Pravastatin Reduces Radiation-Induced Damage to Normal Tissues

In addition to anti-tumor effects, ionizing radiation causes damage in normal tissues located in the radiation portals. Oral complications of radiotherapy in the head and neck region are the result of the deleterious effects of radiation on, e.g., salivary glands, oral mucosa, bone, dentition, masticatory musculature, and temporomandibular joints. The clinical consequences of radiotherapy include mucositis, hyposalivation, taste loss, osteoradionecrosis, radiation caries, and trismus. Mucositis and taste loss are reversible consequences that usually subside early post-irradiation, while hyposalivation is normally irreversible. Furthermore, the risk of developing radiation caries and osteoradionecrosis is a life-long threat. All these consequences form a heavy burden for the patients and have a tremendous impact on their quality of life during and after radiotherapy. In this review, the radiation-induced changes in healthy oral tissues and the resulting clinical consequences are discussed.

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Mechanism, Prevention, and Treatment of Radiation-Induced Salivary Gland Injury Related to Oxidative Stress

Antioxidants ◽

10.3390/antiox10111666 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1666

Author(s):

Zijing Liu ◽

Lihua Dong ◽

Zhuangzhuang Zheng ◽

Shiyu Liu ◽

Shouliang Gong ◽

...

Keyword(s):

Oxidative Stress ◽

Head And Neck ◽

Clinical Symptoms ◽

Clinical Manifestations ◽

Serious Adverse Event ◽

Oral Infections ◽

Normal Tissues ◽

Radiation Induced ◽

Swallowing Muscles

Radiation therapy is a common treatment for head and neck cancers. However, because of the presence of nerve structures (brain stem, spinal cord, and brachial plexus), salivary glands (SGs), mucous membranes, and swallowing muscles in the head and neck regions, radiotherapy inevitably causes damage to these normal tissues. Among them, SG injury is a serious adverse event, and its clinical manifestations include changes in taste, difficulty chewing and swallowing, oral infections, and dental caries. These clinical symptoms seriously reduce a patient’s quality of life. Therefore, it is important to clarify the mechanism of SG injury caused by radiotherapy. Although the mechanism of radiation-induced SG injury has not yet been determined, recent studies have shown that the mechanisms of calcium signaling, microvascular injury, cellular senescence, and apoptosis are closely related to oxidative stress. In this article, we review the mechanism by which radiotherapy causes oxidative stress and damages the SGs. In addition, we discuss effective methods to prevent and treat radiation-induced SG damage.

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Potential markers and metabolic processes involved in the mechanism of radiation-induced heart injury

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2017-0121 ◽

2017 ◽

Vol 95 (10) ◽

pp. 1190-1203 ◽

Cited By ~ 19

Author(s):

Jan Slezak ◽

Branislav Kura ◽

Pavel Babal ◽

Miroslav Barancik ◽

Miroslav Ferko ◽

...

Keyword(s):

Biological Molecules ◽

Cardiac Damage ◽

Normal Tissues ◽

Cell Dysfunction ◽

Complex Process ◽

Radiation Induced ◽

Acute Increase ◽

Heart Blood ◽

Chest Irradiation ◽

Molecular Signals

Irradiation of normal tissues leads to acute increase in reactive oxygen/nitrogen species that serve as intra- and inter-cellular signaling to alter cell and tissue function. In the case of chest irradiation, it can affect the heart, blood vessels, and lungs, with consequent tissue remodelation and adverse side effects and symptoms. This complex process is orchestrated by a large number of interacting molecular signals, including cytokines, chemokines, and growth factors. Inflammation, endothelial cell dysfunction, thrombogenesis, organ dysfunction, and ultimate failing of the heart occur as a pathological entity — “radiation-induced heart disease” (RIHD) that is major source of morbidity and mortality. The purpose of this review is to bring insights into the basic mechanisms of RIHD that may lead to the identification of targets for intervention in the radiotherapy side effect. Studies of authors also provide knowledge about how to select targeted drugs or biological molecules to modify the progression of radiation damage in the heart. New prospective studies are needed to validate that assessed factors and changes are useful as early markers of cardiac damage.

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Pharmacological Interventions for the Prevention and Treatment of Kidney Injury Induced by Radiotherapy: Molecular Mechanisms and Clinical Perspectives

Current Molecular Pharmacology ◽

10.2174/1874467214666210824123212 ◽

2021 ◽

Vol 14 ◽

Author(s):

Adeleh Sahebnasagh ◽

Fatemeh Saghafi ◽

Saeed Azimi ◽

Ebrahim Salehifar ◽

Seyed Jalal Hosseinimehr

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Cell Injury ◽

Kidney Injury ◽

Pharmacological Interventions ◽

Normal Tissues ◽

Radiation Induced ◽

Effects Of Radiation ◽

Preclinical And Clinical Studies ◽

Radiation Beams

: More than half of cancer patients need radiotherapy during the course of their treatment. Despite the beneficial aspects, the destructive effects of radiation beams on normal tissues lead to oxidative stress, inflammation, and cell injury. Kidneys are affected during radiotherapy of abdominal malignancies. Radiation nephropathy eventually leads to the release of factors triggering systemic inflammation. Currently, there is no proven prophylactic or therapeutic intervention for the management of radiation-induced nephropathy. This article reviews the biomarkers involved in the pathophysiology of radiation-induced nephropathy and its underlying molecular mechanisms. The efficacy of compounds with potential radio-protective properties on amelioration of inﬂammation and oxidative stress is also discussed. By outlining the approaches for preventing and treating this critical side effect, we evaluate the potential treatment of radiation-induced nephropathy. Available preclinical and clinical studies on these compounds are also scrutinized.

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

Frontiers in Public Health ◽

10.3389/fpubh.2020.601124 ◽

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.

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CLO19-037: Reducing the Duration, Incidence and Severity of Mucosal Injury Due to Cancer Radiation therapy (RT); Positive Randomized Phase 2b Trial Results With GC4419 (Avasopasem Manganese), a Small Molecule Superoxide (SO) Dismutase (SOD) Mimetic

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2018.7136 ◽

2019 ◽

Vol 17 (3.5) ◽

pp. CLO19-037

Author(s):

Jon T. Holmlund ◽

Carryn M. Anderson ◽

Stephen T. Sonis ◽

Robert Beardsley ◽

Dennis Riley ◽

...

Keyword(s):

Locally Advanced ◽

Mucosal Injury ◽

Cheek Pouch ◽

Hamster Cheek Pouch ◽

Open Label ◽

Who Grade ◽

Normal Tissues ◽

Intensity Modulated ◽

Hpv Status ◽

Radiation Induced

Introduction: RT-induced SO contributes to initiation of mucosal injury; eg, oral mucositis (OM) and esophagitis. GC4419 specifically mimics SOD’s dismutation of SO to hydrogen peroxide (H2O2), interdicting OM initiation. GC4419 reduced RT-severe OM (SOM) in a hamster cheek pouch model, and protected mucosa and other normal tissues from radiation-induced injury in other animal models. In a published phase 1b/2a open-label trial (Anderson et al, IJROBP, 1 Feb 2018), GC4419 attenuated SOM in patients (Pts) receiving intensity-modulated RT (IMRT) plus concurrent cisplatin (CDDP) for locally advanced head & neck cancer (HNC). Objectives: Determine whether GC4419 reduces duration, incidence, & severity of SOM. Methods: Pts with locally advanced oral cavity or oropharyngeal cancer; definitive or postoperative intensity-modulated (IM)RT (approximately 70 Gy [>50 Gy to > 2 oral sites]) plus CDDP (weekly or q3wk) were randomized (stratification: tumor HPV status, CDDP schedule) to 30 or 90 mg of GC4419, or placebo (PBO), 60-minute IV infusion, M–F, ending <60 minutes before IMRT delivered in 35 fractions over 7 weeks. WHO grade OM was assessed by trained evaluators biw during IMRT & qwk for up to 8 wks after IMRT. Primary endpoint: duration of SOM. Efficacy was tested for each active dose vs PBO (ITT population) by a sequential, conditional approach (2-sided alpha, 0.05). Results: 223 pts (44 sites): 90 mg (n=76), 30 mg (n=73), or PBO (n=74). Baseline patient and tumor characteristics and treatment delivery were balanced. Efficacy: At 90 mg GC4419 vs PBO, duration of SOM was significantly reduced (median, 1.5 vs 19 d; P=.024). SOM incidence (43% vs 65%; P=.009), and grade 4 incidence (16% vs 30%; P=.045) also improved. There were intermediate improvements with 30 mg. Safety was comparable across arms; no significant GC4419-specific toxicity; other known toxicities of IMRT/CDDP were not increased. Conclusions: GC4419 demonstrated a significant, clinically meaningful reduction of SOM duration, and dose-dependent improvements in other SOM parameters, with acceptable safety. A confirmatory phase 3 trial (NCT03689712) is in progress. Clinical trials to reduce RT-related esophagitis are also planned.

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Silencing Egr1 Attenuates Radiation-Induced Apoptosis in Normal Tissues while Killing Cancer Cells and Delaying Tumor Growth

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-14-1051 ◽

2015 ◽

Vol 14 (10) ◽

pp. 2343-2352 ◽

Cited By ~ 21

Author(s):

Diana Yi Zhao ◽

Keith M. Jacobs ◽

Dennis E. Hallahan ◽

Dinesh Thotala

Keyword(s):

Tumor Growth ◽

Cancer Cells ◽

Normal Tissues ◽

Radiation Induced ◽

Induced Apoptosis

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The Neuroprotective and Anti-Inflammatory Effects of Annona Muricata (Graviola) on Radiation-Induced Rat Sciatic Nerve Injury.

10.21203/rs.3.rs-804331/v1 ◽

2021 ◽

Author(s):

Emrah Keskin ◽

Özlem Elmas ◽

Havva Hande Keser Şahin ◽

Çağhan Tönge ◽

Ahmet Günaydın

Keyword(s):

Sciatic Nerve ◽

Ionizing Radiation ◽

Nerve Injury ◽

Sciatic Nerve Injury ◽

Albino Rats ◽

Annona Muricata ◽

Leaf Extracts ◽

Normal Tissues ◽

Radiation Induced ◽

Wistar Albino Rats

Abstract Background: In radiotherapy (RT) exposure area, normal tissues are also affected that may cause serious complications in the patients. This study aimed to evaluate Annona muricata’s radioprotective effects on sciatic nerve injury due to ionizing radiation (IR). Methods and Results: 32 adult female Wistar albino rats separated into 4 equal groups; Control (C), Annona muricata leaf extracts (AME), radiation (RAD), radiation and Annona muricata leaf extracts (AME+RAD). In groups AME and AME+RAD, Annona muricata leaf extracts were administered at a dose of 300 mg/kg for the first day and 50 mg/kg everyday for following one week intraperitoneally. In RAD and AME+RAD, rats were exposed to a single dose of 20 Gray IR to their right legs. All the subjects were sacrified at the end of the first month. Oxidative stress biochemical parameters (SOD, CAT and GPx) from blood samples were analyzed. Right sciatic nerves extracted and histomorphology evaluated. Statistically significant vasculature, degenerative and necrotic changes were observed in RAD, compared to C and AME (p<0,01). Swelling in myelin sheath was predominantly seen in RAD. Alterations in the level of CAT (p<0,01), SOD (p<0,01) and GPx (p<0,05) in AME+RAD group compared to RAD group were found to be statistically significant.Conclusion: Our study unveiled that AM could have a potential of biochemically and histomorphology healing on sciatic nerve injury due to ionizing radiation.

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Predictors of radiation-induced complications in radiation oncology based on cell survival tests after ex vivo exposure: literature review

Український радіологічний та онкологічний журнал ◽

10.46879/ukroj.1.2021.89-118 ◽

2021 ◽

Vol 29 (1) ◽

pp. 89-118

Author(s):

V. A. Vinnikov ◽

T. V. Rubleva

Keyword(s):

Cell Death ◽

Cell Survival ◽

Radiation Oncology ◽

Radiation Effects ◽

Ex Vivo ◽

Radiation Toxicity ◽

Normal Tissues ◽

Intrinsic Radiosensitivity ◽

Radiation Induced ◽

Clonogenic Cell

Background. Among cancer patients receiving radiotherapy about 5–15 % may have adverse reactions in normal tissues and organs that limit their treatment in a full, originally scheduled regimen. The development of biomarkers and assays for radiation oncology allowing the prediction of patients’ normal tissue toxicity requires a lot of resourses, threfore its current status amd potential directions for future research have to be periodically analyzed and re-evaluated. Purpose – this review summarizes the methodological approaches and developments in the area of functional laboratory assays based on ex vivo cell survival for the prediction of the individual clinical radiosensitivity. Materials and methods. Data for the analysis and systematization were obtained from the full-text articles published in peer review international scientific journals (in English) in 1990–2020, which were selected by the extensive search in PubMed information database and cross references on the topic “Functional cellular tests for intrinsic radiosensitivity to predict adverse radiation effects and radiotherapy complications”. Results. In theory, it might be expected that clonogenic cell survival after ex vivo irradiation can surve as the best individual predictor of radiation toxicity, as it is an integral indicator of cell damage and decline of their regenerative potential. Tendentially, fibroblasts, as a test system for such studies, did not show significant advantages over lymphocytes either in detecting inter-individual variations in the intrinsic cellular radiosensitivity or in predicting clinical radiation toxicity, even for that in skin. It was found that clonogenic cell survival assay, being very time consuming and technically demanding, also suffers from the lack of sensitivity and specificity, essential uncertainty and low reproducibility of the results, and thus is not suitable for the sceening for the abnormal intrinsic radiosensitivity. However, this type of assays is applicable for the radiobiological expertise post factum in individual cases with unexpected, extreme radiation lesions. Radiation-induced lymphocyte apoptosis assay seems to be more promising however still requires further fundamental research for better understanding of its background and more validation studies in order to assess the optimum patient groups, radiotherapy regimens and adverse effects for its confident use in clinical practice. Changes in the regulation of cell cycle check-points (radiationinduced delay) ex vivo can have either positive or inverted association, or no correlation with clinical radiation responses in tissues, thus so far cannot be included in the toolbox of applied radiobiological tests. Conclusions. To date, in the practice of clinical radiobiology, there are no fully validated and standardized functional tests based on the cell survival after ex vivo irradiation, which would allow a sufficiently accurate prediction of adverse radiation effects in normal tissues of radiotherapy patients. In general, ex vivo tests based on the evaluation of only one form of cell death in one cell type are not fully reliable as a “stand alone” assay, because different pathways of cell death probably play different roles and show different dose response within the overal reaction of the irradiated tissue or critical organ. Such tests should become a part of the multiparametric predictive platforms.

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