar que: o imazapic inibiu o desenvolvimento de ambas as plantas daninhas, alcançando resultados superiores a 80% de controle em todas as avaliações, para a dose recomendada, nos dois fluxos de emergência; a eficácia no controle de capim-colchão foi ligeiramente superior à do controle do capim-marmelada; e o herbicida imazapic apresentou-se como uma opção interessante para manejo dessas plantas daninhas.The objective of this work was to evaluate the control of two emergence fluxes of the weeds Brachiaria plantaginea and Digitaria horizontalis by the herbicide imazapic applied under pre-emergence conditions, by analyzing the dose-response curves. The experimental design adopted was randomized blocks, with four replicates, with each plot being a 3L capacity pot, filled with clay soil plus Brachiaria plantaginea and Digitaria horizontalis seeds. Considering D as the

  5. Dosimetry using radiosensitive gels in radiotherapy: significance and methods; Dosimetrie par gels radiosensibles en radiotherapie. Interet et methodes

    Energy Technology Data Exchange (ETDEWEB)

    Gibon, D. [Dept. de Radiotherapie, Centre Oscar Lambret, Lille Cedex (France); Bourel, P. [Lab. de Biophysique, Inst. de Technologie Medicale, Centre Hospitalier Universitaire, Lille (France); Castelain, B. [Dept. de Radiotherapie, Centre Oscar Lambret, Lille Cedex (France); Marchandise, X.; Rousseau, J. [Lab. de Biophysique, Inst. de Technologie Medicale, Centre Hospitalier Universitaire, Lille (France)

    2001-02-01

    The goal of conformal radiotherapy is to concentrate the dose in a well-defined volume by avoiding the neighbouring healthy structures. This technique requires powerful treatment planning software and a rigorous control of estimated dosimetry. The usual dosimetric tools are not adapted to visualize and validate complex 3D treatment. Dosimetry by radiosensitive gel permits visualization and measurement of the three-dimensional dose distribution. The objective of this work is to report on current work in this field and, based on our results and our experience, to draw prospects for an optimal use of this technique. Further developments will relate to the realization of new radiosensitive gels satisfying, as well as possible, cost requirements, easy realization and use, magnetic resonance imagery (MRI) sensitivity, tissue equivalence, and stability. Other developments focus on scanning methods, especially in MRI to measure T1 and T2. (author)

  6. Relation of nuclear volume and radiosensitivity to ploidy level in higher plants and a yeast

    Energy Technology Data Exchange (ETDEWEB)

    Conger, A.D. (Temple Univ., Philadelphia, PA); Sparrow, A.H.; Schwemmer, S.S.; Klug, E.E.

    1982-01-01

    The relation between ploidy level and radiosensitivity for lethality among plants was examined to see if any major determinant could be found for the relation observed, and if any generalization could be derived. Data are presented on nuclear volume, interphase chromosome volume and acute lethal dose for x% killing for polyploid series of species within 11 genera, 117 species or varieties, of herbaceous higher plants and one species of the yeast Saccharomyces. Radiosensitivity data were obtained for 6 genera, 66 species' or varieties. In general, within any one genus, nuclear volume increases proportional to ploidy level. The relative increase of nuclear volume with ploidy is about the same for all 12 genera; it is less rapid than linear in the range 2x to 4x but almost linear from 4x to the higher ploidy levels. On the average, relative acute lethal dose of haploids is half that of diploids, is about constant from diploid to 10-diploid, and then decreases with increasing ploidy. When we compare the dose absorbed per average chromosome for x% killing, greater consistency is found both within and between genera. In general, the average haploid chromosome, and cell, is twice as sensitive as the diploid. In the range 2- to 10-ploid, chromosome sensitivity remains about constant and equal to the diploid. From 10- to 20-ploid, chromosome sensitivity increases rather smoothly up to about three to four times the diploid value for all six genera of herbaceous plants. Sensitivity of yeast chromosomes increases with ploidy at a faster rate, and to a much greater extent. In the range 2- to 10-ploid, it appears that the sensitizing effect of increased target size is about compensated for by the protective effect of the equivalent increase in genetic redundancy, leading to the net constancy in sensitivity. At the higher ploidy levels, genomic and chromosomal size do not account for the radiosensitivity increase.

  7. Comparison of organic and inorganic germanium compounds in cellular radiosensitivity and preparation of germanium nanoparticles as a radiosensitizer.

    Science.gov (United States)

    Lin, Ming-Hsing; Hsu, Tzu-Sheng; Yang, Pei-Ming; Tsai, Meng-Yen; Perng, Tsong-Pyng; Lin, Lih-Yuan

    2009-03-01

    The aim of this work is to compare the radiosensitizing effect between organic and inorganic germanium compounds and to investigate whether nanometer-sized germanium particles can act as radiosensitizers. Bis (2-carboxyethylgermanium) sesquioxide (Ge-132), germanium oxide (GeO(2)) and germanium nanoparticles were used in this study. Cell viability was determined by clonogenic survival assay. Cellular DNA damage was evaluated by alkaline comet assay, confocal microscopy and the cellular level of phospho-histone H2AX (gamma-H2AX). Nanometer-sized germanium particles were fabricated. They have a similar radiosensitizing effect as that of GeO(2). Conversely, Ge-132 did not enhance the radiosensitivity of cells. Comet assay was employed to evaluate the level of DNA damage and confirmed that inorganic germanium compounds enhanced cellular radiosensitivity. Notably, the comet assay indicated that the nanoparticle itself caused a higher level of DNA damage. The possibility that germanium nanoparticles per se caused DNA damage was ruled out when the cellular level of gamma-H2AX was examined. We demonstrated that inorganic but not organic germanium compounds exerted radiosensitizing effect in cells. Nanometer-sized germanium particles were fabricated and were able to enhance the radiosensitivity of cells. Confounding effect may occur when comet assay is used to estimate the level of DNA damage in the presence of germanium nanoparticles.

  8. SU-C-207-02: A Method to Estimate the Average Planar Dose From a C-Arm CBCT Acquisition

    Energy Technology Data Exchange (ETDEWEB)

    Supanich, MP [Rush University Medical Center, Chicago, IL (United States)

    2015-06-15

    Purpose: The planar average dose in a C-arm Cone Beam CT (CBCT) acquisition had been estimated in the past by averaging the four peripheral dose measurements in a CTDI phantom and then using the standard 2/3rds peripheral and 1/3 central CTDIw method (hereafter referred to as Dw). The accuracy of this assumption has not been investigated and the purpose of this work is to test the presumed relationship. Methods: Dose measurements were made in the central plane of two consecutively placed 16cm CTDI phantoms using a 0.6cc ionization chamber at each of the 4 peripheral dose bores and in the central dose bore for a C-arm CBCT protocol. The same setup was scanned with a circular cut-out of radiosensitive gafchromic film positioned between the two phantoms to capture the planar dose distribution. Calibration curves for color pixel value after scanning were generated from film strips irradiated at different known dose levels. The planar average dose for red and green pixel values was calculated by summing the dose values in the irradiated circular film cut out. Dw was calculated using the ionization chamber measurements and film dose values at the location of each of the dose bores. Results: The planar average dose using both the red and green pixel color calibration curves were within 10% agreement of the planar average dose estimated using the Dw method of film dose values at the bore locations. Additionally, an average of the planar average doses calculated using the red and green calibration curves differed from the ionization chamber Dw estimate by only 5%. Conclusion: The method of calculating the planar average dose at the central plane of a C-arm CBCT non-360 rotation by calculating Dw from peripheral and central dose bore measurements is a reasonable approach to estimating the planar average dose. Research Grant, Siemens AG.

  9. Preclinical Evaluation of Genexol-PM, a Nanoparticle Formulation of Paclitaxel, as a Novel Radiosensitizer for the Treatment of Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Werner, Michael E.; Cummings, Natalie D.; Sethi, Manish; Wang, Edina C.; Sukumar, Rohit [Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Moore, Dominic T. [Division of Biostatistics and Data Management, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Wang, Andrew Z., E-mail: zawang@med.unc.edu [Laboratory of Nano- and Translational Medicine, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Carolina Center for Cancer Nanotechnology Excellence, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States)

    2013-07-01

    Purpose: A key research objective in radiation oncology is to identify agents that can improve chemoradiation therapy. Nanoparticle (NP) chemotherapeutics possess several properties, such as preferential accumulation in tumors, that are uniquely suited for chemoradiation therapy. To facilitate the clinical translation of NP chemotherapeutics in chemoradiation therapy, we conducted preclinical evaluation of Genexol-PM, the only clinically approved NP chemotherapeutic with a controlled drug release profile, as a radiosensitizer using non-small cell lung cancer (NSCLC) as a model disease. Methods and Materials: The physical characteristics and drug release profile of Genexol-PM were characterized. Genexol-PM's efficacy as a radiosensitizer was evaluated in vitro using NSCLC cell lines and in vivo using mouse xenograft models of NSCLC. Paclitaxel dose to normal lung and liver after Genexol-PM administration were quantified and compared with that after Taxol administration. Results: Genexol-PM has a size of 23.91 ± 0.41 nm and surface charge of −8.1 ± 3.1 mV. It releases paclitaxel in a controlled release profile. In vitro evaluation of Genexol-PM as a radiosensitizer showed it is an effective radiosensitizer and is more effective than Taxol, its small molecule counterpart, at the half maximal inhibitory concentration. In vivo study of Genexol-PM as a radiosensitizer demonstrated that it is more effective as a radiosensitizer than Taxol. We also found that Genexol-PM leads to lower paclitaxel exposure to normal lung tissue than Taxol at 6 hours postadministration. Conclusions: We have demonstrated that Genexol-PM is more effective than Taxol as a radiosensitizer in the preclinical setting and holds high potential for clinical translation. Our data support the clinical evaluation of Genexol-PM in chemoradiation therapy for NSCLC.

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

    Energy Technology Data Exchange (ETDEWEB)

    Rockwell, S.; Kapp, D.S.

    1982-06-01

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

  11. 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

  12. Functional genomic and radiosensitivity of human keratinocytes: from differentiated to stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Lamartine, J.; Rachidi, W.; Franco, N.; Lemaitre, G.; Vaigot, P.; Le Minter, P.; Waksman, G.; Martin, M.T. [Evry Univ. Lab. of Genomic and Radiobiology of Keratinocytes, Service de Genomique Fonctionnelle, CEA, 91 (France)

    2006-07-01

    Despite improvements in radiation techniques, patients can still experience radiation toxicity on the skin. Keratinocytes from the basal layer of the epidermis have been long proposed by ICRP as the main target of ionizing radiation in human skin, both for early and late effects of radiation. But the exact roles of these cells in radiation skin damage are still largely unknown., This is why a new program was started to define the radiosensitivity of human keratinocytes according to their differentiation. In a first study was characterized the response of differentiated keratinocytes to low and high doses of gamma radiation (1). To examine whether the response to low doses was different from that induced by high doses, cultured primary keratinocytes isolated from adult normal skin were irradiated with single doses of 1 c Gray or 2 c Gy. A major finding of this study was the identification of an important number of low dose specific genes (140), most of which were modulated at 48 h. Clustering analysis also revealed low dose specific profiles. These results show for the first time that low dose ionizing irradiation is able to induce specific transcriptional responses in human keratinocytes. Then came the part to characterize the radiosensitivity of human basal keratinocytes. The results show for the first time that keratinocytes stem cells from human epidermis are more resistant than proliferative basal keratinocytes. In summary, using cellular biology and functional genomics, we are improving the knowledge on the effects of ionizing radiation on human epidermis, one of the main target tissue of radiation in the human body. (N.C.)

  13. Development of a Novel Enzyme-Targeting Radiosensitizer (New KORTUC Using a Gelatin-Based Hydrogel Instead of a Sodium Hyaluronate

    Directory of Open Access Journals (Sweden)

    Shiho Morita-Tokuhiro

    2016-01-01

    Full Text Available We recently developed Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas (KORTUC as a strategy to increase intratumoral oxygen concentrations and degrade antioxidant enzymes such as peroxidase and catalase. We then developed KORTUC II, which uses sodium hyaluronate containing hydrogen peroxide as a radiosensitizer. KORTUC II requires twice-weekly administration to sustain its effects, but decreasing the frequency of radiosensitizer injections to once-weekly would reduce the burden on the patients and the physicians. The goal of this study was thus to develop a new formulation of KORTUC (New KORTUC that only requires once-weekly administration. We performed experimental studies using a mouse tumor model and biodegradable hydrogel. C3H/He mice were allocated to control, KORTUC, or hydrogel groups. At 72 h after injection, each tumor was irradiated with a 6 MeV electron beam to a total dose of 30 Gy. During a 62-day observation period, changes in tumor volume and survival rates were assessed in each group. Tumor growth rate was slowest in the hydrogel groups. These data suggest that hydrogel could represent a useful adjunct as a long-acting radiosensitizer in place of sodium hyaluronate. New KORTUC, which contains hydrogen peroxide and hydrogel, exerted a radiosensitizing effect that persisted beyond 72 h following injection of the agent. Use of this new formulation allows radiosensitizer injections to be performed once-weekly with good effect.

  14. Inhibition on Numb/Notch signal pathway enhances radiosensitivity of lung cancer cell line H358.

    Science.gov (United States)

    Song, Shi-Gang; Yu, Hong-Yang; Ma, Yan-Wei; Zhang, Feng; Xu, Xiang-Ying

    2016-10-01

    The objective of the study is to investigate the effects of the Numb/Notch signal pathway on the radiosensitivity of lung cancer cell line H358. MTT assay and colony forming assay were used to detect the effects of different doses of X-rays and MW167 on the in vitro proliferation of the lung cancer cell line H358. Flow cytometry was applied to evaluate the effects of X rays on the apoptosis of H358. Scratch assay and Transwell invasion assay were used to examine the effects of X-rays on the migration and invasion abilities of H358. The mRNA and protein expressions in the signal pathway were detected by real-time PCR and western blot. Assays in vitro confirmed the effects of the Numb/Notch pathway inhibitor on the radiosensitivity to lung cancer. MW167 enhanced the inhibiting effects of X-ray on the proliferation of H358 cell line. After the addition of MW167, the apoptosis rates significantly increased, but the invasion and migration abilities decreased significantly. Meanwhile, MW167 could dose-dependently promote the increase of expression of Numb, which is the upstream gene of the Numb/Notch signaling pathway, but inhibit the expression of and HES1. In vivo experiments revealed that cell proliferation was suppressed in the radiation, pathway inhibitor, and pathway inhibitor + radiation groups, and the pathway inhibitor + radiation group exhibited more active anti-tumor ability when compared with the blank group (all P pathway inhibitor + radiation group exhibited more significant alternation when compared with the blank group (all P pathway inhibitor + radiation group showed more active apoptosis when compared with the blank group (all P pathway enhances the effects of radiotherapy on the radiosensitivity of the lung cancer cell line H358, and thus the Numb/Notch pathway may be a new target of radiotherapy for lung cancer.

  15. Cytogenetic Reconstruction of Gamma-Ray Doses Delivered to Atomic Bomb Survivors: Dealing with Wide Distributions of Photon Energies and Contributions from Hematopoietic Stem/Progenitor Cells.

    Science.gov (United States)

    Nakamura, Nori; Hirai, Yuko; Kodama, Yoshiaki; Hamasaki, Kanya; Cullings, Harry M; Cordova, Kismet A; Awa, Akio

    2017-08-11

    Retrospective estimation of the doses received by atomic bomb (A-bomb) survivors by cytogenetic methods has been hindered by two factors: One is that the photon energies released from the bomb were widely distributed, and since the aberration yield varies depending on the energy, the use of monoenergetic (60)Co gamma radiation to construct a calibration curve may bias the estimate. The second problem is the increasing proportion of newly formed lymphocytes entering into the lymphocyte pool with increasing time intervals since the exposures. These new cells are derived from irradiated precursor/stem cells whose radiosensitivity may differ from that of blood lymphocytes. To overcome these problems, radiation doses to tooth enamel were estimated using the electron spin resonance (ESR; or EPR, electron paramagnetic resonance) method and compared with the cytogenetically estimated doses from the same survivors. The ESR method is only weakly dependent on the photon energy and independent of the years elapsed since an exposure. Both ESR and cytogenetic doses were estimated from 107 survivors. The latter estimates were made by assuming that although a part of the cells examined could be lymphoid stem or precursor cells at the time of exposure, all the cells had the same radiosensitivity as blood lymphocytes, and that the A-bomb gamma-ray spectrum was the same as that of the (60)Co gamma rays. Subsequently, ESR and cytogenetic endpoints were used to estimate the kerma doses using individual DS02R1 information on shielding conditions. The results showed that the two sets of kerma doses were in close agreement, indicating that perhaps no correction is needed in estimating atomic bomb gamma-ray doses from the cytogenetically estimated (60)Co gamma-ray equivalent doses. The present results will make it possible to directly compare cytogenetic doses with the physically estimated doses of the survivors, which would pave the way for testing whether or not there are any systematic

  16. Nicotinamide increases thyroid radiosensitivity by stimulating nitric oxide synthase expression and the generation of organic peroxides.

    Science.gov (United States)

    Agote Robertson, M; Finochietto, P; Gamba, C A; Dagrosa, M A; Viaggi, M E; Franco, M C; Poderoso, J J; Juvenal, G J; Pisarev, M A

    2006-01-01

    Differentiated thyroid cancer and hyperthyroidism are treated with radioiodine. However, when the radioisotope dose exceeds certain limits, the patient must be hospitalized to avoid contact with people that would otherwise be exposed to radiation. It would be desirable to obtain a similar therapeutic effect using lower radioiodine doses. Radiosensitizers can be utilized for this purpose. Nicotinamide (NA) increases thyroid radiosensitivity to 131I in both normal and goitrous glands. NA causes a significant increase in thyroid blood flow, which would increase tissue oxygenation and tissue damage via free radicals. Wistar rats were treated with either nicotinamide (NA), 131I or both. The expression of the three isoforms of nitric oxide synthase (NOS) in the thyroid (Western blot) and the activities of SOD, GPx, catalase and organic peroxides were determined. Treatment with NA or 131I increased the expression of eNOS and the generation of organic peroxides. When administered jointly, they showed a synergistic effect. No changes were observed in the other NOS isoforms or in the activities of catalase, glutathione peroxidase and superoxide dismutase. NA potentiates the effect of 131I by increasing eNOS, which would in turn stimulate NO production, increasing thyroid blood flow and tissue damage via organic peroxides.

  17. Icaritin synergistically enhances the radiosensitivity of 4T1 breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Jinsheng Hong

    Full Text Available Icaritin (ICT is a hydrolytic form of icariin isolated from plants of the genus Epimedium. This study was to investigate the radiosensitization effect of icaritin and its possible underlying mechanism using murine 4T1 breast cancer cells. The combination of Icaritin at 3 µM or 6 µM with 6 or 8 Gy of ionizing radiation (IR in the clonogenic assay yielded an ER (enhancement ratio of 1.18 or 1.28, CI (combination index of 0.38 or 0.19 and DRI (dose reducing index of 2.51 or 5.07, respectively. These strongly suggest that Icaritin exerted a synergistic killing (? effect with radiation on the tumor cells. This effect might relate with bioactivities of ICT: 1 exert an anti-proliferative effect in a dose- and time-dependent manner, which is different from IR killing effect but likely work together with the IR effect; 2 suppress the IR-induced activation of two survival paths, ERK1/2 and AKT; 3 induce the G2/M blockage, enhancing IR killing effect; and 4 synergize with IR to enhance cell apoptosis. In addition, ICT suppressed angiogenesis in chick embryo chorioallantoic membrane (CAM assay. Taken together, ICT is a new radiosensitizer and can enhance anti-cancer effect of IR or other therapies.

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

    Energy Technology Data Exchange (ETDEWEB)

    Weiss, C. [Dept. of Radiation Oncology, Friedrich Alexander Univ. of Erlangen-Nuernberg, Erlangen (Germany); Div. of Radiobiology, Friedrich Alexander Univ. of Erlangen-Nuernberg, Erlangen (Germany); Grabenbauer, G.G.; Sauer, R. [Dept. of Radiation Oncology, Friedrich Alexander Univ. of Erlangen-Nuernberg, Erlangen (Germany); Distel, L. [Div. of Radiobiology, Friedrich Alexander Univ. of Erlangen-Nuernberg, Erlangen (Germany)

    2003-02-01

    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 {mu}mol/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 {mu}mol/l dFdC, 12.2-fold for 1,000 {mu}mol/l dFdC at 25 Gy) was noted. Enhancement factors were inversely correlated with increasing X-ray dose (7.8-fold for 0.5 {mu}mol/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.)

  19. Radiosensitivity to high energy iron ions is influenced by heterozygosity for Atm, Rad9 and Brca1

    Science.gov (United States)

    Zhou, G.; Smilenov, L. B.; Lieberman, H. B.; Ludwig, T.; Hall, E. J.

    2010-09-01

    Loss of function of DNA repair genes has been implicated in the development of many types of cancer. In the last several years, heterozygosity leading to haploinsufficiency for proteins involved in DNA repair was shown to play a role in genomic instability and carcinogenesis after DNA damage is induced, for example by ionizing radiation. Since the effect of heterozygosity for one gene is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes critical to pathways that control DNA damage signaling, repair or apoptosis. We investigated the role of heterozygosity for Atm, Rad9 and Brca1 on cell oncogenic transformation and cell survival induced by 1 GeV/ n56Fe ions. Our results show that cells heterozygous for both Atm and Rad9 or Atm and Brca1 have high survival rates and are more sensitive to transformation by high energy iron ions when compared with wild-type controls or cells haploinsufficient for only one of these proteins. Since mutations or polymorphisms for similar genes exist in a small percentage of the human population, we have identified a radiosensitive sub-population. This finding has several implications. First, the existence of a radiosensitive sub-population may distort the shape of the dose-response relationship. Second, it would not be ethical to put exceptionally radiosensitive individuals into a setting where they may potentially be exposed to substantial doses of radiation.

  20. RADIOSENSITIVITY TO HIGH ENERGY IRON IONS IS INFLUENCED BY HETEROZYGOSITY for ATM, RAD9 and BRCA1

    Science.gov (United States)

    Zhou, G.; Smilenov, L. B.; Lieberman, H. B.; Ludwig, T.; Hall, E. J.

    2013-01-01

    Loss of function of DNA repair genes has been implicated in the development of many types of cancer. In the last several years, heterozygosity leading to haploinsufficiency for proteins involved in DNA repair was shown to play a role in genomic instability and carcinogenesis after DNA damage is induced, for example by ionizing radiation. Since the effect of heterozygosity for one gene is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes critical to pathways that control DNA damage signaling, repair or apoptosis. We investigated the role of heterozygosity for Atm, Rad9 and Brca1 on cell oncogenic transformation and cell survival induced by 1GeV/n 56Fe ions. Our results show that cells heterozygous for both Atm and Rad9 or Atm and Brca1 have high survival rates and are more sensitive to transformation by high energy Iron ions when compared with wild-type controls or cells haploinsufficient for only one of these proteins. Since mutations or polymorphisms for similar genes exist in a small percentage of the human population, we have identified a radiosensitive sub-population. This finding has several implications. First, the existence of a radiosensitive sub-population may distort the shape of the dose-response relationship. Second, it would not be ethical to put exceptionally radiosensitive individuals into a setting where they may potentially be exposed to substantial doses of radiation. PMID:24431481

  1. The temporal organization of processes of cell reproduction and its connection with rhythms of radiosensitivity of the body

    Science.gov (United States)

    Druzhinin, Y. P.; Romanov, Y. A.; Vatsek, A.

    1974-01-01

    Radiosensitivity of individual phases of the mitotic cycle was studied in synchronous cell cultures and in several biological objects. It was found that radiosensitivity changed essentially according to phases of the mitotic cycle, depending on the kind of cells, evaluation criteria and the radiation dosage. Tests on partially synchronized HeLa cell populations, according to the criterion of survival, showed them most sensitive during mitosis, as well as in later G sub 1- or early DNA-synthesizing stages. With radiation in doses of 300 rad, the proportion of surviving cells showed a sensitivity directly before DNA synthesis of approximately 4 times higher than the later S-phase and during the major portion of G sub 1- and G sub 2-periods. Sensitivity of cells in mitosis was approximately 3 times higher than in late G sub 1- and early S-phases.

  2. Characterization and radiosensitivity of fibroblasts derived from squamous cell carcinomas of the head and neck, and the surrounding oral mucosa

    Energy Technology Data Exchange (ETDEWEB)

    Stausboel-Groen, B.; Moeller Bentzen, S. [Danish Cancer Society, Aarhus (Denmark). Dept. of Experimental Clinical Oncology; Overgaard, J. [Danish Cancer Society, Aarhus (Denmark). Dept. of Experimental Clinical Oncology]|[Danish Cancer Society, Aarhus (Denmark). Dept. of Oncology

    1998-12-31

    Recently, extensive stromal fibroblast contamination has been reported in the modified Courtenay-Mills soft agar clonogenic assay for cellular in vitro radiosensitivity in tumour biopsies. The aim of the present study was to evaluate the hypothesis that an immunocytochemical analysis added to the modified Courtenay-Mills soft agar clonogenic assay provides a measure of both fibroblast and tumour cell radiosensitivity. Therefore, fibroblast derived from squamos cell carcinomas of the head and neck, and from the surrounding oral mucosa were compared for immunocytochemistry, DNA ploidy, plating efficiency and surviving fraction of cells after a radiation dose of 2 Gy. The results of our study suggest that the stromal fibroblast derived from tumour biopsies are representative of normal fibroblasts with respect to the characteristics examined using mucosal fibroblasts as normal controls. (orig.)

  3. Foot-and-mouth disease vaccine potency testing: the influence of serotype, type of adjuvant, valency, fractionation method, and virus culture on the dose-response curve in cattle.

    Science.gov (United States)

    Jamal, Syed M; Bouma, Annemarie; van den Broek, Jan; Stegeman, Arjan; Chénard, Gilles; Dekker, Aldo

    2008-11-25

    The aim of this study was to determine a relationship between vaccine potency (amount of PD50 per dose) and fraction of clinically protected cattle following homologous challenge with infectious foot-and-mouth disease (FMD) virus, and to determine the effect of method of fractionation, serotype, type of adjuvant, valency and type of virus culture on the dose-response curve. Data from 297 potency tests of FMD vaccines, comprising 4004 vaccinated cattle, performed at the FMD vaccine production facility in the Netherlands, were used for the present study. A generalised linear mixed effect model was used to analyse the results. Our study showed that the relation between FMD vaccine potency and fraction protected was also affected by the serotype and type of adjuvant. No common level of protection could be assigned to all FMD vaccines with the same amount of PD50 per dose, this information is essential when designing a new standard FMD vaccines control.

  4. Nuclear 3D organization and radiosensitivity

    Science.gov (United States)

    Eidelman, Y. A.; Slanina, S. V.; Aleshchenko, A. V.; Sen'ko, O. V.; Kononkova, A. D.; Andreev, S. G.

    2017-01-01

    Current mechanisms of radiation-induced chromosomal aberration (CA) formation suggest misrepair of chromosomal lesions being in spatial proximity. In this case CAs have to depend on pattern of chromosomal contacts and on chromosome spatial organization in a cell nucleus. We were interested in whether variation of nucleus 3D organization results in difference of radiation induced CA formation frequency. Experimental data available do not provide information sufficient for definite conclusions. To have more deep insight in this issue we developed the biophysical modeling technique taking into account different levels of chromosome/nuclear organization and radiation damage of DNA and chromosomes. Computer experiments on gamma irradiation were carried out for two types of cells with different 3D organization of nuclei, preferentially peripheral and internal. CA frequencies were found to depend on spatial positioning of chromosomes within a nucleus which determines a pattern of interchromosomal contacts. For individual chromosomes this effect can be more pronounced than for genome averaged. Since significant part of aberrations, for example dicentrics, results in cell death, the proposed technique is capable of evaluating radiosensitivity of cells, both normal and cancer, with the incorporation of 3D genome information. This predictive technology allows to reduce uncertainties of prognosis of biological effects of radiation compared to phenomenological methods and may have variety of biomedical applications, in particular, in cancer radiation therapy.

  5. Radiosensitivity and cancer-related genes

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Akihisa; Ohnishi, Takeo [Nara Medical Univ., Kashihara (Japan)

    1997-03-01

    The influence of several cancer-related genes, myc, fos, jun, ras, raf mos, cot, src, erbB, bcl-2, RB and p53, on radiosensitivity has been shown by tranfection studies. This review focuses on the functions of growth arrest, DNA repair and apoptosis regulated by these cancer-related genes. Resistance to apoptosis has emerged as a major category of radiation sensitivity. In the near future, it might be clear which of the cancer-related genes acts in an important role in apoptosis pathway after irradiation. In addition, there is no direct evidence in the activation of DNA repair during the cell cycle arrest. Therefore, identification of factors directly acting on radiation sensitivity will offer new strategies in cancer predictical assay using biopsied tumor specimens in radiotherapy. Further studies are must to be carried out for detection of common mutations in cancer-related genes for predictical assay and the potential for induction of apoptosis by radiotherapy and genetherapy. (author). 107 refs.

  6. Radiosensitizing and Hyperthermic Properties of Hyaluronan Conjugated, Dextran-Coated Ferric Oxide Nanoparticles: Implications for Cancer Stem Cell Therapy

    Directory of Open Access Journals (Sweden)

    Ranjeeta Thapa

    2015-01-01

    Full Text Available Cytotoxicity, radiosensitivity, and hyperthermia sensitivity of hyaluronan-mediated dextran-coated super paramagnetic iron oxide nanoparticles (HA-DESPIONs were assessed in CD44-expressing head and neck squamous cell carcinoma (HNSCC cell lines at clinically relevant radiation dose and temperatures. Low-passage HNSCC cells were exposed to HA-DESPIONs and cytotoxicity was assessed using MTT assay. Radiosensitizing properties of graded doses of HA-DESPIONs were assessed in both unsorted and CD44-sorted cells using clonogenic assay in combination with 2 Gy exposure to X-rays. Hyperthermia-induced toxicity was measured at 40°C, 41°C, and 42°C using clonogenic assay. Cell death was assessed 24 hours after treatment using a flow cytometry-based apoptosis analysis. Results showed that HA-DESPIONs were nontoxic at moderate concentrations and did not directly radiosensitize the cell lines. Further, there was no significant difference in the radiosensitivity of CD44high and CD44low cells. However, HA-DESPIONs enhanced the effect of hyperthermia which resulted in reduced cell survival that appeared to be mediated through apoptosis. We demonstrated that HA-DESPIONs are nontoxic and although they do not enhance radiation sensitivity, they did increase the effect of local hyperthermia. These results support further development of drug-attached HA-DESPIONs in combination with radiation for targeting cancer stem cells (CSCs and the development of an alternating magnetic field approach to activate the HA-DESPIONs attached to CSCs.

  7. Kinetic Modeling Reveals the Roles of Reactive Oxygen Species Scavenging and DNA Repair Processes in Shaping the Dose-Response Curve of KBrO₃-Induced DNA Damage.

    Science.gov (United States)

    Spassova, Maria A; Miller, David J; Nikolov, Alexander S

    2015-01-01

    We have developed a kinetic model to investigate how DNA repair processes and scavengers of reactive oxygen species (ROS) can affect the dose-response shape of prooxidant induced DNA damage. We used as an example chemical KBrO3 which is activated by glutathione and forms reactive intermediates that directly interact with DNA to form 8-hydroxy-2-deoxyguanosine DNA adducts (8-OH-dG). The single strand breaks (SSB) that can result from failed base excision repair of these adducts were considered as an effect downstream from 8-OH-dG. We previously demonstrated that, in the presence of effective base excision repair, 8-OH-dG can exhibit threshold-like dose-response dependence, while the downstream SSB can still exhibit a linear dose-response. Here we demonstrate that this result holds for a variety of conditions, including low levels of GSH, the presence of additional SSB repair mechanisms, or a scavenger. It has been shown that melatonin, a terminal scavenger, inhibits KBrO3-caused oxidative damage. Our modeling revealed that sustained exposure to KBrO3 can lead to fast scavenger exhaustion, in which case the dose-response shapes for both endpoints are not substantially affected. The results are important to consider when forming conclusions on a chemical's toxicity dose dependence based on the dose-response of early genotoxic events.

  8. Proton and photon beams interaction with radiosensitizing agents in human glioblastoma cells

    Science.gov (United States)

    Lafiandra, M.

    2016-03-01

    In oncological field, chemoradiotherapy treatments that combine radiations to radiosensitizing chemical agents are spreading out. The aim of this kind of treatment is to obtain a better tumor local control and at the same time to reduce the distant failure. The combination of radiation with microtubule-stabilizing agents is very promising in cancer therapy. In the present study, the combination of clinical proton beams and the microtubule-stabilizing agent Epothilone B has been investigated in human glioblastoma cells cultured in vitro. Photon beams have been used for comparison. Cell survival has been evaluated by colony forming assay and the interaction mechanism between radiation and Epothilone B has been investigated: survival curves relative to the combined treatment (protons or photons with Epothilone B) showed a linear trend, different from the linear quadratic behavior found with radiation alone. The analysis performed showed a synergism in the radiation-drug interaction. Thus, Epothilone B in conjunction with radiation acts as a radiosensitizer. Finally proton Relative Biological Effectiveness has been determined and results are reported in this paper.

  9. 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.

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

    Directory of Open Access Journals (Sweden)

    Bearss David

    2009-12-01

    Full Text Available Abstract Purpose 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. Materials and methods 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. Results 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. Conclusions 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. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-11-12

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

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

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

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

  14. Cytogenetic monitoring, radiosensitivity study and adaptive response of workers exposed to low level ionizing radiation; Monitorizacao citogenetica, estudo de radiossensibilidade e resposta adaptativa em profissionais expostos a baixos niveis de radiacao ionizante

    Energy Technology Data Exchange (ETDEWEB)

    Peitl Junior, Paulo

    1996-07-01

    The objectives of the present study were: To determine the frequencies of chromosome aberrations in lymphocytes from individuals belonging to professionally exposed groups, under normal conditions; to determine the possible differences in radiosensitivity between the lymphocytes of technicians and controls after in vitro irradiation with gamma rays during the G{sub 1} phase of the cell cycle (radiosensitivity study), and to examine the influence of in vivo and in vitro pre-exposure to low doses of radiation on the frequency of chromosome aberrations induced in vitro by high doses (study of the adaptive response) in a group of technicians (T) compared to controls (C). (author)

  15. Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants

    Science.gov (United States)

    Asaad, N. A.; Zeng, Z. C.; Guan, J.; Thacker, J.; Iliakis, G.

    2000-01-01

    The radiosensitizing effect of caffeine has been associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints, but several lines of evidence also implicate inhibition of DNA repair. The role of DNA repair inhibition in caffeine radiosensitization remains uncharacterized, and it is unknown which repair process, or lesion, is affected. We show that a radiosensitive cell line, mutant for the RAD51 homolog XRCC2 and defective in homologous recombination repair (HRR), displays significantly diminished caffeine radiosensitization that can be restored by expression of XRCC2. Despite the reduced radiosensitization, caffeine effectively abrogates checkpoints in S and G2 phases in XRCC2 mutant cells indicating that checkpoint abrogation is not sufficient for radiosensitization. Another radiosensitive line, mutant for XRCC3 and defective in HRR, similarly shows reduced caffeine radiosensitization. On the other hand, a radiosensitive mutant (irs-20) of DNA-PKcs with a defect in non-homologous end-joining (NHEJ) is radiosensitized by caffeine to an extent comparable to wild-type cells. In addition, rejoining of radiation-induced DNA DSBs, that mainly reflects NHEJ, remains unaffected by caffeine in XRCC2 and XRCC3 mutants, or their wild-type counterparts. These observations suggest that caffeine targets steps in HRR but not in NHEJ and that abrogation of checkpoint response is not sufficient to explain radiosensitization. Indeed, immortalized fibroblasts from AT patients show caffeine radiosensitization despite the checkpoint defects associated with ATM mutation. We propose that caffeine radiosensitization is mediated by inhibition of stages in DNA DSB repair requiring HRR and that checkpoint disruption contributes by allowing these DSBs to transit into irreparable states. Thus, checkpoints may contribute to genomic stability by promoting error-free HRR.

  16. Effects of fluticasone propionate on arachidonic acid metabolites in BAL-fluid and methacholine dose-response curves in non-smoking atopic asthmatics

    Directory of Open Access Journals (Sweden)

    S. E. Overbeek

    1996-01-01

    Full Text Available Hyperresponsiveness of the airways to nonspecific stimuli is a characteristic feature of asthma. Airway responsiveness is usually characterized in terms of the position and shape of the dose–response curve to methacholine (MDR. In the study we have investigated the influence of fluticasone propionate (FP, a topically active glucocorticoid, on arachidonic acid (AA metabolites in broncho-alveolar lavage (BAL fluid (i.e. TxB2, PGE2, PGD2, 6kPGF1α and LTC4 on the one hand and MDR curves on the other hand. The effect of FP was studied in a randomized, double-blind, placebo-controlled design in 33 stable nonsmoking asthmatics; 16 patients received FP (500 μg b.i.d. whereas 17 patients were treated with placebo. We found that the forced expiratory volume in 1s (FEV1 % predicted increased, the log2PC20 methacholine increased and the plateau value (% fall in FEV1 decreased after a 12 week treatment period. No changes in AA-metabolites could be determined after treatment except for PGD2 which decreased nearly significantly (p = 0.058 within the FP treated group, whereas the change of PGD2 differed significantly (p = 0.05 in the FP treated group from placebo. The levels of the other AA metabolites (i.e. TxB2, PGE2, 6kPGF1α and LTC4 remained unchanged after treatment and were not significantly different from the placebo group. Our results support the hypothesis that although FP strongly influences the position, the shape and also the maximum response plateau of the MDR curve, this effect is not mainly achieved by influence on the level of AA metabolites. Other pro-inflammatory factors may be of more importance for the shape of the MDR curve. It is suggested that these pro-inflammatory factors are downregulated by FP.

  17. Modulation of Sonic hedgehog signaling and WW domain containing oxidoreductase WOX1 expression enhances radiosensitivity of human glioblastoma cells.

    Science.gov (United States)

    Chiang, Ming-Fu; Chen, Hsin-Hong; Chi, Chih-Wen; Sze, Chun-I; Hsu, Ming-Ling; Shieh, Hui-Ru; Lin, Chin-Ping; Tsai, Jo-Ting; Chen, Yu-Jen

    2015-03-01

    WW domain containing oxidoreductase, designated WWOX, FOR or WOX1, is a known pro-apoptotic factor when ectopically expressed in various types of cancer cells, including glioblastoma multiforme (GBM). The activation of sonic hedgehog (Shh) signaling, especially paracrine Shh secretion in response to radiation, is associated with impairing the effective irradiation of cancer cells. Here, we examined the role of Shh signaling and WOX1 overexpression in the radiosensitivity of human GBM cells. Our results showed that ionizing irradiation (IR) increased the cytoplasmic Shh and nuclear Gli-1 content in GBM U373MG and U87MG cells. GBM cells with exogenous Shh treatment exhibited similar results. Pretreatment with Shh peptides protected U373MG and U87MG cells against IR in a dose-dependent manner. Cyclopamine, a Hedgehog/Smoothened (SMO) inhibitor, reversed the protective effect of Shh in U87MG cells. Cyclopamine increased Shh plus IR-induced H2AX, a marker of DNA double-strand breaks, in these cells. To verify the role of Shh signaling in the radiosensitivity of GBM cells, we tested the effect of the Gli family zinc finger 1 (Gli-1) inhibitor zerumbone and found that it could sensitize GBM cells to IR. We next examined the role of WOX1 in radiosensitivity. Overexpression of WOX1 enhanced the radiosensitivity of U87MG (possessing wild type p53 or WTp53) but not U373MG (harboring mutant p53 or MTp53) cells. Pretreatment with Shh peptides protected both WOX1-overexpressed U373MG and U87MG cells against IR and increased the cytoplasmic Shh and nuclear Gli-1 content. Zerumbone enhanced the radiosensitivity of WOX1-overexpressed U373MG and U87MG cells. In conclusion, overexpression of WOX1 preferentially sensitized human GBM cells possessing wild type p53 to radiation therapy. Blocking of Shh signaling may enhance radiosensitivity independently of the expression of p53 and WOX1. The crosstalk between Shh signaling and WOX1 expression in human glioblastoma warrants further

  18. Oral buspirone causes a shift in the dose-response curve between the elevated-plus maze and Vogel conflict tests in Long-Evans rats: relation of brain levels of buspirone and 1-PP to anxiolytic action.

    Science.gov (United States)

    Vaidya, A H; Rosenthal, D I; Lang, W; Crooke, J J; Benjamin, D; Ilyin, S E; Reitz, A B

    2005-05-01

    Most studies concerning the effects of oral buspirone in the rat elevated plus-maze (EPM) test, spontaneous motor activity (SMA) test, and Vogel conflict (VC) test have used Sprague-Dawley or Wistar rats. Although it has been documented that the behavior of Long-Evans rats is more sensitive to detection of anxiolytics when compared to the aforementioned strains, the effects of oral buspirone have not been fully characterized in the Long-Evans strain in the EPM and VC tests. Thus, we studied the effects of orally administered buspirone (0.03-10.0 mg/kg) in the EPM, SMA, and VC (0.3-60.0 mg/kg) tests in Long-Evans rats. In a separate experiment, brain and plasma concentrations of buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP) were determined after oral administration of buspirone (0.3 and 10 mg/kg) to relate the behavioral effects of buspirone with brain and plasma concentrations of buspirone and 1-PP. Our results showed that buspirone exhibited an inverted-U-shaped dose-response curve in both the EPM and the VC tests. In the EPM, buspirone produced anxiolytic activity in a low, narrow dose-range (0.03, 0.1, 0.3 mg/kg, p.o.) with maximum efficacy at 0.3 mg/kg, whereas in the VC test, significant anxiolytic activity was observed in a high, narrow dose-range (10, 30 mg/kg, p.o.) with maximum efficacy occurring at 10 mg/kg. In the SMA test, buspirone (10 mg/kg, p.o.) significantly decreased horizontal activity and vertical movements suggestive of sedation. Also, one hour following oral doses of buspirone (0.3 and 10 mg/kg), both buspirone and 1-PP concentrations were higher in brain when compared with those in plasma. Additionally, the concentrations of 1-PP were always higher in brain and in plasma compared with the concentrations of buspirone. Of particular interest is our finding of the shift in the dose-response curve between the EPM and VC tests. This shift in the dose-response curve is discussed in relation to brain levels of buspirone and 1-PP levels and their

  19. Superiority of Low Energy 160 KV X-Rays Compared to High Energy 6 MV X-Rays in Heavy Element Radiosensitization for Cancer Treatment

    Science.gov (United States)

    Lim, Sara N.; Pradhan, Anil K.; Nahar, Sultana N.; Barth, Rolf F.; Yang, Weilian; Nakkula, Robin J.; Palmer, Alycia; Turro, Claudia

    2013-06-01

    High energy X-rays in the MeV range are generally employed in conventional radiation therapy from linear accelerators (LINAC) to ensure sufficient penetration depths. However, lower energy X-rays in the keV range may be more effective when coupled with heavy element (high-Z or HZ) radiosensitizers. Numerical simulations of X-ray energy deposition for tumor phantoms sensitized with HZ radiosensitizers were performed using the Monte Carlo code Geant4. The results showed enhancement in energy deposition to radiosensitized phantoms relative to unsensitized phantoms for low energy X-rays in the keV range. In contrast, minimal enhancement was seen using high energy X-rays in the MeV range. Dose enhancement factors (DEFs) were computed and showed radiosensitization only in the low energy range rat glioma cells following irradiation with both low energy 160 kV and high energy 6 MV X-ray sources. The platinum compound, pyridine terpyridine Pt(II) nitrate, was initially used because it was 7x less toxic that an equivalent amount of carboplatin in vitro studies. This would allow us to separate the radiotoxic and the chemotoxic effects of HZ sensitizers. Results from this study showed a 10-fold dose dependent reduction in surviving fractions (SF) of radiosensitized cells treated with low energy 160 kV X-rays compared to those treated with 6 MV X-rays. This is in agreement with our simulations that show an increase in dose deposition in radiosensitized tumors for low energy X-rays. Due to unforeen in vivo toxicity, however, another in vitro study was performed using the commonly used, Pt-based chemotherapeutic drug carboplatin which confirmed earlier results. This lays the ground work for a planned in vivo study using F98 glioma bearing rats. This study demonstrates that while high energy X-rays are commonly used in cancer radiotherapy, low energy keV X-rays might be much more effective with HZ radiosensitization.

  20. A quantitative measurement of antiviral activity of anti-human immunodeficiency virus type 1 drugs against simian immunodeficiency virus infection: dose-response curve slope strongly influences class-specific inhibitory potential.

    Science.gov (United States)

    Deng, Kai; Zink, M Christine; Clements, Janice E; Siliciano, Robert F

    2012-10-01

    Simian immunodeficiency virus (SIV) infection in macaques is so far the best animal model for human immunodeficiency virus type 1 (HIV-1) studies, but suppressing viral replication in infected animals remains challenging. Using a novel single-round infectivity assay, we quantitated the antiviral activities of antiretroviral drugs against SIV. Our results emphasize the importance of the dose-response curve slope in determining the inhibitory potential of antiretroviral drugs and provide useful information for regimen selection in treating SIV-infected animals in models of therapy and virus eradication.

  1. 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.

  2. Internalization pathways into cancer cells of gadolinium-based radiosensitizing nanoparticles.

    Science.gov (United States)

    Rima, Wael; Sancey, Lucie; Aloy, Marie-Thérèse; Armandy, Emma; Alcantara, Gustavo B; Epicier, Thierry; Malchère, Annie; Joly-Pottuz, Lucile; Mowat, Pierre; Lux, François; Tillement, Olivier; Burdin, Béatrice; Rivoire, Annie; Boulé, Christelle; Anselme-Bertrand, Isabelle; Pourchez, Jérémie; Cottier, Michèle; Roux, Stéphane; Rodriguez-Lafrasse, Claire; Perriat, Pascal

    2013-01-01

    Over the last few decades, nanoparticles have been studied in theranostic field with the objective of exhibiting a long circulation time through the body coupled to major accumulation in tumor tissues, rapid elimination, therapeutic potential and contrast properties. In this context, we developed sub-5 nm gadolinium-based nanoparticles that possess in vitro efficient radiosensitizing effects at moderate concentration when incubated with head and neck squamous cell carcinoma cells (SQ20B). Two main cellular internalization mechanisms were evidenced and quantified: passive diffusion and macropinocytosis. Whereas the amount of particles internalized by passive diffusion is not sufficient to induce in vitro a significant radiosensitizing effect, the cellular uptake by macropinocytosis leads to a successful radiotherapy in a limited range of particles incubation concentration. Macropinocytosis processes in two steps: formation of agglomerates at vicinity of the cell followed by their collect via the lamellipodia (i.e. the "arms") of the cell. The first step is strongly dependent on the physicochemical characteristics of the particles, especially their zeta potential that determines the size of the agglomerates and their distance from the cell. These results should permit to control the quantity of particles internalized in the cell cytoplasm, promising ambitious opportunities towards a particle-assisted radiotherapy using lower radiation doses.

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

    Science.gov (United States)

    Harada, S.; Ehara, S.; Ishii, K.; Yamazaki, H.; Matsuyama, S.; Kamiya, T.; Sakai, T.; Arakawa, K.; Sato, T.; Oikawa, S.

    2007-07-01

    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 2 solution (0.34 mol/l) using a microatomizer. These capsules were irradiated by a single dose of 2, 5, or 10 Gy 60Co γ-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 μm, and that of the liquid core was 10.2 ± 4.3 μm. 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.

  4. CpG oligodeoxyribonucleotide 7909 enhances radiosensitivity via downregulating Oct-4 expression in radioresistant lung cancer cells

    Directory of Open Access Journals (Sweden)

    Xing N

    2015-06-01

    Full Text Available Na Xing,1 Tiankui Qiao,1 Xibing Zhuang,1 Sujuan Yuan,1 Qi Zhang,1 Guoxiong Xu2 1Department of Oncology, 2Center Laboratory, Jinshan Hospital, Fudan University, Shanghai, People’s Republic of China Abstract: Radiotherapy is a powerful cure for local advanced non-small cell lung cancer. However, radioresistance and tumor relapse still occur in a high proportion of patients. Octamer-4 (Oct-4, a transcription factor of the POU family, plays a key role in maintaining chemoradioresistant properties and regulating cancer progression. In this study, we demonstrated that Oct-4 expression was significantly increased in radioresistant H460 (H460R cell line. CpG oligodeoxyribonucleotide (CpG-ODN 7909 sensitized H460R cells when combined with irradiation treatment. The clonogenic capacity was significantly decreased, and the values of D0 and Dq were lower than those of irradiation alone group. The sensitive enhancement ratio (SER of D0 was 1.224. This combined treatment led to a dramatic reduction in Oct-4 expression in a dose-dependent manner and also showed increased percentage of cells in the radiosensitive G2/M phase relative to either treatment alone. These results identified that Oct-4 was involved in radioresistance. CpG-ODN 7909 could enhance radiosensitivity partly through downregulating Oct-4 expression in radioresistant lung cancer cells. Keywords: CpG-ODN, Oct-4, lung cancer, TLR9, radiosensitivity

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

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  6. Neutron spectra and dose equivalents calculated in tissue for high-energy radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Kry, Stephen F.; Howell, Rebecca M.; Salehpour, Mohammad; Followill, David S. [Department of Radiation Physics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030 (United States)

    2009-04-15

    Neutrons are by-products of high-energy radiation therapy and a source of dose to normal tissues. Thus, the presence of neutrons increases a patient's risk of radiation-induced secondary cancer. Although neutrons have been thoroughly studied in air, little research has been focused on neutrons at depths in the patient where radiosensitive structures may exist, resulting in wide variations in neutron dose equivalents between studies. In this study, we characterized properties of neutrons produced during high-energy radiation therapy as a function of their depth in tissue and for different field sizes and different source-to-surface distances (SSD). We used a previously developed Monte Carlo model of an accelerator operated at 18 MV to calculate the neutron fluences, energy spectra, quality factors, and dose equivalents in air and in tissue at depths ranging from 0.1 to 25 cm. In conjunction with the sharply decreasing dose equivalent with increased depth in tissue, the authors found that the neutron energy spectrum changed drastically as a function of depth in tissue. The neutron fluence decreased gradually as the depth increased, while the average neutron energy decreased sharply with increasing depth until a depth of approximately 7.5 cm in tissue, after which it remained nearly constant. There was minimal variation in the quality factor as a function of depth. At a given depth in tissue, the neutron dose equivalent increased slightly with increasing field size and decreasing SSD; however, the percentage depth-dose equivalent curve remained constant outside the primary photon field. Because the neutron dose equivalent, fluence, and energy spectrum changed substantially with depth in tissue, we concluded that when the neutron dose equivalent is being determined at a depth within a patient, the spectrum and quality factor used should be appropriate for depth rather than for in-air conditions. Alternately, an appropriate percent depth-dose equivalent curve

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2005-05-01

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

  8. SU-E-T-668: Radiosensitizing Effect of Bosutinib On Prostate and Colon Cancers: A Pilot in Vitro Study

    Energy Technology Data Exchange (ETDEWEB)

    Wang, B; Cvetkovic, D; Chen, L; Ma, C [Fox Chase Cancer Center, Philadelphia, PA (United States); Wang, C [Fox Chase Cancer Center, Philadelphia, PA (United States); West China Hospital, Sichuan University, Chengdu, Sichuan (China)

    2015-06-15

    Purpose: Recently it has been reported that Bosutinib, a clinical kinase inhibitor, can enhance the tumor cell chemosensitivity by overriding DNA damage checkpoints. However, to the best of our knowledge, there is no report on its effect on cell radiosensitivity in the literature. The objective of the present study is to determine whether Bosutinib has the potential to be used as a radiosensitizer for various cancer cell lines. Methods: In this study, we tested 4 cell lines derived from human prostate (LNCaP, PC-3, DU-145) and colon (HT-29) cancers. The cells were seeded into 12-well plates 24 hours prior to the radiation treatments. For each cell line, we designed 4 study groups, namely, the control, Bosutinib, radiotherapy, and radiotherapy+Bosutinib groups. We used 6 MV photon beams from a Siemens Artiste accelerator to deliver 2 Gy dose in one fraction to the cells in the radiotherapy and radiotherapy+Bosutinib groups. Immediately after irradiation, the cells in the radiotherapy+Bosutinib group were treated with Bosutinib (1µM) for 3 hours. The cell survival was evaluated through clonogenic assays. Results: The cell survival rates of the LNCaP, PC-3, DU-145, and HT-29 cells were found to be 21%, 92%, 76%, and 93% for the radiotherapy group; 21%, 69%, 67%, and 81% for the radiotherapy+Bosutinib group; and 103%, 107%, 86%, and 102% for the Bosutinib group, respectively. Although synergetic cell killing was not seen for the LNCaP and DU-145 cell lines in this study, the cell survival data from the clonogenic assay indicated that Bosutinib could enhance the sensitivity of PC-3 and HT-29 cells to radiation treatment. Conclusion: Our preliminary results demonstrated the possibility of Bosutinib as a radiosensitizer for certain prostate and colon cancers, which are resistant to radiotherapy. Further studies are warranted to quantify the radiosensitizing effect of Bosutinib.

  9. 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.

  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. 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

  12. Calculation of dose absorbed for the verification of the calibration curves UH-Density electronic relative obtained with various mannequins; Calculo de dosis absorbida para la verificacion de las curvas de calibracion UH-Densidad electronica relativa obtenidas con distintos maniquies

    Energy Technology Data Exchange (ETDEWEB)

    Perez Alvarez, M. E.; Sena Espinel, E. de; Delgado Aparicio, J. M.; Martin Rincon, C.; Garcia Repiso, S.; Ramos Pacho, J. A.; Verde Velasco, J. M.; Gomez Gonzalez, N.; Cons Perez, N.; Saez Beltran, M.

    2013-07-01

    In order to discern with what calibration curve is obtained a more accurate dosimetry distribution, dose measurements are carried out on the treatment unit and the values found are evaluated. (Author)

  13. 不同性别癫痫患者维库溴铵剂量-反应曲线的测定%Investigating the dose-response curves of vecuronium in different gender epilepsy patients

    Institute of Scientific and Technical Information of China (English)

    刘中杰; 张庆国; 卢爱珠; 赖露颖; 李乐; 徐世元

    2015-01-01

    Objective To evaluate the gender differences in dose-response curve of vecuronium in epilepsy patients and provide a reference for its individualized application.Methods Hundred ASA grade Ⅰ-Ⅱ epilepsy patients were enrolled in this study.All patients were divided into male group (group M) and female group (group F)(n=50),they recieved the method of single dose injection under midazolam-fentanyl intravenous anesthesia.Every patient received intravenous single bolus of 20,30,40,50,60 μg/kg of vecuronium respectively(n=l0).The neuromuscular block was measured by neuromuscular transmission monitor and the responses were defined in terms of the percentages of maximum suppression in T1 of train of four stimulation (TOF) of the adductor pollicis muscle.According to log-probit transformation of the data of dose and response,the dose-response curve of vecuronium was established through linear regression.The onset time of vecuronium was also observed.Results The 50% effective dose (ED50),75% effective dose (ED75),90% effective dose (ED90),95% effective dose (ED95) values of vecuronium in male epilepsy patients were (31±6),(40±8),(50±9),(57±7) μg/kg.The ED50,ED75,ED90,ED95 values of vecuronium in female epilepsy patients were(31±6),(40±7),(50±9),(58±9) μg/kg.No significant difference in onset time was observed among 5 dose groups (P>0.05).Conclusions There was no gender difference in dose-response curve of vecuronium in epilepsy patients.%目的 研究性别对癫痫患者维库溴铵量效关系的影响,为维库溴铵个体化应用提供参考. 方法 选取择期癫痫手术患者100例,美国麻醉医师协会(ASA)分级Ⅰ~Ⅱ级,年龄19岁~4l岁,病史2年~23年,分为男性组(M组)与女性组(F组),每组各50例,均有服用抗癫痫药物史,术前无酸碱平衡及水电解质紊乱,心、肺、肝、肾功能正常.每组患者按随机数字表法分为20、30、40、50、60 μg/kg 5个剂量组,每组10例.记录拇

  14. Comparison of in vivo translocation frequencies with in vitro G{sub 2} radiosensitivity in radiation workers occupationally exposed to external radiation

    Energy Technology Data Exchange (ETDEWEB)

    Cadwell, Kevin K; Whitehouse, Caroline A; Tawn, E Janet [Westlakes Research Institute, Moor Row, Cumbria, CA24 3JY (United Kingdom); Tarone, Robert E [International Epidemiology Institute, 1455 Research Boulevard, Rockcliffe, MD 20850 (United States)], E-mail: ejtawn@uclan.ac.uk

    2008-03-01

    A group of retired workers from the British Nuclear Fuels plc facility at Sellafield who had been studied for in vivo translocation frequencies in blood lymphocytes were resampled and analysed for in vitro chromosomal radiosensitivity. Significant variation in response to a dose of 0.5 Gy given at the G{sub 2} stage of the cell cycle was observed between individuals (P < 0.001). In a regression analysis that included age, cumulative occupational radiation dose and in vitro G{sub 2} radiation-induced aberration frequencies as independent variables, only cumulative occupational radiation dose had a significant influence on chromosomal translocation frequency (P = 0.0036). G{sub 2} in vitro radiosensitivity is assumed to be a marker for genetic polymorphic variation in DNA damage recognition and repair genes. Therefore, since in vivo translocation frequencies can be considered a surrogate for cancer risk, this lack of association with G{sub 2} in vitro radiosensitivity suggests that such genetic variation has no impact on the response to low dose chronic exposure. (note)

  15. Bryostatin-1 causes radiosensitization of BMG-1 malignant glioma cells through differential activation of protein kinase-Cδ not evident in the non-malignant AA8 fibroblasts.

    Science.gov (United States)

    Dagur, Raghubendra Singh; Hambarde, Shashank; Chandna, Sudhir

    2015-03-01

    Bryostatin-1 (bryo-1), a non-phorbol ester, is known to sensitize mammalian cells against certain chemotherapeutic drugs. We assessed its ability to modify radiation response of mammalian cells using Chinese hamster fibroblasts AA8 cells and human malignant glioma BMG-1 cells. In the malignant glioma BMG-1 cell line, bryo-1 pre-treatment significantly enhanced radiation-induced growth inhibition and cytogenetic damage, and further reduced the clonogenic cell survival as compared to cells irradiated at the clinically relevant dose of 2 Gy. PKCδ expression increased significantly when bryo-1 pre-treated BMG-1 glioma cells were irradiated at 2 Gy and induced prolonged ERK-1/2 activation associated with p21 overexpression. Silencing PKCδ resulted in inhibition of bryo-1-induced radiosensitization. In contrast, bryo-1 failed to alter radiosensitivity (cell survival; growth inhibition; cytogenetic damage) or activate ERK1/2 pathway in the AA8 fibroblasts despite PKCδ phosphorylation at its regulatory (Y155) domain, indicating alternate mechanisms in these non-malignant cells as compared to the glioma cells. This study suggests that bryo-1 may effectively enhance the radiosensitivity of malignant cells and warrants further in-depth investigations to evaluate its radiosensitizing potential in various cell types.

  16. In vitro radiosensitivity of human leukemia cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Weichselbaum, R.R.; Greenberger, J.S.; Schmidt, A.; Karpas, A.; Moloney, W.C.; Little, J.B.

    1981-05-01

    The in vitro radiobiologic survival values (anti n, D/sub 0/) of four tumor lines derived from human hematopoietic tumors were studied. These cell lines were HL60 promyelocytic leukemia; K562 erythroleukemia; 45 acute lymphocytic leukemia; and 176 acute monomyelogenous leukemia. More cell lines must be examined before the exact relationship between in vitro radiosensitivity and clinical radiocurability is firmly established.

  17. Inhibiting DNA-PKCS radiosensitizes human osteosarcoma cells.

    Science.gov (United States)

    Mamo, Tewodros; Mladek, Ann C; Shogren, Kris L; Gustafson, Carl; Gupta, Shiv K; Riester, Scott M; Maran, Avudaiappan; Galindo, Mario; van Wijnen, Andre J; Sarkaria, Jann N; Yaszemski, Michael J

    2017-04-29

    Osteosarcoma survival rate has not improved over the past three decades, and the debilitating side effects of the surgical treatment suggest the need for alternative local control approaches. Radiotherapy is largely ineffective in osteosarcoma, indicating a potential role for radiosensitizers. Blocking DNA repair, particularly by inhibiting the catalytic subunit of DNA-dependent protein kinase (DNA-PKCS), is an attractive option for the radiosensitization of osteosarcoma. In this study, the expression of DNA-PKCS in osteosarcoma tissue specimens and cell lines was examined. Moreover, the small molecule DNA-PKCS inhibitor, KU60648, was investigated as a radiosensitizing strategy for osteosarcoma cells in vitro. DNA-PKCS was consistently expressed in the osteosarcoma tissue specimens and cell lines studied. Additionally, KU60648 effectively sensitized two of those osteosarcoma cell lines (143B cells by 1.5-fold and U2OS cells by 2.5-fold). KU60648 co-treatment also altered cell cycle distribution and enhanced DNA damage. Cell accumulation at the G2/M transition point increased by 55% and 45%, while the percentage of cells with >20 γH2AX foci were enhanced by 59% and 107% for 143B and U2OS cells, respectively. These results indicate that the DNA-PKCS inhibitor, KU60648, is a promising radiosensitizing agent for osteosarcoma. Copyright © 2017 Elsevier Inc. All rights reserved.

  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.

  19. 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.

  20. Determinants of intrinsic radiosensitivity of mammalian cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Radford, I.R. [Peter MacCallum Cancer Institute, East Melbourne, VIC (Australia). Research Division

    1998-12-31

    Differences in the radiosensitivity of normal and cancerous cells could arise in various ways. Although there is no compelling data to support the view, the currently prevailing opinion is that differences in radiosensitivity are related to differences in some aspect of enzymatic DNA repair. A test of the importance of possible differences in enzymatic DNA repair in determining relative radiosensitivity would be to compare lethality in cells containing equivalent numbers of DNA lesions. Six cell lines were used in these studies: two Chinese hamster (CHO and V79) and a monkey (Vero) fibroblast-like line, a mouse melanoma line (B16-F1), and a rat (RUC-2) and a human (SQ-20B) carcinoma line. This group of cell lines displays a wide range of sensitivities to external beam low-LET radiation, ranging from the relatively radiosensitive B16-F1 and Vero lines through to the highly radioresistant RUC-2 line. However, it is important to note that none of the lines has a demonstrated defect in enzymatic DNA repair and that all appear to die by necrosis following a lethal radiation insult. Despite having significantly different radiosensitivities, CHO and V79 cells showed comparable responses to DNA-associated {sup 125}I-decays with D{sub o} values of around 65. More surprisingly, the radiosensitive B16-F1 line and the radioresistant RUC-2 line both had responses with D{sub o} values of around 133 {sup 125}I-decays. The factor of two difference between the D{sub o} values for these two pairs of cell lines is probably attributable to CHO and V79 cells being pseudo-diploid whereas B 16-F1 and RUC2 appear to have derived from tetraploid cells. The generality of the above result, for DNA lesions of different quality, was tested by comparing the sensitivities of CHO and V79 cells to DNA-associated {sup 3}H-decays. Again, consistent with the {sup 125}I-decay data, there was no significant difference in the D{sub o} values for these lines. Our {sup 3}H- and {sup 125}I-decay data are

  1. The combination of olaparib and camptothecin for effective radiosensitization

    Directory of Open Access Journals (Sweden)

    Miura Katsutoshi

    2012-04-01

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

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

    Directory of Open Access Journals (Sweden)

    John S Hall

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, I. (Gunma Univ., Maebashi (Japan). School of Medicine)

    1981-11-01

    '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 author 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. LD/sub 50/ 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.

  4. The Antiviral Activity of Approved and Novel Drugs against HIV-1 Mutations Evaluated under the Consideration of Dose-Response Curve Slope.

    Directory of Open Access Journals (Sweden)

    Shuai Chang

    Full Text Available This study was designed to identify common HIV-1 mutation complexes affecting the slope of inhibition curve, and to propose a new parameter incorporating both the IC50 and the slope to evaluate phenotypic resistance.Utilizing site-directed mutagenesis, we constructed 22 HIV-1 common mutation complexes. IC50 and slope of 10 representative approved drugs and a novel agent against these mutations were measured to determine the resistance phenotypes. The values of new parameter incorporating both the IC50 and the slope of the inhibition curve were calculated, and the correlations between parameters were assessed.Depending on the class of drug, there were intrinsic differences in how the resistance mutations affected the drug parameters. All of the mutations resulted in large increases in the IC50s of nucleoside reverse transcriptase inhibitors. The effects of the mutations on the slope were the most apparent when examining their effects on the inhibition of non-nucleoside reverse transcriptase inhibitors and protease inhibitors. For example, some mutations, such as V82A, had no effect on IC50, but reduced the slope. We proposed a new concept, termed IIPatoxic, on the basis of IC50, slope and the maximum limiting concentrations of the drug. The IIPatoxic values of 10 approved drugs and 1 novel agent were calculated, and were closely related to the IIPmax values (r > 0.95, p < 0.001.This study confirms that resistance mutations cannot be accurately assessed by IC50 alone, because it tends to underestimate the degree of resistance. The slope parameter is of very importance in the measurement of drug resistance and the effect can be applied to more complex patterns of resistance. This is the most apparent when testing the effects of the mutations on protease inhibitors activity. We also propose a new index, IIPatoxic, which incorporates both the IC50 and the slope. This new index could complement current IIP indices, thereby enabling predict the

  5. Inhibiting PI3K/Akt Pathway Increases DNA Damage of Cervical Carcinoma HeLa Cells by Drug Radiosensitization

    Institute of Scientific and Technical Information of China (English)

    夏曙; 于世英; 付强; 刘飞; 郑微; 付秀根; 赵茵

    2010-01-01

    This study examined the role of PI3K/Akt pathway in radiosensitization of DNA damage of cervical carcinoma cells.The 50% inhibition concentration(IC50) of cisplatin and docetaxel in HeLa cells was detected by Mono-nuclear cell direct cytotoxicity assay(MTT) in vitro.HeLa cells were treated by cisplatin/docetaxel of 10 percent of IC20 alone or combined with LY294002 for 24 h,and then radiated by different doses of X-ray.The cell survival ratio was obtained by means of clone formation.One-hit multi-target mod...

  6. The Influence of Human Interindividual Variability on the Low-Dose Region of Dose-Response Curve Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Primary B Cells.

    Science.gov (United States)

    Dornbos, Peter; Crawford, Robert B; Kaminski, Norbert E; Hession, Sarah L; LaPres, John J

    2016-10-01

    The influence of interindividual variability is not typically assessed in traditional toxicological studies. Given that chemical exposures occur in heterogeneous populations, this knowledge gap has the potential to cause undue harm within the realms of public health and industrial and municipal finances. A recent report from the National Research Council (NRC) suggests that when accounting for interindividual variation in responses, traditionally assumed nonlinear dose-response relationships (DRRs) for noncancer-causing endpoints would better be explained with a linear relationship within the low-dose region. To address this knowledge gap and directly test the NRC's assumption, this study focused on assessing the DRR between 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) exposure and immune suppression in a cohort of unique human donors. Human B cells were isolated from 51 individual donors and treated with logarithmically increasing concentrations of TCDD (0-30 nM TCDD). Two endpoints sensitive to TCDD were assessed: (1) number of IgM-secreting B cells and (2) quantity of IgM secreted. The results show that TCDD significantly suppressed both the number of IgM-secreting B cells and the quantity of IgM secreted (P < .05). Statistical model comparisons indicate that the low-dose region of the two DRRs is best explained with a nonlinear relationship. Rather than assuming low-dose linearity for all noncancer-causing DRRs, our study suggests the need to consider the specific mode of action of toxicants and pharmaceuticals during risk-management decision making. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. Radiosensitivity of pimonidazole-unlabelled intratumour quiescent cell population to γ-rays, accelerated carbon ion beams and boron neutron capture reaction

    Science.gov (United States)

    Masunaga, S; Sakurai, Y; Tanaka, H; Hirayama, R; Matsumoto, Y; Uzawa, A; Suzuki, M; Kondo, N; Narabayashi, M; Maruhashi, A; Ono, K

    2013-01-01

    Objective To detect the radiosensitivity of intratumour quiescent (Q) cells unlabelled with pimonidazole to accelerated carbon ion beams and the boron neutron capture reaction (BNCR). Methods EL4 tumour-bearing C57BL/J mice received 5-bromo-29-deoxyuridine (BrdU) continuously to label all intratumour proliferating (P) cells. After the administration of pimonidazole, tumours were irradiated with c-rays, accelerated carbon ion beams or reactor neutron beams with the prior administration of a 10B-carrier. Responses of intratumour Q and total (P+Q) cell populations were assessed based on frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of pimonidazole-unlabelled tumour cells was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. Results Following c-ray irradiation, the pimonidazole-unlabelled tumour cell fraction showed significantly enhanced radiosensitivity compared with the whole tumour cell fraction, more remarkably in the Q than total cell populations. However, a significantly greater decrease in radiosensitivity in the pimonidazole-unlabelled cell fraction, evaluated using a delayed assay or a decrease in radiation dose rate, was more clearly observed among the Q than total cells. These changes in radiosensitivity were suppressed following carbon ion beam and neutron beam-only irradiaton. In the BNCR, the use of a 10B-carrier, especially L-para-boronophenylalanine-10B, enhanced the sensitivity of the pimonidazole-unlabelled cells more clearly in the Q than total cells. Conclusion The radiosensitivity of the pimonidazole-unlabelled cell fraction depends on the quality of radiation delivered and characteristics of the 10B-carrier used in the BNCR. Advances in knowledge The pimonidazole-unlabelled subfraction of Q tumour cells may be a critical target in tumour control. PMID:23255546

  8. 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.

  9. Radiosensitivity of pimonidazole-unlabelled intratumour quiescent cell population to γ-rays, accelerated carbon ion beams and boron neutron capture reaction.

    Science.gov (United States)

    Masunaga, S; Sakurai, Y; Tanaka, H; Hirayama, R; Matsumoto, Y; Uzawa, A; Suzuki, M; Kondo, N; Narabayashi, M; Maruhashi, A; Ono, K

    2013-01-01

    To detect the radiosensitivity of intratumour quiescent (Q) cells unlabelled with pimonidazole to accelerated carbon ion beams and the boron neutron capture reaction (BNCR). EL4 tumour-bearing C57BL/J mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumour proliferating (P) cells. After the administration of pimonidazole, tumours were irradiated with γ-rays, accelerated carbon ion beams or reactor neutron beams with the prior administration of a (10)B-carrier. Responses of intratumour Q and total (P+Q) cell populations were assessed based on frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of pimonidazole-unlabelled tumour cells was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. Following γ-ray irradiation, the pimonidazole-unlabelled tumour cell fraction showed significantly enhanced radiosensitivity compared with the whole tumour cell fraction, more remarkably in the Q than total cell populations. However, a significantly greater decrease in radiosensitivity in the pimonidazole-unlabelled cell fraction, evaluated using a delayed assay or a decrease in radiation dose rate, was more clearly observed among the Q than total cells. These changes in radiosensitivity were suppressed following carbon ion beam and neutron beam-only irradiaton. In the BNCR, the use of a (10)B-carrier, especially L-para-boronophenylalanine-(10)B, enhanced the sensitivity of the pimonidazole-unlabelled cells more clearly in the Q than total cells. The radiosensitivity of the pimonidazole-unlabelled cell fraction depends on the quality of radiation delivered and characteristics of the (10)B-carrier used in the BNCR. The pimonidazole-unlabelled subfraction of Q tumour cells may be a critical target in tumour control.

  10. MO-FG-BRA-02: Modulation of Clinical Orthovoltage X-Ray Spectrum Further Enhances Radiosensitization of Cancer Cells Targeted with Gold Nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Wolfe, T; Reynoso, F; Cho, J; Quini, C; Cortez, M; Manohar, N; Krishnan, S; Cho, S [UT MD Anderson Cancer Center, Houston, TX (United States)

    2015-06-15

    Purpose: To assess the potential to amplify radiosensitization of cancer cells targeted with gold nanoparticles by augmenting selective spectral components of X-ray beam. Methods: Human prostate cancer cells were treated for 24h with gold nanorods conjugated to goserelin acetate or pegylated, systematically washed and irradiated with 250 kVp X-rays (25mA, 0.25mm Cu- filter, 8x8cm{sup 2} field size, 50cm SSD) with or without an additional 0.25 mm Erbium (Er) filter. As demonstrated in a companion Monte Carlo study, Er-filter acted as an external target to feed Erbium K-shell X-ray fluorescence photons (∼50 keV) into the 250 kVp beam. After irradiation, we performed measurements of clonogenic viability with doses between 0 -6Gy, irreparable DNA damage assay to measure double-strand breaks via γH2AX-foci staining, and production of stable reactive oxygen species (ROS). Results: The clonogenic assay for the group treated with conjugated nanoparticles showed radiosensitization enhancement factor (REF), calculated at the 10% survival fraction aisle, of (1.62±0.07) vs. (1.23±0.04) with/without the Er-filter in the 250 kVp beam, respectively. The group treated with pegylated nanoparticles, albeit retained in modest amounts within the cells, also showed statistically significant REF (1.13±0.09) when the Erbium filter was added to the beam. No significant radiosensitization was observed for other groups. Measurements of ROS levels showed increments of (1.9±0.2) vs. (1.4±0.1) for combined treatment with targeted nanoparticles and Er-filtered beam. γH2AX-foci showed 50% increase for the same treatment combination, confirming the enhanced radiosensitization in a consistent fashion. Conclusion: Our study demonstrates the feasibility of enhancing radiosensitization of cancer cells by combining actively targeted gold nanoparticles and modulating the X-ray spectrum in the desired energy range. The established technique will not only help develop strategies to maximize

  11. Radiosensitizing effect of gold nanoparticles in carbon ion irradiation of human cervical cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Kaur, Harminder; Avasthi, D. K.; Pujari, Geetanjali; Sarma, Asitikantha [Inter University Accelerator Centre, Aruna Asaf Ali Marg, Post box-10502, New Delhi-110067 (India)

    2013-07-18

    Noble metal nanoparticles have received considerable attention in biotechnology for their role in bio sensing due to surface plasmon resonance, medical diagnostics due to better imaging contrast and therapy. The radiosensitization effect of gold nanoparticles (AuNP) has been gaining popularity in radiation therapy of cancer cells. The better depth dose profile of energetic ion beam proves its superiority over gamma radiation for fighting against cancer. In the present work, the glucose capped gold nanoparticles (Glu-AuNP) were synthesised and internalized in the HeLa cells. Transmission electron microscopic analysis of ultrathin sections of Glu-AuNP treated HeLa cells confirmed the internalization of Glu-AuNPs. Control HeLa cells and Glu-AuNp treated HeLa cells were irradiated at different doses of 62 MeV 12C ion beam (LET - 290keV/{mu}m) at BIO beam line of using 15UD Pelletron accelerator at Inter University Accelerator Centre, New Delhi, India. The survival fraction was assessed by colony forming assay which revealed that the dose of carbon ion for 90% cell killing in Glu-AuNP treated HeLa cells and control HeLa cells are 2.3 and 3.2 Gy respectively. This observation shows {approx} 28% reduction of {sup 12}C{sup 6+} ion dose for Glu-AuNP treated HeLa cells as compared to control HeLa cells.

  12. Radiosensitizing effect of gold nanoparticles in carbon ion irradiation of human cervical cancer cells

    Science.gov (United States)

    Kaur, Harminder; Avasthi, D. K.; Pujari, Geetanjali; Sarma, Asitikantha

    2013-07-01

    Noble metal nanoparticles have received considerable attention in biotechnology for their role in bio sensing due to surface plasmon resonance, medical diagnostics due to better imaging contrast and therapy. The radiosensitization effect of gold nanoparticles (AuNP) has been gaining popularity in radiation therapy of cancer cells. The better depth dose profile of energetic ion beam proves its superiority over gamma radiation for fighting against cancer. In the present work, the glucose capped gold nanoparticles (Glu-AuNP) were synthesised and internalized in the HeLa cells. Transmission electron microscopic analysis of ultrathin sections of Glu-AuNP treated HeLa cells confirmed the internalization of Glu-AuNPs. Control HeLa cells and Glu-AuNp treated HeLa cells were irradiated at different doses of 62 MeV 12C ion beam (LET - 290keV/μm) at BIO beam line of using 15UD Pelletron accelerator at Inter University Accelerator Centre, New Delhi, India. The survival fraction was assessed by colony forming assay which revealed that the dose of carbon ion for 90% cell killing in Glu-AuNP treated HeLa cells and control HeLa cells are 2.3 and 3.2 Gy respectively. This observation shows ˜ 28% reduction of 12C6+ ion dose for Glu-AuNP treated HeLa cells as compared to control HeLa cells.

  13. Pediatric patient doses in interventional cardiology procedures; Doses em paciente pediatrico em procedimentos de cardiologia intervencionista

    Energy Technology Data Exchange (ETDEWEB)

    Medeiros, R.B.; Murata, C.H.; Moreira, A.C., E-mail: rbitelli2012@gmail.com, E-mail: camila.murata@gmail.com, E-mail: antonio.xray@gmail.com [Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, SP (Brazil). Escola Pulista de Medicina; Khoury, H.J.; Borras, C., E-mail: hjkhoury@gmail.com, E-mail: cariborras@starpower.net [Universidade Federal de Pernambuco (DEN/UFPE), Recife, PE (Brazil). Dept. de Engenharia Nuclear; Silva, M.S.R da, E-mail: msrochas2003@yahoo.com.br [Instituto Federal de Educacao, Ciencia e Tecnologia de Pernambuco (IFPE), Recife, PE (Brazil)

    2014-07-01

    The radiation doses from interventional procedures is relevant when treating children because of their greater radiosensitivity compared with adults. The purposes of this paper were to estimate the dose received by 18 pediatric patients who underwent cardiac interventional procedures and to correlate the maximum entrance surface air kerma (Ke,max), estimated with radiochromic films, with the cumulative air kerma values displayed at the end of procedures. This study was performed in children up to 6 years. The study was performed in two hospitals, one located in Recife and the other one in São Paulo. The x-ray imaging systems used were Phillips Allura 12 model with image intensifier system and a Phillips Allura FD10 flat panel system. To estimate the Ke,max on the patient’s skin radiochromic films(Gafchromic XR-RV2) were used. These values were estimated from the maximum optical density measured on film using a calibration curve. The results showed cumulative air kerma values ranging from 78.3- 500.0mGy, with a mean value of 242,3 mGy. The resulting Ke,max values ranged from 20.0-461.8 mGy, with a mean value of 208,8 mGy. The Ke,max values were correlated with the displayed cumulative air kerma values. The correlation factor R² was 0.78, meaning that the value displayed in the equipment’s console can be useful for monitoring the skin absorbed dose throughout the procedure. The routine fluoroscopy time records is not able by itself alert the physician about the risk of dose exceeding the threshold of adverse reactions, which can vary from an early erythema to serious harmful skin damage. (author)

  14. 癫痫患者顺式阿曲库铵的剂量反应曲线测定%The measurement of dose-response curve of cisatracurium in epilepsy patients

    Institute of Scientific and Technical Information of China (English)

    刘中杰; 徐世元; 张庆国; 梁启波; 曾繁荣

    2011-01-01

    Objective To determine the dose-response curve and the ED95 of cisatracurium in epilepsy patients. Methods Forty ASA grade Ⅰ or Ⅱ epilepsy patients were randomly divided into four groups. The dose-response curve was determined by single bolus injection of cisatracurium under midazolam-fentanyl intravenous anesthesia. For each group, the dose of cisatracurium were 20,30, 40 and 50 μg/kg respectively. The neuromuscular block was measured by Neuromuscular Transmission Monitor, and the responses were defined in terms of the percentages of maximum suppression in T1 of TOF of the adductor pollicis muscle. After logprobit transformation of the data of dose and response, the dose-response curve of cisatracurium was then established by linear regression. The onset time of cisatracurium was also recorded. Results The ED50, ED75, ED90 and ED95 of cisatracurium in epilepsy patients were 36.3, 46.1, 57.4 and 65.4 μg/kg. There was no significant change in onset time among 4 groups. Conclusion The ED95 of cisatracurium in epilepsy patients is 65.4 μg/kg, which is about 30.8% higher than that in normal human.%目的 采用单次剂量注射法建立癫痫患者顺式阿曲库铵的剂量反应曲线,确定其量效关系及ED95,为癫痫患者合理应用顺式阿曲库铵提供依据.方法 选取择期癫痫手术患者40例,ASA Ⅰ~Ⅱ级,年龄16岁~42岁,病史3年~26年,均具有服用抗癫痫药物史,术前无酸碱平衡及水电解质紊乱,心肺、肝肾功能正常.患者按随机数字法分为20μg/kg组、30μg/kg组、40 μg/kg组、50μg/kg组共4个剂量组,每组10例.记录拇内收肌四个成串刺激反应中第1次反应最大抑制的百分率,并进行概率单位转换,将顺式阿曲库铵的首次剂量进行对数转换,用直线回归方法建立顺式阿曲库铵的剂量-反应曲线,并记录起效时间.结果 癫痫患者顺式阿曲库铵ED50、ED75、ED90、ED95值分别为36.3、46.1、57.4、65.4μg/kg,起效时间在4个剂

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-02-15

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

  16. Rockets, radiosensitizers, and RRx-001: an origin story part I.

    Science.gov (United States)

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

    2016-03-01

    From Adam and Eve, to Darwinism, origin stories attempt to fill in the blanks, connect the dots, and define the turning points that are fundamental to subsequent developments. The purpose of this review is to present the origin story of a one-of-a-kind anticancer agent, RRx-001, which emerged from the aerospace industry as a putative radiosensitizer; not since the dynamite-to-dilator transformation of nitroglycerin in 1878 or the post-World War II explosive-to-elixir conversion of hydralazine, an ingredient in rocket fuel, to an antihypertensive, an antidepressant and an antituberculant, has energetic chemistry been harnessed for therapeutic purposes. This is Part 1 of the radiosensitization story; Parts 2 and 3, which detail the crossover activity of RRx-001 as a chemosensitizer in multiple tumor types and disease states including malaria, hemorrhagic shock and sickle cell anemia, are the subject of future reviews.

  17. Resveratrol and piperine enhance radiosensitivity of tumor cells

    Directory of Open Access Journals (Sweden)

    Jean Kyoung Tak

    2012-04-01

    Full Text Available The use of ionizing radiation (IR is essential for treating manyhuman cancers. However, radioresistance markedly impairsthe efficacy of tumor radiotherapy. IR enhances the productionof reactive oxygen species (ROS in a variety of cells which aredeterminant components in the induction of apoptosis. Muchinterest has developed to augment the effect of radiation in tumorsby combining it with radiosensitizers to improve the therapeuticratio. In the current study, the radiosensitizing effectsof resveratrol and piperine on cancer cells were evaluated.Cancer cell lines treated with these natural products exhibitedsignificantly augmented IR-induced apoptosis and loss of mitochondrialmembrane potential, presumably through enhancedROS generation. Applying natural products as sensitizersfor IR-induced apoptotic cell death offers a promisingtherapeutic approach to treat cancer. [BMB reports 2012;45(4: 242-246

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

    Directory of Open Access Journals (Sweden)

    Jan Sarosik

    2014-02-01

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

  19. Paradoxical role for eicosanoids: radioprotectants and radiosensitizers

    Energy Technology Data Exchange (ETDEWEB)

    Walden Jr, T.L.

    1987-01-01

    Understanding the radiobiology of eicosanoids is complicated by their ability to act as mediators of damage and recovery and as radioprotective agents. Changes in the tissue concentrations of eicosanoids following irradiation are dependent on several factors, including the type of eicosanoid, time postirradiation, radiation dose, and other contributing mediators and enzyme changes in the surrounding microenvironment. Many of these same prostaglandins and the leukotrienes have been shown to be radioprotective when given before irradiation.

  20. Accurate diagnostics of ataxia-telangiectasia cellular phenotype by employing in vitro lymphocyte radiosensitivity testing

    OpenAIRE

    Vujić Dragana S.; Petrović Sandra Ž.; Leskovac Andreja R.; Joksić Ivana D.; Filipović Jelena G.; Valenta-Šobot Ana P.

    2013-01-01

    In this paper we present the data of lymphocyte radiosensitivity testing used for characterization of radiosensitive cellular phenotype and diagnostics of ataxia-telangiectasia disease. We point out the advantage of lymphocyte micronucleus test (CBMN) over other cellular tests for assessment of radiosensitivity: the first advantage of CBMN is that primary patient cells are used (less than 1 ml), the second one is that the results of testing are obtained within 3 days and there is no nee...

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

    Directory of Open Access Journals (Sweden)

    Junko Maeda

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

  3. Differences in radiosensitivity between three HER2 overexpressing cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Steffen, Ann-Charlott; Tolmachev, Vladimir; Stenerloew, Bo [Uppsala University, Unit of Biomedical Radiation Sciences, Department of Oncology, Radiology and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden); Goestring, Lovisa [Affibody AB, Bromma (Sweden); Palm, Stig [Sahlgrenska Academy at Goeteborg University, Department of Radiation Physics, Goeteborg (Sweden); Carlsson, Joergen [Uppsala University, Unit of Biomedical Radiation Sciences, Department of Oncology, Radiology and Clinical Immunology, Rudbeck Laboratory, Uppsala (Sweden); Rudbeck Laboratory, Biomedical Radiation Sciences, Uppsala (Sweden)

    2008-06-15

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

  4. 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.

  5. Thiol reactive nitroimidazoles: radiosensitization studies in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Stratford, I.J.; Adams, G.E.; Hardy, C.; Hoe, S.; O' Neill, P.; Sheldon, P.W. (Medical Research Council, Harwell (UK). Radiobiological Research Unit)

    1984-12-01

    Using Chinese hamster V79 cells in vitro a study was made of the radiosensitizing properties of 4- or 5-nitroimidazoles substituted in the 2,5 or 4 position with various halo, sulphur ether, sulphonamide, sulphonate, ether or nitro groups. Values of E/sub 7//sup 1/ (the one-electron reduction potential measured versus the normal hydrogen electrode at pH7) vary in the range -178 to -565 mV. All the compounds, with one exception, are more efficient radiosensitizers than would be predicted from redox potentials, and the factor Csub(1.6)/Csub(1.6), by which a compound is more efficient has been calculated. The second-order rate constants, k/sub 2/, for reaction of these nitroimidazoles with glutathione and/or dithiothreitol tended to increase with increasing redox potential. However, there is no clear trend between k/sub 2/ and Csub(1.6)/Csub(1.6). The concentration required to cause a 50% depletion of intracellular glutathione was determined for selected compounds, as was the ability of glutathione-S-transferase to catalyse reaction with thiols. These observations suggested the relative thiol reactivity measured under chemically controlled conditions does not necessarily indicate thiol reactivity intracellularly. Studies using MT tumour in mice showed that high levels of radiosensitization seen in vitro could not be duplicated in vivo (attributed to thiol reactivity).

  6. Understanding outliers on the usual dose-response curve: venlafaxine as a way to phenotype patients in terms of their CYP 2D6 status and why it matters.

    Science.gov (United States)

    Preskorn, Sheldon H

    2010-01-01

    Venlafaxine is a model substrate for the drug metabolizing cytochrome P450 (CYP) enzyme 2D6. The desvenlafaxine/venlafaxine ratio, either after a single dose or at steady state, can be used to determine whether a patient is functionally (i.e., phenotypically) a CYP 2D6 extensive or poor metabolizer (EM or PM). In turn, CYP 2D6 EM and PM status is important in determining the efficacy of venlafaxine as an antidepressant. Based on a secondary analysis of four of the venlafaxine registration trials, venlafaxine was effective in patients who were CYP 2D6 EMs versus a parallel placebo-treated control group, whereas it was not effective in patients who were CYP 2D6 PMs. Thus, venlafaxine is a useful example of how drugs can be used to quantify differences in drug metabolizing capacity among patients and how such differences can in turn affect the efficacy of a drug (i.e., make a patient an outlier on the usual dose-response curve).

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

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  8. Human tumor cells segregate into radiosensitivity groups that associate with ATM and TP53 status

    Energy Technology Data Exchange (ETDEWEB)

    Williams, Jerry R.; Yonggang Zhang; Russell, James [Radiobiology Laboratory, Johns Hopkins Oncology Center. Baltimore, MD (United States); Koch, Cameron [Dept. of Radiation Oncology, Univ. of Pennsylvania, Philadelphia, PA (United States); Little, John B. [John B. Little Center, Harvard School of Public Health. Boston, MA (United States)

    2007-07-15

    We seek to determine whether cellular radiosensitivity in nineteen human colorectal tumor cell lines and three human glioblastoma tumor cell lines segregate into statistically distinct groups and whether such groups correlate with gene expression. We measure clonogenic survival in 22 cell lines that vary in radiosensitivity and in expression of selected genes: ATM, TP53, CDKN1A, 14-3-3{sigma}, Ki-ras and DNA mismatch repair genes. We describe and compare radiosensitivity in these cell lines by one-parameter or two parameter analysis. Radiosensitivity varies among and between colorectal tumor cell lines and glioblastoma cell lines. When compared directly using survival, or using two-parameter analysis of radiosensitivity, cell lines distribute into four statistically-significant radiosensitivity groups. These groups associate strongly with the status of two genes, ATM and TP53, but do not associate with CDKN1A, 14-3-3{sigma}, Ki-ras and DNA mismatch repair genes. Intrinsic cellular radiosensitivity of 22 colorectal and glioblastoma cell lines fall into four radiosensitivity groups that associate with expression of ATM and TP53. These analyses suggest multiple mechanisms underlay intrinsic cellular radiosensitivity.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2005-03-01

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

  10. Establishment and verification of dose effect relation curves between T cell receptor gene mutation frequency and ionizing radiation dose%电离辐射与T细胞突变频率的剂量效应关系曲线的建立与验证

    Institute of Scientific and Technical Information of China (English)

    马娅; 侯殿俊; 刘伟; 李洁清; 周桂珍; 乔建维; 封丽

    2011-01-01

    Objective To establish the dose-effect curve between TCR MF and ionizing radiation.Methods Peripheral lymphocytes were collected from 8 healthy adults(4 males and 4 females) and cultured in vitro with 12 well culture plates.They were stimulated by PHA-P and IL-2 after exposed to different doses of irradiation (0.00 -8.00 Gy) and cultured for 7 d.The dose-effect curve was established after measuring TCR MF using flow cytometry.Also,using the same method,we separated and cultured the peripheral lymphocytes collected from 16 radiotherapy cancer patients,whose radiation styles and doses were different,and then measured TCR MF to estimate the whole equivalent dose of radiotherapy patients through the dose-effect curve.Peripheral blood was collected and cultured,chromosome aberration (dicentric and ring) was determined under microscope to estimate irradiation dose.Results The relationship of dose-effect between the TCR MF and ionizing radiation (0.00 -8.00 Gy) was well,the curve of large dose group (2.00 -8.00 Gy),low dose group(0.00 - 1.00 Gy) and 0.00 -8.00 Gy dose group were met with the quadratic polynomial model,the equation was TCR MF =-32.8579 + 20.5436D + 0.6341D2,TCR MF =1.796 + 0.017D + 5.155D2 and TCR MF =- 0.6229 + 6.305D + 0.6919D2,respectively.D was the radiation dose ( Gy ).Using the established curve and the chromosome aberration method to estimate the systemic exposure dosage,the average relative deviation was 16.8%.Conclusion The curve established by the TCR gene mutation analysis technology can be applied to exposure dose eatimation of victims in ionization radiation accidents.%目的 建立T细胞受体基因突变频率(T cell receptor mutation frequency,TCR MF)与电离辐射剂量效应关系曲线.方法 招募8名健康成年人,4男4女.采集其外周血,分离淋巴细胞,分装到12孔培养板中,不同剂量(0.00~8.00 Gy)照射后,用植物血凝素蛋白(PHA-P)刺激,加人重组白介素-2(IL-2)培育7d,以流式细胞仪测量TCR MF

  11. Pharmacokinetics of RK-28 (a new radiosensitizer) and pharmaceutical design of a suppository form using rats

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Nak-Seo; Umejima, Hiroyuki; Miyata, Kaori; Okubo, Mayumi; Goto, Shigeru (Kyushu Univ., Fukuoka (Japan). Faculty of Pharmaceutical Sciences); Kato, Tetsuo; Mikami, Yukio; Sagitani, Hiromichi; Inoue, Haruyuki

    1994-01-01

    The pharmacokinetics of RK-28, a new hypoxic cell radiosensitizer, was studied in rats following its intravenous, intraportal, oral and rectal administration. The pharmaceutical design of an RK-28 suppository form was also examined. After intravenous injection, RK-28 was rapidly removed from the plasma (biological half-life of 17 min) and its area under the curve (AUC) was proportional to the amount of RK-28 administered. The absolute bioavailability of RK-28 was 59.7% for intraportal administration and 36.9% for oral administration. Following oral administration of RK-28, it seems likely that specific acid-catalyzed decomposition of RK-28 takes place in the stomach and then the absorbed RK-28 undergoes first-pass metabolism in the liver. When 'solidified RK-28 suppository,' made by solidifying molten RK-28, was inserted into the rectum, hepatic first-pass metabolism could be avoided substantially. The resulting absolute bioavailability of RK-28 increased to 75%. Furthermore, 'RK-28 emulsion suppository,' prepared by emulsifying RK-28 with 1-hexadecanol and hydrogenated castor oil (HCO 60) at 80degC, showed a plasma concentration-time curve very suitable for radiation therapy; the maximum plasma concentration was attained 30 min after rectal administration and then decreased within a short period. Administration of 'RK-28 emulsion suppository,' resulted in an absolute bioavailability of 76%. (author).

  12. Inhibition of PLK1 in glioblastoma multiforme induces mitotic catastrophe and enhances radiosensitization

    Science.gov (United States)

    Tandle, Anita T.; Kramp, Tamalee; Kil, Whoon J; Halthore, Aditya; Gehlhaus, Kristen; Shankavaram, Uma; Tofilon, Philip J.; Caplen, Natasha J.; Camphausen, Kevin

    2013-01-01

    Glioblastoma multiforme (GBM) is the most common primary brain tumor in the USA with a median survival of approximately 14 months. Low survival rates are attributable to the aggressiveness of GBM and a lack of understanding of the molecular mechanisms underlying GBM. The disruption of signaling pathways regulated either directly or indirectly by protein kinases is frequently observed in cancer cells and thus the development of inhibitors of specific kinases has become a major focus of drug discovery in oncology. To identify protein kinases required for the survival of GBM we performed a siRNA-based RNAi screen focused on the human kinome in GBM. Inhibition of the polo-like kinase 1 (PLK1) induced a reduction in the viability in two different GBM cell lines. To assess the potential of inhibiting PLK1 as a treatment strategy for GBM we examined the effects of a small molecule inhibitor of PLK1, GSK461364A, on the growth of GBM cells. PLK1 inhibition arrested cells in the mitotic phase of the cell cycle and induced cell kill by mitotic catastrophe. GBM engrafts treated with GSK461364A showed statistically significant inhibition of tumor growth. Further, exposure of different GBM cells to RNAi or GSK461364A prior to radiation resulted in an increase in their radiosensitivity with dose enhancement factor ranging from 1.40 to 1.53 with no effect on normal cells. As a measure of DNA double strand breaks, γH2AX levels were significantly higher in the combined modality as compared to the individual treatments. This study suggests that PLK1 is an important therapeutic target for GBM and can enhance radiosensitivity in GBM. PMID:23790466

  13. The role of interleukin-13 in the removal of hyper-radiosensitivity by priming irradiation.

    Science.gov (United States)

    Edin, Nina F Jeppesen

    2014-11-01

    It has previously been demonstrated that the presence of fetal bovine serum is necessary for TGF-β3 (transforming growth factor beta 3)-dependent elimination of low-dose hyper-radiosensitivity (HRS) in cells by 1 h of low-dose-rate γ-irradiation (0.2-0.3 Gy/h). The purpose of the present study was to identify the serum constituent involved. Two human HRS-positive (T-47D, T98G) cell lines were used. The effects of different pretreatments on HRS were investigated using the colony assay. Total inducible nitric oxide synthase (iNOS) levels were measured using a cell-based ELISA assay. The serum factor was identified as interleukin-13 (IL-13). In order for low dose-rate irradiation to eliminate HRS through the TGF-β3-dependent mechanism, the cells must be exposed to IL-13 first. Inhibiting receptor IL-13Rα2 showed that this receptor is involved in the response. Adding IL-13 to serum-free medium restored the properties of full medium but not when an inhibitor of proprotein convertase activity was added together with IL-13. The presence of IL-13 resulted in upregulation of total iNOS protein levels. Thus, this study indicates that IL-13 interacts with the cells though receptor IL-13Rα2 and induces upregulation of iNOS and activation of one or more furin-like proprotein convertases.

  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 Induction of Chromosome Aberrations and Micronuclei in Human Peripheral Blood Lymphocytes at Low Doses of Radiation

    CERN Document Server

    Shmakova, N L; Krasavin, E A; Melnikova, L A; Fadeeva, T A

    2003-01-01

    The chromosome damage induced by the low doses of gamma-irradiation with ^{60}Co and X-rays in peripheral blood lymphocytes has been studied using different cytogenetic assays. Isolated lymphocytes were exposed to 0.01-1.0 Gy, simulated by PHA, and analysed for chromosome aberrations by the metaphase and the anaphase methods, by the micronucleus assay. Despite the quantitative differences in the amount of chromosome damage revealed by different methods, all of them demonstrated complex nonlinear dose dependence of the frequency of aberrant cells and aberrations. At the dose range of 0.01-0.05 Gy the cells showed the highest radiosensitivity; at 0.05-0.5 Gy the dose-independent induction of chromosome damage was revealed. At the doses of 0.5-1.0 Gy the dose-effect curves became linear with the decreased slope compared with the initial one (by a factor of 5 to 10 for different criteria) reflecting a higher radioresistance of the cells. These data confirm the idea that the direct linear extrapolation of high-dos...

  17. Hemopoietic stem-cell compartment of the SCID mouse: Double-exponential survival curve after [gamma] irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Taniguchi, Satoshi (Yokohama City Univ. School of Medicine (Japan) Niigata Univ. (Japan)); Hirabayashi, Yoko; Inoue, Tohru; Kanisawa, Masayoshi; Sasaki, Hideki (Yokohama City Univ. School of Medicine (Japan)); Komatsu, Kenshi (Nagasaki Univ (Japan)); Mori, K.J. (Niigata Univ. (Japan))

    1993-05-15

    It has been reported that SCID (severe combined immunodeficiency, scid/scid) mice are more radiosensitive than normal mice. In the present studies, graded doses of radiation were given to bone marrow cells from SCID mice, and double-exponential survival curves were observed for day-9 and day-12 colony-forming units in the spleen (CFU-S). Single-exponential curves were found for SCID CFU in in vitro assays for granulocyte/macrophage-CFUs and erythroid burst-forming units, as reported elsewhere. Since the size of this more resistant fraction seems to decrease with stem-cell maturation, the finding implies that this fraction is a primitive subpopulation of the stem-cell compartment. The mean lethal dose (D[sub 0]), however, of this less sensitive SCID CFU-S is much less than the D[sub 0] of regular CFU-S in normal littermates. Spleen colonies produced by SCID bone marrow were relatively small and abortive. The size of these colonies decreased nearly exponentially with increasing doses of radiation. These colonies produced by the sensitive fraction have disappeared, being killed by a relatively low dose of radiation. This observation might account for the high lymphomagenesis arising from primitive hemopoietic stem cells in SCID mice, because the smallness of the colonies suggests that there is unrepaired or misrepaired damage. Furthermore, this less sensitive fraction might be a source of the [open quotes]leaky[close quotes] change of T and B cells, possibly due to the induction of an equivocal repair system which appears in the later stages of life in the SCID mice. 34 refs., 5 figs., 3 tabs.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-01-15

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

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

    DEFF Research Database (Denmark)

    Feketeova, Linda; Bassler, Niels

    using mass spectrometry. Understanding the fragmentation of radiosensitizers is crucial in evaluating the radiosensitization potential and developing new and more effective drugs, which may improve TCP in hypoxic tumours when using ion beams such as carbon-12 along with LET-painting techniques. Method...

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

    NARCIS (Netherlands)

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

    1996-01-01

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

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

    NARCIS (Netherlands)

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

    1998-01-01

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

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

    NARCIS (Netherlands)

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

    1996-01-01

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

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

    NARCIS (Netherlands)

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

    1993-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1996-06-01

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

  5. 不同性别癫痫患者顺式阿曲库铵剂量-反应曲线的测定%Investigating the dose-response curves of cisatracurium in the different gender epileptics

    Institute of Scientific and Technical Information of China (English)

    刘中杰; 张庆国; 李乐; 卢爱珠; 赖露颖; 徐世元

    2014-01-01

    Objective To evaluate the gender differences in dose-response curve with cisatra-curium in epileptics.Methods Eighty ASA grade Ⅰ or Ⅱ epileptics were enrolled in this study.All patients were divided into male and the female groups and received the method of single dose injection under midazolam-fentanyl intravenous anesthesia.Each patient received intravenous bolus of 20,30, 40,50μg/kg of cisatracurium respectively.The neuromuscular block was measured by Neuromuscular Transmission Monitor and the responses were defined in terms of the percentages of maximum sup-pression in T1 of TOF of the adductor pollicis muscle.According to log-probit transformation of the data of dose and response,the dose-response curve of cisatracurium was established through linear re-gression.The onset time of cisatracurium was also observed.Results The ED50 ,ED75 ,ED90 ,ED95 values of cisatracurium in male epilepsy patients were 37.2±9.7,48.1±11.3,60.4±12.8,69.3± 14.0 μg/kg and that of female epilepsy patients were 36.6±4.3,47.5±7.7,60.5±14.0,70.1± 19.4 μg/kg.There was no significant difference between the two gender groups.No significant change in onset time was observed among 4 dose groups.Conclusion No gender differences are ob-served in dose-response curve of cisatracurium in epileptics.%目的:研究性别对癫痫手术患者顺式阿曲库铵剂量-反应曲线的影响。方法选取择期癫痫手术患者80例,年龄17~42岁,病史3~26年,分为男性组(M 组)和女性组(F 组),每组按20、30、40、50μg/kg 再分为四个亚组(M1~M4组和 F1~F4组),每组10例。记录拇内收肌四个成串刺激(TOF)第一次反应最大抑制的百分率,并进行概率单位转换,将顺式阿曲库铵的首次剂量进行对数转换,用直线回归方法分别建立男、女患者顺式阿曲库铵剂量-反应曲线,并记录起效时间。结果M组顺式阿曲库铵单次剂量静注 ED50、ED75、ED90、ED95

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

    Institute of Scientific and Technical Information of China (English)

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

    2005-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Underbrink, A.G.; Pond, V.

    1976-12-01

    Various cytological factors, including interphase chromosome volume (ICV), nuclear volume (NV), cell volume, DNA content per nucleus and per chromosome, have been reviewed to determine their usefulness as indices to predict radiosensitivity. Topics discussed are: a historical development of the concept of using karyotypic features to estimate radiosensitivity; interrelationships between cellular parameters; relationship of the karyotype to the duration of mitosis and meiosis; correlations between radiobiological end points and cellular parameters after whole-body irradiation in amphibians, insects and mammals; correlations between radiosensitivity and cellular parameters in diverse single-cell organisms; correlations between radiobiological end points and cellular parameters in higher plants irradiated with neutrons and the value of cell parameters to estimate relative biological effectiveness (RBE); and energy absorption and trends in radiosensitivity among species and radiobiological end points. It is concluded that ICV is usually the most useful parameter for predicting radiosensitivity.

  8. The radiosensitizing effect of Ku70/80 knockdown in MCF10A cells irradiated with X-rays and p(66+Be(40 neutrons

    Directory of Open Access Journals (Sweden)

    Thierens Hubert

    2010-04-01

    Full Text Available Abstract Background A better understanding of the underlying mechanisms of DNA repair after low- and high-LET radiations represents a research priority aimed at improving the outcome of clinical radiotherapy. To date however, our knowledge regarding the importance of DNA DSB repair proteins and mechanisms in the response of human cells to high-LET radiation, is far from being complete. Methods We investigated the radiosensitizing effect after interfering with the DNA repair capacity in a human mammary epithelial cell line (MCF10A by lentiviral-mediated RNA interference (RNAi of the Ku70 protein, a key-element of the nonhomologous end-joining (NHEJ pathway. Following irradiation of control and Ku-deficient cell lines with either 6 MV X-rays or p(66+Be(40 neutrons, cellular radiosensitivity testing was performed using a crystal violet cell proliferation assay. Chromosomal radiosensitivity was evaluated using the micronucleus (MN assay. Results RNAi of Ku70 caused downregulation of both the Ku70 and the Ku80 proteins. This downregulation sensitized cells to both X-rays and neutrons. Comparable dose modifying factors (DMFs for X-rays and neutrons of 1.62 and 1.52 respectively were obtained with the cell proliferation assay, which points to the similar involvement of the Ku heterodimer in the cellular response to both types of radiation beams. After using the MN assay to evaluate chromosomal radiosensitivity, the obtained DMFs for X-ray doses of 2 and 4 Gy were 2.95 and 2.66 respectively. After neutron irradiation, the DMFs for doses of 1 and 2 Gy were 3.36 and 2.82 respectively. The fact that DMFs are in the same range for X-rays and neutrons confirms a similar importance of the NHEJ pathway and the Ku heterodimer for repairing DNA damage induced by both X-rays and p(66+Be(40 neutrons. Conclusions Interfering with the NHEJ pathway enhanced the radiosensitivity of human MCF10A cells to low-LET X-rays and high-LET neutrons, pointing to the importance

  9. 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.

  10. 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.

  11. Factors of late radiosensitivity of normal tissues; Facteurs de radiosensibilite tardive des tissus sains

    Energy Technology Data Exchange (ETDEWEB)

    Azria, A. [CRLC Val d' Aurelle-Paul-Lamarque, departement de radiotherapie, 34 - Montpellier (France); Pointreau, Y. [CHRU Bretonneau, 37 - Tours (France); Toledano, A. [Clinique Hartman, 92 - Neuilly-sur-Seine (France); Ozsahin, M. [CHU Vaudois, Lausanne (Switzerland)

    2010-07-15

    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)

  12. c-MYC is a radiosensitive locus in human breast cells.

    Science.gov (United States)

    Wade, M A; Sunter, N J; Fordham, S E; Long, A; Masic, D; Russell, L J; Harrison, C J; Rand, V; Elstob, C; Bown, N; Rowe, D; Lowe, C; Cuthbert, G; Bennett, S; Crosier, S; Bacon, C M; Onel, K; Scott, K; Scott, D; Travis, L B; May, F E B; Allan, J M

    2015-09-17

    Ionising radiation is a potent human carcinogen. Epidemiological studies have shown that adolescent and young women are at increased risk of developing breast cancer following exposure to ionising radiation compared with older women, and that risk is dose-dependent. Although it is well understood which individuals are at risk of radiation-induced breast carcinogenesis, the molecular genetic mechanisms that underlie cell transformation are less clear. To identify genetic alterations potentially responsible for driving radiogenic breast transformation, we exposed the human breast epithelial cell line MCF-10A to fractionated doses of X-rays and examined the copy number and cytogenetic alterations. We identified numerous alterations of c-MYC that included high-level focal amplification associated with increased protein expression. c-MYC amplification was also observed in primary human mammary epithelial cells following exposure to radiation. We also demonstrate that the frequency and magnitude of c-MYC amplification and c-MYC protein expression is significantly higher in breast cancer with antecedent radiation exposure compared with breast cancer without a radiation aetiology. Our data also demonstrate extensive intratumor heterogeneity with respect to c-MYC copy number in radiogenic breast cancer, suggesting continuous evolution at this locus during disease development and progression. Taken together, these data identify c-MYC as a radiosensitive locus, implicating this oncogenic transcription factor in the aetiology of radiogenic breast cancer.

  13. Tumor radio-sensitivity assessment by means of volume data and magnetic resonance indices measured on prostate tumor bearing rats.

    Science.gov (United States)

    Belfatto, Antonella; White, Derek A; Mason, Ralph P; Zhang, Zhang; Stojadinovic, Strahinja; Baroni, Guido; Cerveri, Pietro

    2016-03-01

    Radiation therapy is one of the most common treatments in the fight against prostate cancer, since it is used to control the tumor (early stages), to slow its progression, and even to control pain (metastasis). Although many factors (e.g., tumor oxygenation) are known to influence treatment efficacy, radiotherapy doses and fractionation schedules are often prescribed according to the principle "one-fits-all," with little personalization. Therefore, the authors aim at predicting the outcome of radiation therapy a priori starting from morphologic and functional information to move a step forward in the treatment customization. The authors propose a two-step protocol to predict the effects of radiation therapy on individual basis. First, one macroscopic mathematical model of tumor evolution was trained on tumor volume progression, measured by caliper, of eighteen Dunning R3327-AT1 bearing rats. Nine rats inhaled 100% O2 during irradiation (oxy), while the others were allowed to breathe air. Second, a supervised learning of the weight and biases of two feedforward neural networks was performed to predict the radio-sensitivity (target) from the initial volume and oxygenation-related information (inputs) for each rat group (air and oxygen breathing). To this purpose, four MRI-based indices related to blood and tissue oxygenation were computed, namely, the variation of signal intensity ΔSI in interleaved blood oxygen level dependent and tissue oxygen level dependent (IBT) sequences as well as changes in longitudinal ΔR1 and transverse ΔR2(*) relaxation rates. An inverse correlation of the radio-sensitivity parameter, assessed by the model, was found with respect the ΔR2(*) (-0.65) for the oxy group. A further subdivision according to positive and negative values of ΔR2(*) showed a larger average radio-sensitivity for the oxy rats with ΔR2(*)<0 and a significant difference in the two distributions (p < 0.05). Finally, a leave-one-out procedure yielded a radio-sensitivity

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

    Directory of Open Access Journals (Sweden)

    Stephen M Schleicher

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

  15. In vitro radiosensitivity of human leukemia cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Weichselbaum, R.R.; Greenberger, J.S.; Schmidt, A.; Karpas, A.; Moloney, W.C.; Little, J.B.

    1981-05-01

    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.

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

    Science.gov (United States)

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

    2015-01-01

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

  17. Additive interactions of pregabalin with lamotrigine, oxcarbazepine and topiramate in the mouse maximal electroshock-induced seizure model: a type I isobolographic analysis for non-parallel dose-response relationship curves.

    Science.gov (United States)

    Luszczki, Jarogniew J; Filip, Damian; Czuczwar, Stanislaw J

    2010-10-01

    The aim of this study was to characterize the anticonvulsant effects of pregabalin (PGB-a third-generation antiepileptic drug) in combination with three second-generation antiepileptic drugs (i.e., lamotrigine [LTG], oxcarbazepine [OXC] and topiramate [TPM]) in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Potential adverse-effect profiles of interactions of PGB with LTG, OXC and TPM at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured. In the mouse MES model, PGB administered singly had its DRRC non-parallel to that for LTG, OXC and TPM. With type I isobolography for non-parallel DRRCs, the combinations of PGB with LTG, OXC and TPM at the fixed-ratio of 1:1 exerted additive interaction. In all combinations, neither motor coordination, long-term memory nor muscular strength were affected. In conclusion, the additive interactions between PGB and LTG, OXC and TPM are worthy of consideration while extrapolating the results from this study to clinical settings.

  18. Cytogenetic Effects of Low Dose Radiation in Mammalian Cells Analysis of the Phenomenon Hypersensitivity and Induced Radioresistence

    CERN Document Server

    Shmakova, N L; Nasonova, E A; Krasavin, E A; Rsjanina, A V

    2001-01-01

    The induction of cytogenetic damage after irradiation of chinese hamster cells and human melanoma cells within dose range 1-200 cGy was studied. The anaphase and metaphase analysis of chromosome damage and micronuclei test were applied. The hypersensitivity (HRS) at doses below 20 cGy and the increased radioresistence at higher doses (IR) were shown with all cytogenetic criteria for both cell lines. The phenomenon of HRS/IR was reproduced in synchronic as well as in asynchronic population of chinese hamster cells. This fact shows that HRS was caused by high radiosensitivity of all cells and can not be explained by any differential sensitivity of cells in different phases of the cell cycle. So it was supposed that the increasing radioresistence is determined by the inclusion of the inducible repair processes in all cells. This conclusion agress with the fact that there was no evidence of HRS on dose-effect curves and that some part of pre-existent damage was repaired after preliminary irradiation with low dose...

  19. The measurement of dose-response curve of cisatracurium in patients with end-stage renal disease%终末期肾病患者顺式阿曲库铵量效关系测定

    Institute of Scientific and Technical Information of China (English)

    葛彦虎; 王宏月; 刘秀珍; 王恒林; 张斌; 王卓强

    2013-01-01

    目的 采用单次剂量注射法测定终末期肾病患者顺式阿曲库铵量效关系. 方法 选取接受肾移植的终末期肾病患者40例,按完全随机方法分为4组,每组10例,对4个剂量组患者按体重注射20、30、40、50 μg/kg的顺式阿曲库铵.选取无神经肌肉病变的患者20例作为对照组,给予相同剂量的苯磺酸顺式阿曲库铵.记录每个患者最大抑制效应,并对最大抑制效应进行概率转换,对应的肌松药剂量进行对数转换,用直线回归方法建立顺式阿曲库铵的剂量-反应曲线. 结果 终末期肾病患者顺式阿曲库铵50%有效剂量(ED50) 、75%有效剂量(ED75)、90%有效剂量(ED90)、95%有效剂量ED95分别为30.88、35.65、40.62、43.85 μg/kg,无神经肌肉病变患者顺式阿曲库铵ED50、ED75、ED90、ED95分别为35.37、42.22、49.60、54.55 μg/kg,终末期肾病患者顺式阿曲库铵ED95明显低于无神经肌肉病变患者ED95 (P<0.01). 结论 终末期肾病患者因周围神经病变累及神经肌肉接头可导致对肌松药的敏感性增加.%Objective To determine the dose-response curve of cisatracurium in patients with end-stage renal disease.Methods Forty patients with end stage renal disease were randomly divided into four groups(n=10),the dose of cisatracurium were 20,30,40 or 50 μg/kg respectively.Twenty patients with normal neural and muscular function were randomly divided into four groups and received the same doses pattern.The dose-response curve was determined by single bolus of cisatracurium under midazolam-fentanyl intravenous anesthesia.Neuromuscular transmission monitoring was used to measure the block effect after injection of cisatracurium,and the responses were defined by terms of the percentages of maximum suppression in twitch response 1 of train of four of the adductor policies muscle.After logarithmic transformation,the dose-response curve of cisatracurium was then established by linear analysis

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

    Directory of Open Access Journals (Sweden)

    Baier Kurt

    2007-11-01

    Full Text Available Abstract Background Hypoxia-inducible factor-1 (HIF-1 overexpression has been linked to tumor progression and poor prognosis. We investigated whether targeting of HIF-1 using chetomin, a disrupter of the interaction of HIF-1 with the transcriptional coactivator p300, influences the radiosensitivity of hypoxic HT 1080 human fibrosarcoma cells. Methods Optimal dose of chetomin was determined by EGFP-HRE gene reporter assay in stably transfected HT 1080 cells. Cells were assayed for expression of the hypoxia-inducible genes carbonic anhydrase 9 (CA9 and vascular endothelial growth factor (VEGF by RT-PCR and for clonogenic survival after irradiation with 2, 5 or 10 Gy, under normoxic or hypoxic (0.1% O2, 12 h conditions in the presence or absence of chetomin (150 nM, 12 h, pre-treatment of 4 h. Results Chetomin treatment significantly reduced CA9 and VEGF mRNA expression in hypoxic cells to 44.4 ± 7.2% and 39.6 ± 16.0%, respectively, of untreated hypoxic controls. Chetomin clearly reduced the modified oxygen enhancement ratio (OER' compared to untreated cells, from 2.02 to 1.27, from 1.86 to 1.22 and from 1.49 to 1.06 at the 50%, 37% and 10% clonogenic survival levels, respectively. Conclusion HIF-1 inhibition by chetomin effectively reduces hypoxia-dependent transcription and radiosensitizes hypoxic HT 1080 human fibrosarcoma cells in vitro.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-05-15

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

  2. Enhancement of radiosensitivity by CpG-oligodeoxyribonucleotide-7909 in human non-small cell lung cancer A549 cells.

    Science.gov (United States)

    Zha, Lin; Qiao, Tiankui; Yuan, Sujuan; Lei, Linjie

    2010-04-01

    CpG-oligodeoxyribonucleotides (CpG-ODNs), which induce signaling through the toll-like receptor 9, are currently under investigation as immunity stimulators against cancer. It has recently been suggested that CpG-ODNs may also enhance sensitivity to traditional therapies including chemotherapy in certain cancer-cell lines. The purpose of this study was to define the activity of CpG-ODN7909 in increasing radiosensitivity of the human non-small cell lung cancer cell line A549 in vitro. First, a dose- and time-dependent inhibitory effect on cell viability was observed after A549 cells were treated with different concentrations of CpG-ODN7909 (5, 10, 30, and 60 microg/mL). Second, decreased cell clonogenic survival, enhanced cell apoptotic index, accumulated percentage of cells in the G2/M phase, and increased tumor necrosis factor (TNF)-alpha secretion were found after combined treatments with 10 microg/mL of CpG-ODN7909 and radiation compared to either treatment alone (p CpG-ODN7909 can increase the radiosensitivity of human non-small cell lung cancer A549 cells, which may be associated with reduced cell clonogenic survival, enhanced apoptosis, prolonged cell-cycle arrest in G2/M, and stimulation of TNF-alpha secretion.

  3. CpG oligodeoxyribonucleotide 7909 enhances radiosensitivity via downregulating Oct-4 expression in radioresistant lung cancer cells.

    Science.gov (United States)

    Xing, Na; Qiao, Tiankui; Zhuang, Xibing; Yuan, Sujuan; Zhang, Qi; Xu, Guoxiong

    2015-01-01

    Radiotherapy is a powerful cure for local advanced non-small cell lung cancer. However, radioresistance and tumor relapse still occur in a high proportion of patients. Octamer-4 (Oct-4), a transcription factor of the POU family, plays a key role in maintaining chemoradioresistant properties and regulating cancer progression. In this study, we demonstrated that Oct-4 expression was significantly increased in radioresistant H460 (H460R) cell line. CpG oligodeoxyribonucleotide (CpG-ODN) 7909 sensitized H460R cells when combined with irradiation treatment. The clonogenic capacity was significantly decreased, and the values of D0 and Dq were lower than those of irradiation alone group. The sensitive enhancement ratio (SER) of D0 was 1.224. This combined treatment led to a dramatic reduction in Oct-4 expression in a dose-dependent manner and also showed increased percentage of cells in the radiosensitive G2/M phase relative to either treatment alone. These results identified that Oct-4 was involved in radioresistance. CpG-ODN 7909 could enhance radiosensitivity partly through downregulating Oct-4 expression in radioresistant lung cancer cells.

  4. 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

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

    OpenAIRE

    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 acc...

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

    OpenAIRE

    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 γ3-irradiation and carbon-ion beam irradiation. DNMT3B RNAi reduced the activation of DNA damage responses induced by γ3-irradiation, including HP1β-, γ3H2AX- and Rad51-foci formation. DNMT3B RNAi impaired damage-dependent H2AX ...

  7. Development of bimetallic (Zn@Au) nanoparticles as potential PET-imageable radiosensitizers.

    Science.gov (United States)

    Cho, Jongmin; Wang, Min; Gonzalez-Lepera, Carlos; Mawlawi, Osama; Cho, Sang Hyun

    2016-08-01

    Gold nanoparticles (GNPs) are being investigated actively for various applications in cancer diagnosis and therapy. As an effort to improve the imaging of GNPs in vivo, the authors developed bimetallic hybrid Zn@Au NPs with zinc cores and gold shells, aiming to render them in vivo visibility through positron emission tomography (PET) after the proton activation of the zinc core as well as capability to induce radiosensitization through the secondary electrons produced from the gold shell when irradiated by various radiation sources. Nearly spherical zinc NPs (∼5-nm diameter) were synthesized and then coated with a ∼4.25-nm gold layer to make Zn@Au NPs (∼13.5-nm total diameter). 28.6 mg of these Zn@Au NPs was deposited (∼100 μm thick) on a thin cellulose target and placed in an aluminum target holder and subsequently irradiated with 14.15-MeV protons from a GE PETtrace cyclotron with 5-μA current for 5 min. After irradiation, the cellulose matrix with the NPs was placed in a dose calibrator to assess the induced radioactivity. The same procedure was repeated with 8-MeV protons. Gamma ray spectroscopy using an high-purity germanium detector was conducted on a very small fraction (<1 mg) of the irradiated NPs for each proton energy. In addition to experimental measurements, Monte Carlo simulations were also performed with radioactive Zn@Au NPs and solid GNPs of the same size irradiated with 160-MeV protons and 250-kVp x-rays. The authors measured 168 μCi of activity 32 min after the end of bombardment for the 14.15-MeV proton energy sample using the (66)Ga setting on a dose calibrator; activity decreased to 2 μCi over a 24-h period. For the 8-MeV proton energy sample, PET imaging was additionally performed for 5 min after a 12-h delay. A 12-h gamma ray spectrum showed strong peaks at 511 keV (2.05 × 10(6) counts) with several other peaks of smaller magnitude for each proton energy sample. PET imaging showed strong PET signals from mostly decaying (66)Ga

  8. Radiosensitivity of peripheral blood lymphocytes in autoimmune disease

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-06-01

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

  9. Survey of radiosensitivity in a variety of human cell strains

    Energy Technology Data Exchange (ETDEWEB)

    Arlett, C.F.; Harcourt, S.A.

    1980-03-01

    Gamma-ray sensitivity for cell killing was assayed in 54 human cell strains, including some derived from individuals suffering from certain hereditary diseases. The overall range of Do values in this study was 38 to 180 rads, indicating a considerable range of variability in humans. The normal sensitivity was described by a range of Do values of 97 to 180 rads. All ten ataxia telangiectasia cell strains tested proved radiosensitive and gave a mean Do value of 57 +- 15 (S.E.) rads, and these represent the most radiosensitive human skin fibroblasts currently available. Representative cell strains from familial retinoblastoma, Fanconi's anemia, and Hutchinson-Gilford progeria occupied positions of intermediate sensitivity, as did one of two ataxia telangiectasia heterozygotes. Six xeroderma pigmentosum cell strains together with two Cockayne's syndrome cell strains (all known to be sensitive to ultraviolet light) fell into the normal range, indicating an absence of cross-sensitivity between ultraviolet light and gamma-irradiation.

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

    Directory of Open Access Journals (Sweden)

    Arif Malik

    2016-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Panicucci, R.; Heal, R.; Laderoute, K.; Cowan, D.; McClelland, R.A.; Rauth, A.M.

    1989-04-01

    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.

  12. Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize

    Science.gov (United States)

    Adams, Stephen R.; Yang, Howard C.; Savariar, Elamprakash N.; Aguilera, Joe; Crisp, Jessica L.; Jones, Karra A.; Whitney, Michael A.; Lippman, Scott M.; Cohen, Ezra E. W.; Tsien, Roger Y.; Advani, Sunil J.

    2016-01-01

    Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery. PMID:27698471

  13. Understanding the radiosensitivity of hematopoietic stem cells through CDNA micro-arrays profiling

    Energy Technology Data Exchange (ETDEWEB)

    Pawlik, A.; Cebo, Ch.; Vaigot, P.; Tronik-Le Roux, D. [Evry Univ., Lab. de Genomique et Radiobiologie de l' Hematopoiese, Service de Genomique Fonctionnelle, CEA, 91 (France)

    2006-07-01

    Eradication of circulating hematopoietic cells has been long known to be the first noticeable somatic effect following total body ionizing radiation (IR) exposure. Among these hematopoietic cells a marked differences in sensitivity to IR have been documented reflecting the remarkable degree of heterogeneity in cell type, proliferative capacity and cell cycle status within the bone marrow cells. From all the hematopoietic cells, the small lymphocyte has the greatest radiosensitivity. In fact, a decline in absolute lymphocyte count has been used to assess IR dose in the early phase of observation after IR exposure. At moderate doses, bone marrow recovery is triggered by the differentiation of stem/early progenitor cells, which confirms further their differential sensitivity to radiation exposure. Although differences in radiosensitivity of the stem cell pool have also been documented, little is known from a molecular viewpoint. To gain insight into the molecular programs underlying the response o f hematopoietic cells to radiation exposure, we have applied a genome wide analysis strategy based on cDNA micro arrays. This technology offers a unique opportunity to dissect complex biological process by assessing three types of questions, which are, in order of complexity: Which genes are differentially expressed among the samples studied:Which genes are expressed in a coordinated manner and what are the regulators involved,what are the global biological pathways mobilized. To answer these questions transcriptional changes occurring after exposure of mice to whole body irradiation (2 Gy) were monitored in bone marrow and spleen. The time course was established in vivo and encompassed the reversible eradication of cells. For each kinetic point RNA was collected from both, spleen or sorted B.M. populations from irradiated and sham irradiated mice. The sham irradiated mice were used to eliminate stress modifications due to handling.The results highlight numerous

  14. Effect of gonadotropin secretion rate on the radiosensitivity of the rat luteinizing hormone-releasing hormone neuron and gonadotroph

    Energy Technology Data Exchange (ETDEWEB)

    Winterer, J.; Barnes, K.M.; Lichter, A.S.; Deluca, A.M.; Loriaux, D.L.; Cutler, G.B. Jr.

    1988-03-01

    To test the hypothesis that the functional state of hypothalamic LHRH neurons and pituitary gonadotrophs might alter their radiosensitivity, we determined the experimental conditions under which the gonadotropin response to castration could be impaired by a single dose of cranial irradiation. Single doses of cranial irradiation greater than 2000 rads were lethal to unshielded rats. Shielding of the oropharynx and esophagus allowed the animals to survive doses up to 5000 rads. Doses between 2000 and 5000 rads had no effect on basal gonadotropin levels for as long as 3 months after irradiation. Irradiation caused a dose- and time-dependent impairment, however, in the gonadotropin response to castration. Impairment of the gonadotropin levels of castrate animals occurred in animals that were irradiated either before or after castration. However, rats irradiated in the castrate state showed a decreased susceptibility to irradiation damage. Additionally, stimulation of the pituitary by LHRH agonist (LHRHa) 3 h before irradiation significantly reduced the impairment of gonadotropin secretion 12-20 weeks after irradiation (P less than 0.05). Thus, increased functional activity of the rat hypothalamus or pituitary at the time of irradiation, induced by either castration or acute LHRHa administration, was associated with some protection against the gonadotropin-lowering effect of irradiation. Based upon these data, we hypothesize that stimulation of gonadotropin secretion at the time of therapeutic cranial irradiation in humans might protect against subsequent impairment of gonadotropin secretion.

  15. Variability among polysulphone calibration curves

    Energy Technology Data Exchange (ETDEWEB)

    Casale, G R [University of Rome ' La Sapienza' , Physics Department, P.le A. Moro 2, I-00185, Rome (Italy); Borra, M [ISPESL - Istituto Superiore per la Prevenzione E la Sicurezza del Lavoro, Occupational Hygiene Department, Via Fontana Candida 1, I-0040 Monteporzio Catone (RM) (Italy); Colosimo, A [University of Rome ' La Sapienza' , Department of Human Physiology and Pharmacology, P.le A. Moro 2, I-00185, Rome (Italy); Colucci, M [ISPESL - Istituto Superiore per la Prevenzione E la Sicurezza del Lavoro, Occupational Hygiene Department, Via Fontana Candida 1, I-0040 Monteporzio Catone (RM) (Italy); Militello, A [ISPESL - Istituto Superiore per la Prevenzione E la Sicurezza del Lavoro, Occupational Hygiene Department, Via Fontana Candida 1, I-0040 Monteporzio Catone (RM) (Italy); Siani, A M [University of Rome ' La Sapienza' , Physics Department, P.le A. Moro 2, I-00185, Rome (Italy); Sisto, R [ISPESL - Istituto Superiore per la Prevenzione E la Sicurezza del Lavoro, Occupational Hygiene Department, Via Fontana Candida 1, I-0040 Monteporzio Catone (RM) (Italy)

    2006-09-07

    Within an epidemiological study regarding the correlation between skin pathologies and personal ultraviolet (UV) exposure due to solar radiation, 14 field campaigns using polysulphone (PS) dosemeters were carried out at three different Italian sites (urban, semi-rural and rural) in every season of the year. A polysulphone calibration curve for each field experiment was obtained by measuring the ambient UV dose under almost clear sky conditions and the corresponding change in the PS film absorbance, prior and post exposure. Ambient UV doses were measured by well-calibrated broad-band radiometers and by electronic dosemeters. The dose-response relation was represented by the typical best fit to a third-degree polynomial and it was parameterized by a coefficient multiplying a cubic polynomial function. It was observed that the fit curves differed from each other in the coefficient only. It was assessed that the multiplying coefficient was affected by the solar UV spectrum at the Earth's surface whilst the polynomial factor depended on the photoinduced reaction of the polysulphone film. The mismatch between the polysulphone spectral curve and the CIE erythemal action spectrum was responsible for the variability among polysulphone calibration curves. The variability of the coefficient was related to the total ozone amount and the solar zenith angle. A mathematical explanation of such a parameterization was also discussed.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-12-15

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

  17. Radiosensitivity, radio-curability and DNA repair; Radiosensibilite, radiocurabilite et reparation

    Energy Technology Data Exchange (ETDEWEB)

    Vogin, G. [Centre Alexis-Vautrin, 6, avenue de Bourgogne, 54511 Vandoeuvre-les-Nancy (France)

    2011-07-15

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

  18. Betulinyl Sulfamates as Anticancer Agents and Radiosensitizers in Human Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Matthias Bache

    2015-11-01

    Full Text Available Betulinic acid (BA, a natural compound of birch bark, is cytotoxic for many tumors. Recently, a betulinyl sulfamate was described that inhibits carbonic anhydrases (CA, such as CAIX, an attractive target for tumor-selective therapy strategies in hypoxic cancer cells. Data on combined CAIX inhibition with radiotherapy are rare. In the human breast cancer cell lines MDA-MB231 and MCF7, the effects of BA and betulinyl sulfamates on cellular and radiobiological behavior under normoxia and hypoxia were evaluated. The two most effective betulinyl sulfamates CAI 1 and CAI 3 demonstrated a 1.8–2.8-fold higher cytotoxicity than BA under normoxia in breast cancer cells, with IC50 values between 11.1 and 18.1 µM. BA exhibits its strongest cytotoxicity with IC50 values of 8.2 and 16.4 µM under hypoxia. All three substances show a dose-dependent increase in apoptosis, inhibition of migration, and inhibition of hypoxia-induced gene expression. In combination with irradiation, betulinyl sulfamates act as radiosensitizers, with DMF10 values of 1.47 (CAI 1 and 1.75 (CAI 3 under hypoxia in MDA-MB231 cells. BA showed additive effects in combination with irradiation. Taken together; our results suggest that BA and betulinyl sulfamates seem to be attractive substances to combine with radiotherapy; particularly for hypoxic breast cancer.

  19. Curcumin potentiates rhabdomyosarcoma radiosensitivity by suppressing NF-κB activity.

    Directory of Open Access Journals (Sweden)

    W Shannon Orr

    Full Text Available Ionizing radiation (IR is an essential component of therapy for alveolar rhabdomyosarcoma. Nuclear factor-kappaB (NF-κΒ transcription factors are upregulated by IR and have been implicated in radioresistance. We evaluated the ability of curcumin, a putative NF-κΒ inhibitor, and cells expressing genetic NF- κΒ inhibitors (IκBα and p100 super-repressor constructs to function as a radiosensitizer. Ionizing radiation induced NF-κΒ activity in the ARMS cells in vitro in a dose- and time-dependent manner, and upregulated expression of NF-κΒ target proteins. Pretreatment of the cells with curcumin inhibited radiation-induced NF-κΒ activity and target protein expression. In vivo, the combination of curcumin and IR had synergistic antitumor activity against Rh30 and Rh41 ARMS xenografts. The greatest effect occurred when tumor-bearing mice were treated with curcumin prior to IR. Immunohistochemistry revealed that combination therapy significantly decreased tumor cell proliferation and endothelial cell count, and increased tumor cell apoptosis. Stable expression of the super-repressor, SR-IκBα, that blocks the classical NF-κB pathway, increased sensitivity to IR, while expression of SR-p100, that blocks the alternative pathway, did not. Our results demonstrate that curcumin can potentiate the antitumor activity of IR in ARMS xenografts by suppressing a classical NF-κΒ activation pathway induced by ionizing radiation. These data support testing of curcumin as a radiosensitizer for the clinical treatment of alveolar rhabdomyosarcoma. IMPACT OF WORK: The NF-κΒ protein complex has been linked to radioresistance in several cancers. In this study, we have demonstrated that inhibiting radiation-induced NF-κΒ activity by either pharmacologic (curcumin or genetic (SR-IκBα means significantly enhanced the efficacy of radiation therapy in the treatment of alveolar rhabdomyosarcoma cells and xenografts. These data suggest that preventing the

  20. 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

  1. Radiosensitivity Parameters For Lethal Mutagenesis In Caenorhabditis Elegans

    Energy Technology Data Exchange (ETDEWEB)

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

    1994-01-01

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

  2. Hypoxic cell radiosensitization by moderate hyperthermia and glucose deprivation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, J.H.; Kim, S.H.; Hahn, E.W.

    1983-02-01

    Cell culture studies were carried out to determine whether moderate hyperthermia reduces the oxygen enhancement ratio of cells under well-defined cultural conditions. Using asynchronously growing HeLa cells, the OER of cells with and without glucose was determined following exposure of cells to moderate hyperthermia, 40.5omicronC for 1 hr, immediately after X irradiation. The OER of cells with 5 mM glucose was 3.2, whereas the OER of glucose-deprived cells was reduced to 2.0. The pH of the cell culture medium was kept at 7.4 throughtout the experiments. The present finding may provide a clue toward further enhancing the radiosensitization of hypoxic cells by heat.

  3. Hypoxic cell radiosensitization by moderate hyperthermia and glucose deprivation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, J.H.; Kim, S.H.; Hahn, E.W.

    1983-02-01

    Cell culture studies were carried out to determine whether moderate hyperthermia reduces the oxygen enhancement ratio of cells under well-defined cultural conditions. Using asynchronously growing HeLa cells, the OER of cells with and without glucose was determined following exposure of cells to moderate hyperthermia, 40.5 degrees C for 1 hr, immediately after X irradiation. The OER of cells with 5 mM glucose was 3.2, whereas the OER of glucose-deprived cells was reduced to 2.0. The pH of the cell culture medium was kept at 7.4 throughout the experiments. The present finding may provide a clue toward further enhancing the radiosensitization of hypoxic cells by heat.

  4. 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.

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

    Science.gov (United States)

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

    2015-12-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2007-04-15

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

  7. Implications on clinical scenario of gold nanoparticle radiosensitization in regards to photon energy, nanoparticle size, concentration and location

    Energy Technology Data Exchange (ETDEWEB)

    Lechtman, E; Mashouf, S; Pignol, J P [Department of Medical Biophysics, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N3M5 (Canada); Chattopadhyay, N; Cai, Z; Reilly, R, E-mail: Jean-Philippe.Pignol@sunnybrook.ca [Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, Ontario M5S 3M2 (Canada)

    2011-08-07

    Gold nanoparticle (AuNP) radiosensitization represents a novel approach to enhance the effectiveness of ionizing radiation. Its efficiency varies widely with photon source energy and AuNP size, concentration, and intracellular localization. In this Monte Carlo study we explored the effects of those parameters to define the optimal clinical use of AuNPs. Photon sources included {sup 103}Pd and {sup 125}I brachytherapy seeds; {sup 169}Yb, {sup 192}Ir high dose rate sources, and external beam sources 300 kVp and 6 MV. AuNP sizes were 1.9, 5, 30, and 100 nm. We observed a 10{sup 3} increase in the rate of photoelectric absorption using {sup 125}I compared to 6 MV. For a {sup 125}I source, to double the dose requires concentrations of 5.33-6.26 mg g{sup -1} of Au or 7.10 x 10{sup 4} 30 nm AuNPs per tumor cell. For 6 MV, concentrations of 1560-1760 mg g{sup -1} or 2.17 x 10{sup 7} 30 nm AuNPs per cell are needed, which is not clinically achievable. Examining the proportion of energy transferred to escaping particles or internally absorbed in the nanoparticle suggests two clinical strategies: the first uses photon energies below the k-edge and takes advantage of the extremely localized Auger cascade. It requires small AuNPs conjugated to tumor targeted moieties and nuclear localizing sequences. The second, using photon sources above the k-edge, requires a higher gold concentration in the tumor region. In this approach, energy deposited by photoelectrons is the main contribution to radiosensitization; AuNP size and cellular localization are less relevant.

  8. Implications on clinical scenario of gold nanoparticle radiosensitization in regards to photon energy, nanoparticle size, concentration and location

    Science.gov (United States)

    Lechtman, E.; Chattopadhyay, N.; Cai, Z.; Mashouf, S.; Reilly, R.; Pignol, J. P.

    2011-08-01

    Gold nanoparticle (AuNP) radiosensitization represents a novel approach to enhance the effectiveness of ionizing radiation. Its efficiency varies widely with photon source energy and AuNP size, concentration, and intracellular localization. In this Monte Carlo study we explored the effects of those parameters to define the optimal clinical use of AuNPs. Photon sources included 103Pd and 125I brachytherapy seeds; 169Yb, 192Ir high dose rate sources, and external beam sources 300 kVp and 6 MV. AuNP sizes were 1.9, 5, 30, and 100 nm. We observed a 103 increase in the rate of photoelectric absorption using 125I compared to 6 MV. For a 125I source, to double the dose requires concentrations of 5.33-6.26 mg g-1 of Au or 7.10 × 104 30 nm AuNPs per tumor cell. For 6 MV, concentrations of 1560-1760 mg g-1 or 2.17 × 107 30 nm AuNPs per cell are needed, which is not clinically achievable. Examining the proportion of energy transferred to escaping particles or internally absorbed in the nanoparticle suggests two clinical strategies: the first uses photon energies below the k-edge and takes advantage of the extremely localized Auger cascade. It requires small AuNPs conjugated to tumor targeted moieties and nuclear localizing sequences. The second, using photon sources above the k-edge, requires a higher gold concentration in the tumor region. In this approach, energy deposited by photoelectrons is the main contribution to radiosensitization; AuNP size and cellular localization are less relevant.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-04-15

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

  10. Genetic Factors Affecting Susceptibility to Low Dose & Low Dose-Rate Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Bedford, Joel

    2014-04-18

    Our laboratory has, among other things, developed and used the gamma H2AX focus assay and other chromosomal and cell killing assays to show that differences in this DNA double strand break (dsb) related response can be clearly and distinctly demonstrated for cells which are mildly hyper-radiosensitive such as those associated with A-T heterozygosity. We have found this level of mild hypersensitivity for cells from some 20 to 30 % of apparently normal individuals and from apparently normal parents of Retinoblastoma patients. We found significant differences in gene expression in somatic cells from unaffected parents of Rb patients as compared with normal controls, suggesting that these parents may harbor some as yet unidentified genetic abnormality. In other experiments we sought to determine the extent of differences in normal human cellular reaponses to radiation depending on their irradiation in 2D monolayer vs 3D organized acinar growth conditions. We exmined cell reproductive death, chromosomal aberration induction, and the levels of γ-H2AX foci in cells after single acute gamma-ray doses and immediately after 20 hours of irradiation at a dose rate of 0.0017 Gy/min. We found no significant differences in the dose-responses of these cells under the 2D or 3D growth conditions. While this does not mean such differences cannot occur in other situations, it does mean that they do not generally or necessarily occur. In another series of studies in collaboration with Dr Chuan Li, with supprt from this current grant. We reported a role for apoptotic cell death in promoting wound healing and tissue regeneration in mice. Apoptotic cells released growth signals that stimulated the proliferation of progenitor or stem cells. In yet another collaboration with Dr, B. Chen with funds from this grant, the relative radiosensitivity to cell killing as well as chromosomal instability of 13 DNA-PKcs site-directed mutant cell lines (defective at phosphorylation sites or kinase

  11. 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.

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

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

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

  13. Competitive but Not Allosteric mTOR Kinase Inhibition Enhances Tumor Cell Radiosensitivity1

    Science.gov (United States)

    Hayman, Thomas J; Kramp, Tamalee; Kahn, Jenna; Jamal, Muhammad; Camphausen, Kevin; Tofilon, Philip J

    2013-01-01

    The mechanistic target of rapamycin (mTOR) is a critical kinase in the regulation of gene translation and has been suggested as a potential target for radiosensitization. The goal of this study was to compare the radiosensitizing activities of the allosteric mTOR inhibitor rapamycin with that of the competitive mTOR inhibitor PP242. On the basis of immunoblot analyses, whereas rapamycin only partially inhibited mTOR complex 1 (mTORC1) activity and had no effect on mTOR complex 2 (mTORC2), PP242 inhibited the activity of both mTOR-containing complexes. Irradiation alone had no effect on mTORC1 or mTORC2 activity. Clonogenic survival was used to define the effects of the mTOR inhibitors on in vitro radiosensitivity. In the two tumor cell lines evaluated, PP242 treatment 1 hour before irradiation increased radiosensitivity, whereas rapamycin had no effect. Addition of PP242 after irradiation also enhanced the radiosensitivity of both tumor lines. To investigate the mechanism of radiosensitization, the induction and repair of DNA double-strand breaks were evaluated according γH2AX foci. PP242 exposure did not influence the initial level of γH2AX foci after irradiation but did significantly delay the dispersal of radiation-induced γH2AX foci. In contrast to the tumor cell lines, the radiosensitivity of a normal human fibroblast cell line was not influenced by PP242. Finally, PP242 administration to mice bearing U251 xenografts enhanced radiation-induced tumor growth delay. These results indicate that in a preclinical tumor model PP242 enhances tumor cell radiosensitivity both in vitro and in vivo and suggest that this effect involves an inhibition of DNA repair. PMID:23730416

  14. Competitive but Not Allosteric mTOR Kinase Inhibition Enhances Tumor Cell Radiosensitivity.

    Science.gov (United States)

    Hayman, Thomas J; Kramp, Tamalee; Kahn, Jenna; Jamal, Muhammad; Camphausen, Kevin; Tofilon, Philip J

    2013-06-01

    The mechanistic target of rapamycin (mTOR) is a critical kinase in the regulation of gene translation and has been suggested as a potential target for radiosensitization. The goal of this study was to compare the radiosensitizing activities of the allosteric mTOR inhibitor rapamycin with that of the competitive mTOR inhibitor PP242. On the basis of immunoblot analyses, whereas rapamycin only partially inhibited mTOR complex 1 (mTORC1) activity and had no effect on mTOR complex 2 (mTORC2), PP242 inhibited the activity of both mTOR-containing complexes. Irradiation alone had no effect on mTORC1 or mTORC2 activity. Clonogenic survival was used to define the effects of the mTOR inhibitors on in vitro radiosensitivity. In the two tumor cell lines evaluated, PP242 treatment 1 hour before irradiation increased radiosensitivity, whereas rapamycin had no effect. Addition of PP242 after irradiation also enhanced the radiosensitivity of both tumor lines. To investigate the mechanism of radiosensitization, the induction and repair of DNA double-strand breaks were evaluated according γH2AX foci. PP242 exposure did not influence the initial level of γH2AX foci after irradiation but did significantly delay the dispersal of radiation-induced γH2AX foci. In contrast to the tumor cell lines, the radiosensitivity of a normal human fibroblast cell line was not influenced by PP242. Finally, PP242 administration to mice bearing U251 xenografts enhanced radiation-induced tumor growth delay. These results indicate that in a preclinical tumor model PP242 enhances tumor cell radiosensitivity both in vitro and in vivo and suggest that this effect involves an inhibition of DNA repair.

  15. Radiosensitivity and capacity for radiation-induced sublethal damage repair of canine transitional cell carcinoma (TCC) cell lines.

    Science.gov (United States)

    Parfitt, S L; Milner, R J; Salute, M E; Hintenlang, D E; Farese, J P; Bacon, N J; Bova, F J; Rajon, D A; Lurie, D M

    2011-09-01

    Understanding the inherent radiosensitivity and repair capacity of canine transitional cell carcinoma (TCC) can aid in optimizing radiation protocols to treat this disease. The objective of this study was to evaluate the parameters surviving fraction at 2 Gy (SF(2) ), α/β ratio and capacity for sublethal damage repair (SLDR) in response to radiation. Dose-response and split-dose studies were performed using the clonogenic assay. The mean SF(2) for three established TCC cell lines was high at 0.61. All the three cell lines exhibited a low to moderate α/β ratio, with the mean being 3.27. Two cell lines exhibited statistically increased survival at 4 and 24 h in the dose-response assay. Overall, our results indicate that the cell lines are moderately radioresistant, have a high repair capacity and behave similarly to a late-responding normal tissue. These findings indicate that the radiation protocols utilizing higher doses with less fractionation may be more effective for treating TCC.

  16. Relationship between individual radiosensitivity and radiation encephalopathy of nasopharyngeal carcinoma after radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Tang Yamei; Peng Ying; Xing Yigang [Dept. of Neurology, The Second Affiliated Hospital, Sun Yat-Sen Univ., Guangzhou (China); Zhang Yinyin [Dept. of Internal Medicine, The Second Affiliated Hospital, Sun Yat-Sen Univ., Guangzhou (China); Guo Ling [Dept. of Nasopharyngeal Carcinoma, Cancer Center of Sun Yat-Sen Univ., Guangzhou (China); Luo Qingliang [Beijing Inst. of Radiation Medicine, BJ (China)

    2008-10-15

    Purpose: to analyze the relationship between individual radiosensitivity and the morbidity and severity of radiation encephalopathy (RE) induced by radiotherapy of nasopharyngeal carcinoma (NPC) patients. Patients and methods: in this study, 26 patients with RE (experimental group) and 26 patients without RE (control group) after radiotherapy of NPC were included. The experimental group was divided into two subgroups, that is, group 1 with 1-2 grade and group 2 with 3-4 grade, according to the RTOG/EORTC Score. Individual radiosensitivity was determined by the total chromosomal aberration rate measured in in vitro irradiated lymphocytes by a metaphase detection technique. Chromosomal aberration rate was correlated to development of RE in order to investigate the relationship between radiosensitivity and RE. Results: the total chromosomal aberration rate was found to be a risk factor for the onset of RE. The total chromosomal aberration rate was positively correlated to the severity of RE. Patients with a high radiosensitivity had shorter latency than those with a low or intermediate radiosensitivity. Conclusion: in NPC patients, individual radiosensitivity as determined by the proportion of lethal chromosomal aberrations in in vitro irradiated lymphocytes might be associated with the development of RE and has the potential to predict the morbidity and severity of RE. (orig.)

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

    Science.gov (United States)

    Kato, Shinya; Kimura, Masatsugu; Miwa, Nobuhiko

    2014-04-01

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

  18. In vitro studies on radiosensitization effect of glucose capped gold nanoparticles in photon and ion irradiation of HeLa cells

    Energy Technology Data Exchange (ETDEWEB)

    Kaur, Harminder; Pujari, Geetanjali [Radiation Biology Group, Inter University Accelerator Centre, Post Box 10502, New Delhi 110067 (India); Semwal, Manoj K. [Army Hospital (R and R), Delhi Cantonment, New Delhi 110010 (India); Sarma, Asitikantha [Radiation Biology Group, Inter University Accelerator Centre, Post Box 10502, New Delhi 110067 (India); Avasthi, Devesh Kumar, E-mail: dka@iuac.res.in [Radiation Biology Group, Inter University Accelerator Centre, Post Box 10502, New Delhi 110067 (India)

    2013-04-15

    Highlights: ► Glucose capped gold nanoparticles (Glu-AuNPs) are synthesized for internalization in HeLa cells (cervical cancer cells). ► Internalization of Glu-AuNPs in HeLa cells is confirmed by cross section TEM of cells. ► Irradiation (by C ion or γ-rays) of HeLa cells with internalized Glu-AuNPs results in enhanced radiosensitization. ► There is about 30% reduction in radiation dose for 90% cell killing of HeLa cells, when internalized by Glu-AuNPs. ► The enhanced radiosensitization due to Glu-AuNPs is of interest for researchers in nanobiotechnology and radiation biology. -- Abstract: Noble metal nanoparticles are of great interest due to their potential applications in diagnostics and therapeutics. In the present work, we synthesized glucose capped gold nanoparticle (Glu-AuNP) for internalization in the HeLa cell line (human cervix cancer cells). The capping of glucose on Au nanoparticle was confirmed by Raman spectroscopy. The Glu-AuNP did not show any toxicity to the HeLa cell. The γ-radiation and carbon ion irradiation of HeLa cell with and without Glu-AuNP were performed to evaluate radiosensitization effects. The study revealed a significant reduction in radiation dose for killing the HeLa cells with internalized Glu-AuNPs as compared to the HeLa cells without Glu-AuNP. The Glu-AuNP treatment resulted in enhancement of radiation effect as evident from increase in relative biological effectiveness (RBE) values for carbon ion irradiated HeLa cells.

  19. Nonhomologous end-joining repair plays a more important role than homologous recombination repair in defining radiosensitivity after exposure to high-LET radiation.

    Science.gov (United States)

    Takahashi, Akihisa; Kubo, Makoto; Ma, Hongyu; Nakagawa, Akiko; Yoshida, Yukari; Isono, Mayu; Kanai, Tatsuaki; Ohno, Tatsuya; Furusawa, Yoshiya; Funayama, Tomoo; Kobayashi, Yasuhiko; Nakano, Takashi

    2014-09-01

    DNA double-strand breaks (DSBs) induced by ionizing radiation pose a major threat to cell survival. The cell can respond to the presence of DSBs through two major repair pathways: homologous recombination (HR) and nonhomologous end joining (NHEJ). Higher levels of cell death are induced by high-linear energy transfer (LET) radiation when compared to low-LET radiation, even at the same physical doses, due to less effective and efficient DNA repair. To clarify whether high-LET radiation inhibits all repair pathways or specifically one repair pathway, studies were designed to examine the effects of radiation with different LET values on DNA DSB repair and radiosensitivity. Embryonic fibroblasts bearing repair gene (NHEJ-related Lig4 and/or HR-related Rad54) knockouts (KO) were used and their responses were compared to wild-type cells. The cells were exposed to X rays, spread-out Bragg peak (SOBP) carbon ion beams as well as with carbon, iron, neon and argon ions. Cell survival was measured with colony-forming assays. The sensitization enhancement ratio (SER) values were calculated using the 10% survival dose of wild-type cells and repair-deficient cells. Cellular radiosensitivity was listed in descending order: double-KO cells > Lig4-KO cells > Rad54-KO cells > wild-type cells. Although Rad54-KO cells had an almost constant SER value, Lig4-KO cells showed a high-SER value when compared to Rad54-KO cells, even with increasing LET values. These results suggest that with carbon-ion therapy, targeting NHEJ repair yields higher radiosensitivity than targeting homologous recombination repair.

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

    Directory of Open Access Journals (Sweden)

    Benjamin J Povinelli

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

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

    Science.gov (United States)

    Povinelli, Benjamin J; Kokolus, Kathleen M; Eng, Jason W-L; Dougher, Christopher W; Curtin, Leslie; Capitano, Maegan L; Sailsbury-Ruf, Christi T; Repasky, Elizabeth A; Nemeth, Michael J

    2015-01-01

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

  2. Clinical application of Chamomilla recutita in phlebitis: dose response curve study Aplicación clínica de la Chamomilla recutita en flebitis: estudio de la curva dosis-respuesta Aplicação clínica da Chamomilla recutita em flebites: estudo de curva dose-resposta

    Directory of Open Access Journals (Sweden)

    Paula Elaine Diniz dos Reis

    2011-02-01

    Full Text Available This experimental and dose-response curve study aimed to carry out the quality control of the Chamomilla recutita sample, as well as to estimate the ideal dose, for anti-inflammatory effect, of the extract of its capitula, in patients with phlebitis due to peripheral intravenous infusion of antineoplastic chemotherapy and to evaluate the toxicity of this extract in human beings. The therapeutic efficacy, concerning the anti-inflammatory potential, of different doses of Chamomilla recutita extract were analyzed and compared in 25 patients. The time of regression of phlebitis was shorter for groups with 2.5% concentration (mean=29.2h, standard deviation = 8.98 and 5% concentration (mean = 38.8h, standard deviation = 17.47. Local toxicity was almost not observed. This research contributes to the innovation of the nursing clinical practice, since it suggests an alternative for the treatment of phlebitis through the clinical use of phytotherapeutic drugs.En este estudio, se buscó realizar el control de calidad de la muestra de Chamomilla recutita, así como estimar la dosis ideal, para efecto antiinflamatorio, de la infusión de sus inflorescencias, en pacientes con flebitis proveniente de introducción intravenosa periférica de quimioterapia antineoplásica y evaluar la toxicidad de esta infusión en los seres humanos. Se trata de estudio experimental, del tipo curva dosis-respuesta, en el cual fue analizada y comparada la eficacia terapéutica, en cuanto al potencial antiinflamatorio, de diferentes dosis de la infusión de la Chamomilla recutita en 25 pacientes. El tiempo de regresión de la flebitis fue menor para los grupos con concentración 2,5% (promedio = 29,2h, desviación estándar = 8,98 y 5% (promedio = 38,8h, desviación estándar = 17,47 y prácticamente no se observó toxicidad local. Esta investigación contribuye para la innovación de la práctica clínica en enfermería, una vez que sugiere una alternativa para el tratamiento de

  3. Dosimetry for synchrotron stereotactic radiotherapy: Monte Carlo simulations and radiosensitive gels; Dosimetrie pour la radiotherapie stereotaxique en rayonnement synchrotron: calculs Monte-Carlo et gels radiosensibles

    Energy Technology Data Exchange (ETDEWEB)

    Boudou, C

    2006-09-15

    High grade gliomas are extremely aggressive brain tumours. Specific techniques combining the presence of high atomic number elements within the tumour to an irradiation with a low x-rays (below 100 keV) beam from a synchrotron source were proposed. For the sake of clinical trials, the use of treatment planning system has to be foreseen as well as tailored dosimetry protocols. Objectives of this thesis work were (1) the development of a dose calculation tools based on Monte Carlo code for particles transport and (2) the implementation of an experimental method for the three dimensional verification of the dose delivered. The dosimetric tool is an interface between tomography images from patient or sample and the M.C.N.P.X. general purpose code. Besides, dose distributions were measured through a radiosensitive polymer gel, providing acceptable results compared to calculations.

  4. RGD-conjugated gold nanorods induce radiosensitization in melanoma cancer cells by downregulating αvβ3 expression

    Directory of Open Access Journals (Sweden)

    Pang B

    2012-02-01

    Full Text Available Wencai Xu1, Teng Luo2, Ping Li1, Chuanqing Zhou2, Daxiang Cui3, Bo Pang4, Qiushi Ren4, Shen Fu11Department of Radiation Oncology, Shanghai Sixth People's Hospital, 2School of Biomedical Engineering, and 3National Key Laboratory of Nano/Micro Fabrication Technology, Key Laboratory for Thin Film and Microfabrication of Ministry of Education, Institute of Micro-Nano Science and Technology, Shanghai Jiao Tong University, Shanghai, 4Department of Biomedical Engineering, College of Engineering, Peking University, Beijing, People's Republic of ChinaBackground: Melanoma is known to be radioresistant and traditional treatments have been intractable. Therefore, novel approaches are required to improve the therapeutic efficacy of melanoma treatment. In our study, gold nanorods conjugated with Arg-Gly-Asp peptides (RGD-GNRs were used as a sensitizer to enhance the response of melanoma cells to 6 mV radiation.Methods and materials: A375 melanoma cells were treated by gold nanorods or RGD-GNRs with or without irradiation. The antiproliferative impact of the treatments was measured by MTT assay. Radiosensitizing effects were determined by colony formation assay. Apoptosis and cell cycle data were measured by flow cytometry. Integrin αvβ3expression was also investigated by flow cytometry.Results: Addition of RGD-GNRs enhanced the radiosensitivity of A375 cells with a dose-modifying factor of 1.35, and enhanced radiation-induced apoptosis. DNA flow cytometric analysis indicated that RGD-GNRs plus irradiation induced significant G2/M phase arrest in A375 cells. Both spontaneous and radiation-induced expressions of integrin αvβ3 were downregulated by RGD-GNRs.Conclusion: Our study indicated that RGD-GNRs could sensitize melanoma A375 cells to irradiation. It was hypothesized that this was mainly through downregulation of radiation-induced αvβ3, in addition to induction of a higher proportion of cells within the G2/M phase. The combination of RGD-GNRs and

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-01-01

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

  6. Multiphasic growth curve analysis.

    NARCIS (Netherlands)

    Koops, W.J.

    1986-01-01

    Application of a multiphasic growth curve is demonstrated with 4 data sets, adopted from literature. The growth curve used is a summation of n logistic growth functions. Human height growth curves of this type are known as "double logistic" (n = 2) and "triple logistic" (n = 3) growth curves (Bock

  7. The influence of the dose calculation resolution of VMAT plans on the calculated dose for eye lens and optic apparatus

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jong Min; Park, So Yeon; Kim, Jung In; Kim, Jin Ho [Dept. of Radiation Oncology, Seoul National University Hospital, Seoul (Korea, Republic of); Wu, Hong Gyun [Dept. of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2015-10-15

    Since those organs are small in volume, dose calculation for those organs seems to be more susceptible to the calculation grid size in the treatment planning system (TPS). Moreover, since they are highly radio-sensitive organs, especially eye lens, they should be considered carefully for radiotherapy. On the other hand, in the treatment of head and neck (H and N) cancer or brain tumor that generally involves radiation exposure to eye lens and optic apparatus, intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) techniques are frequently used because of the proximity of various radio-sensitive normal organs to the target volumes. Since IMRT and VMAT can deliver prescription dose to target volumes while minimizing dose to nearby organs at risk (OARs) by generating steep dose gradients near the target volumes, high dose gradient sometimes occurs near or at the eye lenses and optic apparatus. In this case, the effect of dose calculation resolution on the accuracy of calculated dose to eye lens and optic apparatus might be significant. Therefore, the effect of dose calculation grid size on the accuracy of calculated doses for each eye lens and optic apparatus was investigated in this study. If an inappropriate calculation resolution was applied for dose calculation of eye lens and optic apparatus, considerable errors can be occurred due to the volume averaging effect in high dose gradient region.

  8. 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.

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

    Institute of Scientific and Technical Information of China (English)

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

    2005-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-09-09

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

  11. In vitro effects of piracetam on the radiosensitivity of hypoxic cells (adaptation of MTT assay to hypoxic conditions); Effets in vitro du piracetam sur la radiosensibilite des cellules hypoxiques (adapatation du test au MTT aux conditions d`hypoxie)

    Energy Technology Data Exchange (ETDEWEB)

    Gheuens, E.E.O.; Bruijn, E.A. de; Van der Heyden, S.; Van Oosterom, A.T. [Universitaire Instelling Antwerpen, Antwerp (Belgium); Lagarde, P. [Universitaire Instelling Antwerpen, Antwerp (Belgium)]|[Institut Bergonie, 33 - Bordeaux (France); Pooter, C.M.J. de [Universitaire Instelling Antwerpen, Antwerp (Belgium)]|[Hopital de Middelheim, Anvers (Belgium); Chomy, F. [Institut Bergonie, 33 - Bordeaux (France)

    1995-12-31

    This paper describes the adaptation of the MTT assay to hypoxic conditions in order to test the in vitro effect of piracetam on hypoxic cells and particularly on the radiosensitivity of hypoxic cells since this drug has shown clinical effect on acute and chronic hypoxia. The V79 cell line was selected by reference to preliminary hypoxic experiments using clonogenic assay and euoxic experiments using clonogenic and MTT assays. Cell growth and survival in our hypoxic conditions were assessed using MTT assay with an enclosure and special 48-well plates both made of glass. Growth curves on glass plates after 1-hour exposure to nitrogen versus air were comparable, so there is no bias effect due to gas composition. Survival curves using MTT versus reference clonogenic assay were comparable after radiation exposure in eu- and hypoxic conditions, and confirm the validity of our original technique for creating hypoxia. The Oxygen Enhancement Ratio was of about 3 for 1-hour hypoxic exposure. Piracetam gave no cytotoxic effect up to 10 mM of piracetam. Growth curves after continuous drug exposure and 1-hour euoxic versus hypoxic exposure gave no cytotoxic effect up to 10 mM of piracetam. Survival curves after continuous drug exposure to 10 mM of piracetam gave no significant effect on the radiosensitivity of hypoxic V79 cells using MTT or clonogenic assay. (author). 32 refs., 6 figs.

  12. Donor-specific cell-based assays in studying sensitivity to low-dose radiation: a population-based perspective

    Directory of Open Access Journals (Sweden)

    Dora eIl'yasova

    2014-11-01

    Full Text Available Currently, a linear no-threshold model is used to estimate health risks associated with exposure to low-dose radiation, a prevalent exposure in the general population, because the direct estimation from epidemiological studies suffers from uncertainty. This model has been criticized based on unique biology of low-dose radiation. Whether the departure from linearity is toward increased or decreased risk is intensely debated. We present an approach based on individual radiosensitivity testing and discuss how individual radiosensitivity can be assessed with the goal to develop a quantifiable measure of cellular response that can be conducted via high-throughput population testing.

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

    Directory of Open Access Journals (Sweden)

    Jayant S Goda

    2016-01-01

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

  14. 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.)

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

    Science.gov (United States)

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

    2016-02-01

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

  16. Targeted Radiosensitization by the Chk1 Inhibitor SAR-020106

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-03-15

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

  17. Estimation of breast dose reduction potential for organ-based tube current modulated CT with wide dose reduction arc

    Science.gov (United States)

    Fu, Wanyi; Sturgeon, Gregory M.; Agasthya, Greeshma; Segars, W. Paul; Kapadia