T lymphocytes to predict radiation-induced late effects in normal tissues

Radiotherapy (RT) is a central component of standard treatment for many cancer patients. RT alone or in multimodal treatment strategies has a documented contribution to enhanced local control and overall survival of cancer patients, and cancer cure. Clinical RT aims at maximizing tumor control, while minimizing the risk for RT-induced adverse late effects. However, acute and late toxicities of IR in normal tissues are still important biological barriers to successful RT: While curative RT may not be tolerable, sub-optimal tolerable RT doses will lead to fatal outcomes by local recurrence or metastatic disease, even when accepting adverse normal tissue effects that decrease the quality of life of irradiated cancer patients. Technical improvements in treatment planning and the increasing use of particle therapy have allowed for a more accurate delivery of IR to the tumor volume and have thereby helped to improve the safety profile of RT for many solid tumors. With these technical and physical strategies reaching their natural limits, current research for improving the therapeutic gain of RT focuses on innovative biological concepts that either selectively limit the adverse effects of RT in normal tissues without protecting the tumor or specifically increase the radiosensitivity of the tumor tissue without enhancing the risk of normal tissue complications. The biology-based optimization of RT requires the identification of biological factors that are linked to differential radiosensitivity of normal or tumor tissues, and are amenable to therapeutic targeting. Extracellular adenosine is an endogenous mediator critical to the maintenance of homeostasis in various tissues. Adenosine is either released from stressed or injured cells or generated from extracellular adenine nucleotides by the concerted action of the ectoenzymes ectoapyrase (CD39) and 5′ ectonucleotidase (NT5E, CD73) that catabolize ATP to adenosine. Recent work revealed a role of the immunoregulatory CD73/adenosine system in radiation-induced fibrotic disease in normal tissues suggesting a potential use as novel therapeutic target for normal tissue protection. The present review summarizes relevant findings on the pathologic roles of CD73 and adenosine in radiation-induced fibrosis in different organs (lung, skin, gut, and kidney) that have been obtained in preclinical models and proposes a refined model of radiation-induced normal tissue toxicity including the disease-promoting effects of radiation-induced activation of CD73/adenosine signaling in the irradiated tissue environment. However, expression and activity of the CD73/adenosine system in the tumor environment has also been linked to increased tumor growth and tumor immune escape, at least in preclinical models. Therefore, we will discuss the use of pharmacologic inhibition of CD73/adenosine-signaling as a promising strategy for improving the therapeutic gain of RT by targeting both, malignant tumor growth and adverse late effects of RT with a focus on fibrotic disease. The consideration of the therapeutic window is particularly important in view of the increasing use of RT in combination with various molecularly targeted agents and immunotherapy to enhance the tumor radiation response, as such combinations may result in increased or novel toxicities, as well as the increasing number of cancer survivors.

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Radiation-Induced Vascular Injury and Its Relation to Late Effects in Normal Tissues

Advances in Radiation Biology ◽

10.1016/b978-0-12-035409-2.50007-2 ◽

1981 ◽

pp. 37-73 ◽

Cited By ~ 104

Author(s):

Marilyn P. Law

Keyword(s):

Vascular Injury ◽

Late Effects ◽

Normal Tissues ◽

Radiation Induced

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Sarcoma in irradiated area (SARI): radiation-induced CD8 T-lymphocytes apoptosis as a potential predisposition factor: results of the SARI trial

European Journal of Cancer ◽

10.1016/s0959-8049(17)30576-2 ◽

2017 ◽

Vol 72 ◽

pp. S153-S154

Author(s):

P. Maingon ◽

C. Mirjolet ◽

G. Truc ◽

P.C. Karine ◽

G. Nöel ◽

...

Keyword(s):

T Lymphocytes ◽

Cd8 T Lymphocytes ◽

Radiation Induced

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Pravastatin Reduces Radiation-Induced Damage to Normal Tissues

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2016.06.2031 ◽

2016 ◽

Vol 96 (2) ◽

pp. E560-E561 ◽

Cited By ~ 1

Author(s):

H. Doi ◽

S. Matsumoto ◽

S. Odawara ◽

T. Shikata ◽

M. Tanooka ◽

...

Keyword(s):

Normal Tissues ◽

Radiation Induced

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Oral Sequelae of Head and Neck Radiotherapy

Critical Reviews in Oral Biology & Medicine ◽

10.1177/154411130301400305 ◽

2003 ◽

Vol 14 (3) ◽

pp. 199-212 ◽

Cited By ~ 479

Author(s):

A. Vissink ◽

J. Jansma ◽

F.K.L. Spijkervet ◽

F.R. Burlage ◽

R.P. Coppes

Keyword(s):

Head And Neck ◽

Neck Region ◽

Normal Tissues ◽

Radiation Caries ◽

Temporomandibular Joints ◽

Clinical Consequences ◽

Radiation Induced ◽

Heavy Burden ◽

Effects Of Radiation ◽

Induced Changes

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

Cancers ◽

10.3390/cancers11050727 ◽

2019 ◽

Vol 11 (5) ◽

pp. 727 ◽

Cited By ~ 3

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.

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