scholarly journals Targeted Radiotherapy: Microgray Doses and the Bystander Effect

Dose-Response ◽  
2007 ◽  
Vol 5 (3) ◽  
pp. dose-response.0 ◽  
Author(s):  
Robert J. Mairs ◽  
Natasha E. Fullerton ◽  
Michael R. Zalutsky ◽  
Marie Boyd
Keyword(s):  
Indirect Effects ◽  
Bystander Effect ◽  
High Dose ◽  
Protective Effects ◽  
Survival Fraction ◽  
Bystander Effects ◽  
High Let ◽  
Radiation Induced ◽  
Clonogenic Cell ◽  
Dose Dependent

Indirect effects may contribute to the efficacy of radiotherapy by sterilizing malignant cells that are not directly irradiated. However, little is known of the influence of indirect effects in targeted radionuclide treatment. We compared γ-radiation-induced bystander effects with those resulting from exposure to three radiohaloanalogues of meta-iodobenzylguanidine (MIBG): [131I]MIBG (low linear energy transfer (LET) β-emitter), [123I]MIBG (high LET Auger electron emitter), and meta-[211At]astatobenzylguanidine ([211At]MABG) (high LET α-emitter). Cells exposed to media from γ-irradiated cells exhibited a dose-dependent reduction in survival fraction at low dosage and a plateau in cell kill at > 2 Gy. Cells treated with media from [131I]MIBG demonstrated a dose-response relationship with respect to clonogenic cell death and no annihilation of this effect at high radiopharmaceutical dosage. In contrast, cells receiving media from cultures treated with [211At]MABG or [123I]MIBG exhibited dose-dependent toxicity at low dose but elimination of cytotoxicity with increasing radiation dose (i.e. U-shaped survival curves). Therefore radionuclides emitting high LET radiation may elicit toxic or protective effects on neighboring untargeted cells at low and high dose respectively. We conclude that radiopharmaceutical-induced bystander effects may depend on LET and be distinct from those elicited by conventional radiotherapy.

scholarly journals Acute Skin Damage and Late Radiation-Induced Fibrosis and Inflammation in Murine Ears after High-Dose Irradiation

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 727 ◽  
Author(s):  
Annique C. Dombrowsky ◽  
Jannis Schauer ◽  
Matthias Sammer ◽  
Andreas Blutke ◽  
Dietrich W. M. Walsh ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Late Effects ◽  
Transforming Growth Factor ◽  
Scoring Systems ◽  
High Dose ◽  
Skin Damage ◽  
Fractional Dose ◽  
Radiation Induced ◽  
Tissue Alterations ◽  
Dose Dependent

The use of different scoring systems for radiation-induced toxicity limits comparability between studies. We examined dose-dependent tissue alterations following hypofractionated X-ray irradiation and evaluated their use as scoring criteria. Four dose fractions (0, 5, 10, 20, 30 Gy/fraction) were applied daily to ear pinnae. Acute effects (ear thickness, erythema, desquamation) were monitored for 92 days after fraction 1. Late effects (chronic inflammation, fibrosis) and the presence of transforming growth factor beta 1 (TGFβ1)-expressing cells were quantified on day 92. The maximum ear thickness displayed a significant positive correlation with fractional dose. Increased ear thickness and erythema occurred simultaneously, followed by desquamation from day 10 onwards. A significant dose-dependency was observed for the severity of erythema, but not for desquamation. After 4 × 20 and 4 × 30 Gy, inflammation was significantly increased on day 92, whereas fibrosis and the abundance of TGFβ1-expressing cells were only marginally increased after 4 × 30 Gy. Ear thickness significantly correlated with the severity of inflammation and fibrosis on day 92, but not with the number of TGFβ1-expressing cells. Fibrosis correlated significantly with inflammation and fractional dose. In conclusion, the parameter of ear thickness can be used as an objective, numerical and dose-dependent quantification criterion to characterize the severity of acute toxicity and allow for the prediction of late effects.

scholarly journals Protective Effects of p53 Regulatory Agents Against High-LET Radiation-Induced Injury in Mice

2020 ◽  
Vol 8 ◽  
Author(s):  
Akinori Morita ◽  
Bing Wang ◽  
Kaoru Tanaka ◽  
Takanori Katsube ◽  
Masahiro Murakami ◽  
...  
Keyword(s):  
Cell Death ◽  
Radiation Injury ◽  
Ion Irradiation ◽  
Heavy Ion ◽  
Protective Effects ◽  
Iron Ion ◽  
Normal Tissues ◽  
High Let Radiation ◽  
High Let ◽  
Radiation Induced

Radiation damage to normal tissues is one of the most serious concerns in radiation therapy, and the tolerance dose of the normal tissues limits the therapeutic dose to the patients. p53 is well known as a transcription factor closely associated with radiation-induced cell death. We recently demonstrated the protective effects of several p53 regulatory agents against low-LET X- or γ-ray-induced damage. Although it was reported that high-LET heavy ion radiation (>85 keV/μm) could cause p53-independent cell death in some cancer cell lines, whether there is any radioprotective effect of the p53 regulatory agents against the high-LET radiation injury in vivo is still unclear. In the present study, we verified the efficacy of these agents on bone marrow and intestinal damages induced by high-LET heavy-ion irradiation in mice. We used a carbon-beam (14 keV/μm) that was shown to induce a p53-dependent effect and an iron-beam (189 keV/μm) that was shown to induce a p53-independent effect in a previous study. Vanadate significantly improved 60-day survival rate in mice treated with total-body carbon-ion (p < 0.0001) or iron-ion (p < 0.05) irradiation, indicating its effective protection of the hematopoietic system from radiation injury after high-LET irradiation over 85 keV/μm. 5CHQ also significantly increased the survival rate after abdominal carbon-ion (p < 0.02), but not iron-ion irradiation, suggesting the moderate relief of the intestinal damage. These results demonstrated the effectiveness of p53 regulators on acute radiation syndrome induced by high-LET radiation.

scholarly journals Radiation-induced Non-targeted Effect and Carcinogenesis; Implications in Clinical Radiotherapy

2018 ◽  
Vol 8 (4 Dec) ◽  
Author(s):  
R Yahyapour ◽  
A Salajegheh ◽  
A Safari ◽  
P Amini ◽  
A Rezaeyan ◽  
...  
Keyword(s):  
Bystander Effect ◽  
Secondary Cancer ◽  
Interesting Phenomenon ◽  
Bystander Effects ◽  
Appropriate Treatment ◽  
Radiation Induced ◽  
High Doses ◽  
Clinical Radiotherapy ◽  
Improve Cost

Bystander or non-targeted effect is known to be an interesting phenomenon in radiobiology. The genetic consequences of bystander effect on non-irradiated cells have shown that this phenomenon can be considered as one of the most important factors involved in secondary cancer after exposure to ionizing radiation. Every year, millions of people around the world undergo radiotherapy in order to cure different types of cancers. The most crucial aim of radiotherapy is to improve treatment efficiency by reducing early and late effects of exposure to clinical doses of radiation. Secondary cancer induction resulted from exposure to high doses of radiation during treatment can reduce the effectiveness of this modality for cancer treatment. The perception of carcinogenesis risk of bystander effects and factors involved in this phenomenon might help reduce secondary cancer incidence years after radiotherapy. Different modalities such as radiation LET, dose and dose rate, fractionation, types of tissue, gender of patients, etc. may be involved in carcinogenesis risk of bystander effects. Therefore, selecting an appropriate treatment modality may improve cost-effectiveness of radiation therapy as well as the quality of life in survived patients. In this review, we first focus on the carcinogenesis evidence of non-targeted effects in radiotherapy and then review physical and biological factors that may influence the risk of secondary cancer induced by this phenomenon.

scholarly journals Curcumin Ameliorates Benzo[a]pyrene-Induced DNA Damages in Stomach Tissues of Sprague-Dawley Rats

2019 ◽  
Vol 20 (22) ◽  
pp. 5533 ◽  
Author(s):  
Kyeong Seok Kim ◽  
Na Yoon Kim ◽  
Ji Yeon Son ◽  
Jae Hyeon Park ◽  
Su Hyun Lee ◽  
...  
Keyword(s):  
High Dose ◽  
Dependent Manner ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Dna Damages ◽  
Glucose Levels ◽  
Cooking Process ◽  
Sprague Dawley Rats ◽  
Cyp1a1 Expression ◽  
Dose Dependent

Benzo[a]pyrene (BaP) is a well-known carcinogen formed during the cooking process. Although BaP exposure has been implicated as one of the risk factors for lung cancer in animals and humans, there are only limited data on BaP-induced gastrointestinal cancer. Therefore, this study investigated the protective effects of curcumin on BaP-induced DNA damage in rat stomach tissues. BaP (20 mg/kg/day) and curcumin (50, 100, or 200 mg/kg) were administered daily to Sprague-Dawley rats by oral gavage over 30 days. Curcumin was pre-administered before BaP exposure. All rats were euthanized, and liver, kidney, and stomach tissues were removed at 24 h after the last treatment. We observed that aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glucose levels were significantly reduced in rats treated with high dose co-administration of curcumin (200 mg/kg) compared to BaP alone. The expression levels of cytochrome P450 (CYP) 1A1 and CYP1B1 were significantly increased in the liver of rats treated with BaP. However, co-administration of curcumin (200 mg/kg) with BaP markedly reduced CYP1A1 expression in a dose-dependent manner. Furthermore, plasma levels of BaP-diolepoxide (BPDE) and BaP metabolites were significantly reduced by co-administration of curcumin (200 mg/kg). Additionally, co-administration of curcumin (200 mg/kg) with BaP significantly reduced the formation of BPDE-I-DNA and 8-hydroxydeoxy guanosine (8-OHdG) adducts in the liver, kidney, and stomach tissues. The inhibition of these adduct formations were more prominent in the stomach tissues than in the liver. Overall, our observations suggest that curcumin might inhibit BaP-induced gastrointestinal tumorigenesis and shows promise as a chemopreventive agent.

DNA Methyltransferases Modulate the Bystander Effect in Mouse Embryonic Stem Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4154-4154
Author(s):  
Rebecca E. Rugo ◽  
Michael W. Epperly ◽  
Darcy Franicola ◽  
Benjamin Greenberger ◽  
Paavani Komanduri ◽  
...  
Keyword(s):  
Dna Damage ◽  
Bystander Effect ◽  
Embryonic Stem ◽  
Dna Methyltransferases ◽  
Epigenetic Mechanisms ◽  
Bystander Effects ◽  
Strand Breaks ◽  
Radiation Induced ◽  
Bystander Cells ◽  
Gpx Activity

Abstract Cells exposed to radiation or other genotoxic agents can induce DNA damage and other stress responses in non-irradiated cells that are either cultured with the irradiated cells or have been exposed to culture medium from irradiated cells. This is called the bystander effect. In a previous study we found that the descendents of bystander cells exposed to Mitomycin C (MMC) are themselves capable of inducing homologous recombination in un-exposed cells. This suggests that MMC induces persistent and transmissible changes in expression in bystander cells. Bystander effects are likely caused by epigenetic mechanisms rather than “classic” mutations, i.e. changes in DNA sequence. One of the epigenetic mechanisms cells employ for changing expression is DNA methylation in which DNA methyltransferases (DNMTs) add a methyl group to the 5 carbon of cytosine. In this study we asked if ionizing radiation can induce transmissible DNA damage in bystander cells by examining if bystander cells exposed to irradiated cells were themselves able to induce damage in naive cells. Furthermore, we asked if this was dependent on DNMT activity in the irradiated cells. We irradiated wild-type (WT) and DNMT triple knockout (DNMT TKO) mouse embryonic stem cells (ESCs) and after two weeks of continuous culture, we collected conditioned medium (CM). CM was then added to cultures of naive WT ESCs (primary bystanders). Three weeks later, CM was collected from the primary bystanders and added to naïve WT cells (secondary bystanders). We assessed DNA damage by evaluating strand breaks using the alkaline Comet assay and sister chromatid exchange (SCE) analysis. As expected, we found that medium from cells irradiated with 5 Gy induced modest damage in bystander cells. The median Olive tail moment was 2.8 in bystander cells exposed to conditioned medium from irradiated cells compared to 1.0 in control bystander cells (p < 0.0001). Homologous recombination was 0.15 chromatid exchanges per chromosome compared to 0.092 in control bystanders (p < 0.0001). We also observed an increase in strand breaks in secondary bystanders of a similar magnitude to that found in primary bystanders, indicating that radiation-induced bystanders are themselves able to induce damage. In contrast to WT cells, the irradiated DNMT TKO cells did not induce strand breaks in bystander cells, as measured by the Comet assay, but did induce HR. Surprisingly, we also observed that un-irradiated DNMT TKO cells induce DNA damage in bystanders, and furthermore that the magnitude of the effect is similar to that induced by irradiated WT cells. These data suggest that methyltransferases have a complex role in bystander effects. Bystander effects may be mediated by free radicals. To see if the DNMT TKO cells had changes in antioxidant levels, glutathione (GSH) and glutathione peroxidase (GPX) activity were determined. There was no significant change in GSH levels between WT and DNMT TKO cells. However, DNMT TKO cells had significantly higher levels of GPX activity (275.4 + 19.8 mU/mg protein) compared to control cells (122.0 + 16.4 mU/mg, p= 0.0001). Taken together, these results show that radiation-induced bystander cells can themselves induce damage in un-irradiated cells and suggest that cells lacking DNA methylation activity can induce bystander effects.

High-LET Ion Radiolysis of Water: Visualization of the Formation and Evolution of Ion Tracks and Relevance to the Radiation-Induced Bystander Effect

2006 ◽  
Vol 165 (4) ◽  
pp. 485-491 ◽  
Author(s):  
Yusa Muroya ◽  
Ianik Plante ◽  
Edouard I. Azzam ◽  
Jintana Meesungnoen ◽  
Yosuke Katsumura ◽  
...  
Keyword(s):  
Bystander Effect ◽  
Ion Tracks ◽  
High Let ◽  
Radiation Induced ◽  
Formation And Evolution ◽  
Radiation Induced Bystander Effect

scholarly journals Shifting the Immune-Suppressive to Predominant Immune-Stimulatory Radiation Effects by SBRT-PArtial Tumor Irradiation Targeting HYpoxic Segment (SBRT-PATHY)

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 50
Author(s):  
Slavisa Tubin ◽  
Seema Gupta ◽  
Michael Grusch ◽  
Helmuth H. Popper ◽  
Luka Brcic ◽  
...  
Keyword(s):  
Radiation Effects ◽  
Bystander Effect ◽  
Current Evidence ◽  
Optimal Timing ◽  
High Dose ◽  
Tumor Irradiation ◽  
Immune Mediated ◽  
High Single Dose ◽  
Radiation Induced ◽  
Hypoxic Tumor

Radiation-induced immune-mediated abscopal effects (AE) of conventional radiotherapy are very rare. Whole-tumor irradiation leads to lymphopenia due to killing of immune cells in the tumor microenvironment, resulting in immunosuppression and weak abscopal potential. This limitation may be overcome by partial tumor irradiation sparing the peritumoral immune-environment, and consequent shifting of immune-suppressive to immune-stimulatory effect. This would improve the radiation-directed tumor cell killing, adding to it a component of immune-mediated killing. Our preclinical findings showed that the high-single-dose irradiation of hypoxic tumor cells generates a stronger bystander effect (BE) and AE than the normoxic cells, suggesting their higher “immunogenic potential”. This led to the development of a novel Stereotactic Body RadioTherapy (SBRT)-based PArtial Tumor irradiation targeting HYpoxic segment (SBRT-PATHY) for induction of the immune-mediated BE and AE. Encouraging SBRT-PATHY-clinical outcomes, together with immunohistochemical and gene-expression analyses of surgically removed abscopal-tumor sites, suggested that delivery of the high-dose radiation to the partial (hypoxic) tumor volume, with optimal timing based on the homeostatic fluctuation of the immune response and sparing the peritumoral immune-environment, would significantly enhance the immune-mediated anti-tumor effects. This review discusses the current evidence on the safety and efficacy of SBRT-PATHY in the treatment of unresectable hypoxic bulky tumors and its bystander and abscopal immunomodulatory potential.

The radiation-induced bystander effect: evidence and significance

2004 ◽  
Vol 23 (2) ◽  
pp. 61-65 ◽  
Author(s):  
Edouard I Azzam ◽  
John B Little
Keyword(s):  
Ionizing Radiation ◽  
Radiation Exposure ◽  
Low Dose ◽  
Bystander Effect ◽  
Current Knowledge ◽  
Biological Effects ◽  
High Dose ◽  
Adaptive Responses ◽  
Radiation Induced

A multitude of biological effects observed over the past two decades in various in vivo and in vitro cell culture experiments have indicated that low dose/low fluence ionizing radiation has significantly different biological responses than high dose radiation. Exposure of cell populations to very low fluences of particles or incorporated radionuclides results in significant biological effects occurring in both the irradiated and nonirradiated cells in the population. Cells recipient of growth medium from irradiated cultures can also respond to the radiation exposure. This phenomenon, termed the ‘bystander response’, has been postulated to impact both the estimation of risks of exposure to ionizing radiation and radiotherapy. Amplification of radiation-induced cyto-toxic and genotoxic effects by the bystander effect is in contrast to the observations of adaptive responses, which are generally induced following exposure to low dose, low linear energy transfer radiation and which tend to attenuate radiation-induced damage. In this article, the evidence for existence of radiation-induced bystander effects and our current knowledge of the biochemical and molecular events involved in mediating these effects are described. Potential similarities between factors that mediate the radiation-induced bystander and adaptive responses are highlighted.

scholarly journals Protective effects of seabuckthorn pulp and seed oils against radiation-induced acute intestinal injury

2017 ◽  
Vol 58 (1) ◽  
pp. 24-32 ◽  
Author(s):  
Jing Shi ◽  
Lan Wang ◽  
Yan Lu ◽  
Yue Ji ◽  
Yaqing Wang ◽  
...  
Keyword(s):  
Map Kinases ◽  
Seed Oil ◽  
Intestinal Injury ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Inflammatory Factors ◽  
High Dose ◽  
Seed Oils ◽  
Protective Effects ◽  
Radiation Induced ◽  
Post Radiation

Abstract Radiation-induced gastrointestinal syndrome, including nausea, diarrhea and dehydration, contributes to morbidity and mortality after medical or industrial radiation exposure. No safe and effective radiation countermeasure has been approved for clinical therapy. In this study, we aimed to investigate the potential protective effects of seabuckthorn pulp and seed oils against radiation-induced acute intestinal injury. C57/BL6 mice were orally administered seabuckthorn pulp oil, seed oil and control olive oil once per day for 7 days before exposure to total-body X-ray irradiation of 7.5 Gy. Terminal deoxynucleotidyl transferase dUTP nick end labeling, quantitative real-time polymerase chain reaction and western blotting were used for the measurement of apoptotic cells and proteins, inflammation factors and mitogen-activated protein (MAP) kinases. Seabuckthorn oil pretreatment increased the post-radiation survival rate and reduced the damage area of the small intestine villi. Both the pulp and seed oil treatment significantly decreased the apoptotic cell numbers and cleaved caspase 3 expression. Seabuckthorn oil downregulated the mRNA level of inflammatory factors, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and IL-8. Both the pulp and seed oils elevated the level of phosphorylated extracellular-signal-regulated kinase and reduced the levels of phosphorylated c-Jun N-terminal kinase and p38. Palmitoleic acid (PLA) and alpha linolenic acid (ALA) are the predominant components of pulp oil and seed oil, respectively. Pretreatment with PLA and ALA increased the post-radiation survival time. In conclusion, seabuckthorn pulp and seed oils protect against mouse intestinal injury from high-dose radiation by reducing cell apoptosis and inflammation. ALA and PLA are promising natural radiation countermeasure candidates.

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