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Among other nanoparticle systems, gold nanoparticles have been explored as radiosensitizers. While most of the research in this area has focused on either gold nanoparticles with diameters of less than 2 nm or particles with micrometer dimensions, it has been shown that nanoparticles 50 nm in diameter have the highest cellular uptake. We present the results of in vitro studies that focus on the radiosensitization properties of nanoparticles in the size range from 14–74 nm. Radiosensitization was dependent on the number of gold nanoparticles internalized within the cells. Gold nanoparticles 50-nm in diameter showed the highest radiosensitization enhancement factor (REF) (1.43 at 220 kVp) compared to gold nanoparticles of 14 and 74 nm (1.20 and 1.26, respectively). Using 50-nm gold nanoparticles, the REF for lower- (105 kVp) and higher- (6 MVp) energy photons was 1.66 and 1.17, respectively. DNA double-strand breaks were quantified using radiation-induced foci of γ-H2AX and 53BP1, and a modest increase in the number of foci per nucleus was observed in irradiated cell populations with internalized gold nanoparticles. The outcome of this research will enable the optimization of gold nanoparticle-based sensitizers for use in therapy.
56Fe-particle radiation-induced brain disturbances are a major health concern for astronauts during long-term space travel. The present study investigated temporal modifications within the brain after 56Fe-particle exposure using in vivo magnetic resonance imaging (MRI) correlated to histology. Male Sprague-Dawley rats were exposed to brain-only 56Fe-particle radiation. MRI including T2-weighted, diffusion-weighted, pre/postcontrast enhanced T1-weighted imaging was performed 0.25–18 months after exposure. T2 relaxation times and the apparent diffusion coefficient were quantified within the hippocampus, entorhinal cortex, retrosplenial cortex and thalamus, and correlative histopathology was then performed at each time. In the absence of visible lesions on MR images, the apparent diffusion coefficient and T2 relaxation times revealed 56Fe-particle-induced dynamic changes in all ROIs over the 18-month time course. The patterns of MR changes were spatially similar within the different regions. The temporal alterations in the apparent diffusion coefficient corresponded to the glial cell changes within the brain. Quantitative MRI provides a non-invasive approach to monitor spatio-temporal brain alterations after 56Fe-particle irradiation. The apparent diffusion coefficient appears to be a sensitive metric to reveal ongoing tissue modifications involving multiple cellular components in vivo.
Shilpa Kulkarni, Sanchita P. Ghosh, Merriline Satyamitra, Steven Mog, Kevin Hieber, Lyudmila Romanyukha, Kristen Gambles, Raymond Toles, Tzu-Cheg Kao, Martin Hauer-Jensen, K. Sree Kumar
We analyzed the radioprotective effects of gamma-tocotrienol (GT3) on hematopoietic stem cells (HSCs) and progenitor cells (HPCs) in sublethally irradiated mice. Flow cytometry analysis indicated that radiation depleted HPCs (c-Kit, Lin−) to 40% at days 2 and 4 after total-body irradiation (TBI) in all treatment groups. The HPC numbers in GT3-treated mice recovered almost completely (90%) at day 7 but remained depleted in vehicle-treated mice (30%) even at day 13 after TBI. An in vitro colony-forming assay on sorted HSCs (Lin−, Sca1, c-Kit) indicated that TBI reduced the number of colonies to 40% and 50% at day 17 and 60, respectively, in vehicle-treated groups compared to unirradiated controls (naïve). GT3-treated irradiated mice maintained higher numbers of colonies (86% and 80% compared to naïve mice), thereby preserving the self-renewable capacity of HSCs. Histopathology of sternal bone marrow indicated more regenerative microfoci for myeloid cells and megakaryocytes and higher overall cellularity in GT3-treated mice compared to vehicle controls at days 7 and 13 after TBI. GT3 treatment also reduced the frequency of micronucleated erythrocytes significantly in irradiated mice. Our results demonstrate that GT3 protected hematopoietic tissue by preserving the HSCs and HPCs and by preventing persistent DNA damage.
Numerous in vitro and in vivo studies have shown that the endothelial cells of the microvasculature of the lung and kidney are damaged by exposure to ionizing radiation, and this sustained endothelial cell injury is involved in the early and late radiation effects observed in these tissues. It is well accepted that ionizing radiation causes the generation of reactive oxygen species during exposure that results in damage to DNA and cellular organelles. It is more controversial, however, whether additional biochemical events or long-lived radicals occur and persist postirradiation that amplify and initiate new forms of cellular damage. Two families of Eukarion (EUK) compounds have been synthesized that possess superoxide dismutase (SOD), catalase and peroxidase activities. The Mn porphyrins are available orally whereas the salen Mn complexes are administered by injection. In the present study we have examined the ability of these SOD/catalase mimetics to prevent apoptosis of endothelial cells when administered 1 h postirradiation (mitigation). A range of salen Mn complex (EUK-189 and EUK-207) and Mn porphyrins (EUK-418, -423, -425, -450, -451, -452, -453) were used to treat endothelial cells 1 h after the cells received 2–20 Gy ionizing radiation in vitro. Two lead compounds, EUK-207 at a dose of 30 µM and EUK-451 at a dose of 10 µM, exhibited low toxicity and mitigated radiation-induced apoptosis. Future animal studies will test whether these compounds protect when administered after radiation exposure as would be done after a radiological accident or a terrorism event.
Genetic lesions and cell death associated with exposure to ionizing radiation have generally been attributed to DNA damage arising as a consequence of deposition of energy in the cell nucleus. However, reports of radiation-induced bystander effects, in which DNA damage is produced in nonirradiated cells as a consequence of communication with irradiated cells, indicate additional mechanisms. At present, most information has been obtained using in vitro systems, and the in vivo significance of bystander factors is not clear. In this study we show that signals generated in vivo in the bone marrow of CBA/Ca mice irradiated with 4 Gy γ rays 24 h previously, but not immediately postirradiation, are able to induce DNA damage and apoptosis in nonirradiated bone marrow cells. The signaling mechanism involves FasL, TNF-α, nitric oxide and superoxide and macrophages are implicated as a source of damaging signals. Such delayed bystander-type damage demonstrates the importance of studying tissue responses subsequent to the radiation exposure as well as effects at the time of irradiation when considering the mechanisms underlying the consequences of radiation exposures.
We examined bystander cell death produced in T98G cells by exposure to irradiated cell conditioned medium (ICCM) produced by high-energy 20 MeV electrons at a dose rate of 10 Gy min−1 and doses up to 20 Gy. ICCM induced a bystander response in T98G glioma cells, reducing recipient cell survival by more than 25% below controls at 5 and 10 Gy. Higher doses increased survival to near control levels. ICCM was analyzed for the presence of transforming growth factor α (TGF-α) and transforming growth factor β1 (TGF-β1). Monoclonal antibodies for TGF-α (mAb TGF-α) and TGF-β1 (mAb TGF-β1) were added to the ICCM to neutralize any potential effect of the cytokines. The results indicate that TGF-α was not present in the ICCM and addition of mAb TGF-α to the ICCM had no effect on bystander cell survival. No active TGF-β1 was present in the ICCM; however, addition of mAb TGF-β1 completely abolished bystander death of reporter cells at all doses. These results indicate that bystander cell death can be induced in T98G glioma if a large enough radiation stress is applied and that TGF-β1 plays a downstream role in this response.
The aim of this investigation was to explore whether the occurrence and the magnitude of radiation-induced, medium-mediated bystander effects could be influenced by the time of transfer of secreted bystander factors. HaCaT cells were exposed to 0.1 and 1.0 Gy of γ radiation. These doses did not induce a significant reduction in the clonogenic survival of irradiated cells compared to controls. Bystander cells either were co-cultured with irradiated cells or received medium from irradiated cells. The bystander effects analyzed included end points related to survival (clonogenic potential and cell proliferation) and DNA damage (micronucleus induction and γ-H2AX formation). The bystander effects we investigated either were lacking or varied from potentially protective to detrimental responses in relation to the dose of radiation and the time between irradiation of donor cells and bystander exposure. Our results suggest that the experimental time schedule is important for both the occurrence and the detection of bystander effects in vitro.
The established dogma in radiation sciences that underlies radiation protection and therapeutic applications is that radiation effects require induction of DNA damage only in cells that are directly hit by the radiation. However, extensive work during the last decade demonstrates that DNA damage responses can be detected in cells that are only bystanders. Such effects include cell killing and responses associated with DNA and chromosome damage. Here, we developed a strategy for investigating bystander effects on chromosomal integrity by premature chromosome condensation using hybrid cell formation between nontargeted human lymphocytes and targeted CHO cells or vice versa. We reasoned that signaling molecules generated in the targeted component of the hybrid will transfer to the nontargeted cell, inducing damage detectable at the chromosomal level. The results indicate that bystander cytogenetic effects between CHO and human lymphocytes cannot be detected under the experimental conditions used. This may be due either to the lack of communication of such responses between the components of the hybrid or to their abrogation by the experimental manipulations. These observations and the methodology developed should be useful in the further development of protocols for investigating bystander responses and for elucidating the underlying mechanisms.
The yeast DEL assay is an effective method for measuring intrachromosomal recombination events resulting in DNA deletions that when occurring in mammalian cells are often associated with genomic instability and carcinogenesis. Here we used the DEL assay to measure γ-ray-induced DNA deletions throughout different phases of yeast culture growth. Whereas yeast survival differed by only up to twofold throughout the yeast growth phase, proliferating cells in lag and early exponential growth phases were tenfold more sensitive to ionizing radiation-induced DNA deletions than cells in stationary phase. Radiation-induced DNA deletion potential was found to correlate directly with the fraction of cells in S/G2 phase. The ability of the antioxidants l-ascorbic acid and DMSO to protect against radiation-induced DNA deletions was also measured within the different phases of yeast culture growth. Yeast cells in lag and early exponential growth phases were uniquely protected by antioxidant treatment, whereas nondividing cells in stationary phase could not be protected against the induction of DNA deletions. These results are compared with those from mammalian cell studies, and the implications for radiation-induced carcinogenesis and radioprotection are discussed.
Dan Jia, Nathan A. Koonce, Roopa Halakatti, Xin Li, Shmuel Yaccoby, Frances L. Swain, Larry J. Suva, Leah Hennings, Marc S. Berridge, Scott M. Apana, Kevin Mayo, Peter M. Corry, Robert J. Griffin
The effects of ionizing radiation, with or without the anti-angiogenic agent anginex (Ax), on multiple myeloma growth were tested in a SCID-rab mouse model. Mice carrying human multiple myeloma cell-containing pre-implanted bone grafts were treated weekly with various regimens for 8 weeks. Rapid multiple myeloma growth, assessed by bioluminescence intensity (IVIS), human lambda Ig light chain level in serum (ELISA), and the volume of bone grafts (caliper), was observed in untreated mice. Tumor burden in mice receiving combined therapy was reduced to 59% (by caliper), 43% (by ELISA), and 2% (by IVIS) of baseline values after 8 weeks of treatment. Ax or radiation alone slowed but did not stop tumor growth. Four weeks after the withdrawal of the treatments, tumor burden remained minimal in mice given Ax radiation but increased noticeably in the other three groups. Multiple myeloma suppression by Ax radiation was accompanied by a marked decrease in the number and activity of osteoclasts in bone grafts assessed by histology. Bone graft integrity was preserved by Ax radiation but was lost in the other three groups, as assessed by microCT imaging and radiography. These results suggest that radiotherapy, when primed by anti-angiogenic agents, may be a potent therapy for focal multiple myeloma.
Traditionally, the assessment of the effects of radiation on living tissue has been made in terms of absorbed dose. This concept, however, might not be the most appropriate when considering the effects arising from the inhalation of insoluble radioactive particulates in inhomogeneous tissue such as the lung. We have therefore applied microdosimetric methods to this problem and, in particular, investigated in detail how energy depositions are distributed when α particles travel through parenchymal lung tissue. Sections of material derived from rat, beagle and human lung were examined in an image analyzer, and an imaginary plutonium dioxide particulate was placed on the surface of an alveolar sac. The hypothetical α particles emitted from it were followed to the ends of their tracks so that the effects of the material's real structure could be followed in detail. It was found that, taking such detail into account, the α particles traveled much greater distances than might have been thought on the basis of a uniform, structureless lung. It was also found that the specific energy distributions can cover several orders of magnitude and can differ significantly between tissue as a whole, cells and nuclei at low exposures. Attempts are made to correlate these results with recently published data on beagle dogs that had inhaled graded exposure levels of plutonium dioxide aerosols.
Nadejda Y. Mudie, Anthony J. Swerdlow, Boris I. Gusev, Minouk J. Schoemaker, Ludmila M. Pivina, Svetlana Chsherbakova, Almagul Mansarina, Susanne Bauer, Yuri Jakovlev, Kazbek N. Apsalikov
The population of the Semipalatinsk region of Kazakhstan was chronically exposed to radioactive fallout from above-ground nuclear tests conducted during 1949–1956 by the Soviet Union. We investigated the effect of radiation exposure and other factors on risks of twinning overall and of same- and different-sex twinning and hence estimated dizygotic and monozygotic twinning rates in 11,605 deliveries around Semipalatinsk, 141 of which were twin, to 3992 mothers exposed to fallout during 1949–1956. Overall, the same-sex twinning rate was 7.85 [95% confidence interval (CI): 6.24, 9.47] per 1000 and the opposite-sex twinning rate was 4.45 (95% CI: 3.23, 5.67). Twinning rates did not differ significantly between radiation exposure categories, parental age at main radiation exposure, or year of birth. Different-sex, but not same-sex, twinning increased with maternal age (Ptrend = 0.04) but not with other demographic factors and was increased soon after radiation exposure [OR = 4.08 (95% CI: 1.11, 15.07)] for births occurring within 5 years compared with more than 20 years after exposure; this effect was similar in villages with low and high radiation exposure, however, so interpretation is uncertain.
Understanding of the role of radiation as a cause of kidney cancer remains limited. The most common types of kidney cancer are renal cell carcinoma and renal pelvis carcinoma. It has been posited that these entities differ in their degree of radiogenicity. Recent analyses of cancer incidence and mortality in the Life Span Study (LSS) of Japanese atomic bomb survivors have examined associations between ionizing radiation and renal cell carcinoma, but these analyses have not reported results for cancer of the renal pelvis and ureters. This paper reports the results of analyses of kidney cancer incidence during the period 1958–1998 among 105,427 atomic bomb survivors. Poisson regression methods were used to derive estimates of associations between radiation dose (in sievert, Sv) and cancer of the renal parenchyma (n = 167), and cancer of the renal pelvis and ureter (n = 80). Heterogeneity by cancer site was tested by joint modeling of cancer risks. Radiation dose was positively associated with cancers of the renal pelvis and ureter [excess relative rate (ERR)/Sv = 1.65; 90% confidence interval (CI): 0.37, 3.78]. The magnitude of this association was larger than the estimated association between radiation dose and cancer of the renal parenchyma (ERR/Sv = 0.27; 90% CI = −0.19, 0.98). While the association between radiation and cancer of the renal parenchyma was of greater magnitude at ages <55 years (ERR/Sv = 2.82; 90% CI = 0.45, 8.89) than at older attained ages (ERR/Sv = −0.11; 90% CI = nd, 0.53), the association between radiation and cancers of the renal pelvis and ureter varied minimally across these categories of attained age. A test of heterogeneity of type-specific risks provides modest support for the conclusion that risks vary by kidney cancer site (LRT = 2.34, 1 d.f., P = 0.13). Since some studies of radiation-exposed populations examine these sites in aggregate, results were also derived for the combined category of cancer of the renal parenchyma, renal pelvis and ureters. Overall, there was a positive association between radiation and the combined category of cancer of the renal parenchyma, renal pelvis and ureters (ERR/Sv = 0.60, 90% CI: 0.09, 1.30). Updated follow-up of the LSS cohort provides substantial additional information on the association between radiation and cancer of the renal pelvis and ureter, a site not examined in recent reports on analyses of these data. The results are suggestive of differences between the different regions of the kidney in sensitivity to the carcinogenic effects of ionizing radiation.
Temperature-dependent kinetics for the reactions of hydroxyl radicals and hydrated electrons with the anti-cancer drug nedaplatin have been determined using a combination of electron pulse radiolysis and absorption spectroscopy. Under physiological pH and chloride concentrations, the kinetics was well described by the equations
and
corresponding to Arrhenius activation energies of 15.88 ± 1.16 and 14.14 ± 1.41 kJ mol−1 for hydroxyl radical oxidation and hydrated electron reduction, respectively. Through a comparison of spectral and kinetic literature it is believed that the oxidation reaction gives predominantly an intermediate Pt(III) species, whereas reduction gives a Pt(I) moiety. Analogous hydrated electron measurements for the Pt(IV) drug satraplatin showed multiple-component decays at higher temperatures (>20°C), indicating that significant thermal degradation of this chemical occurs. From double-exponential curve fitting, the satraplatin reduction kinetics was found to be well described by the equation
giving an activation energy of 22.78 ± 1.78 kJ mol−1 for this reaction. This measured temperature dependence was consistent with several model Pt(IV) compounds also investigated in this study, with all these data suggesting that the metal ion reduction to give Pt(III) was the dominant reaction occurring.
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