scholarly journals The CD73/Ado System—A New Player in RT Induced Adverse Late Effects

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1578 ◽  
Author(s):  
Simone de Leve ◽  
Florian Wirsdörfer ◽  
Verena Jendrossek

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.

2015 ◽  
Vol 14 (10) ◽  
pp. 2343-2352 ◽  
Author(s):  
Diana Yi Zhao ◽  
Keith M. Jacobs ◽  
Dennis E. Hallahan ◽  
Dinesh Thotala

2020 ◽  
Author(s):  
Yesuf Adem Siraj ◽  
Melese Gebeyehu Byadgelegn ◽  
Mensur Osman Yassin ◽  
Yohannes Zenebe Chekol

Abstract Background: Colorectal cancer is one of the top ten cancer death in the world. Despite an increased prevalence of colorectal cancer has been documented from developing countries, reports on gut microbiota among colorectal cancer patients are none especially in Ethiopia. Therefore, the current study evaluated cultivable aerobic bacterial distributions among malignant tissue of colorectal cancer and its adjacent normal biopsies. Methods: Fifteen CRC patients who were undergoing colorectal cancer resection surgery during April 2017 to February 2018 at Felege Hiwot Referral and University of Gondar Teaching Hospitals were included. Biopsy specimens were taken from malignant and its adjacent normal tissues. Bacterial cultivation, quantification and characterization of saline washed biopsies were performed under aerobic and candle jar conditions. Differences in bacterial microbiota compositions between malignant and normal tissue biopsies were evaluated and analyzed using Microsoft excel 2010 and GraphPad Prism5 statistical software. Results: Fifteen CRC patients were participated with a mean age of 53.8 ± 10.8 years old and majorities (73.3%) of patients were in between the age groups of 40 and 60 years old. The mean ± SD bacterial microbiota of malignant biopsies (3.2x10 5 ± 1.6x10 5 CFU/ml) was significantly fewer than that of adjacent normal tissue biopsies (4.0x10 5 ± 2.2x10 5 CFU/ml). This dysbacteriosis is positively correlated with the occurrence of CRC (p=0.019). Proteobacteria (55.6%), Firmicutes (33.3%) and Fusobacteria (11.1%) were the most frequently isolated phyla from non-malignant biopsies while only Proteobacteria (58.8%) and Firmicutes (41.2%) were from malignant ones. Family level differences were observed among phyla (Firmicutes and Proteobacteria) isolated from the study participants. For instance, the relative abundance of family Bacillaceae from malignant (26%) was lower than the normal biopsies (39%). On other hand, family Enterobacteriaceae was twice more abundant in malignant tissues (45%) than in its matched normal tissues (23%). Furthermore, the family Enterococcaceae (14%) of family Firmicutes was solely isolated from malignant tissue biopsies. Conclusion: The overall microbial composition of normal and malignant tissues was considerably different among the study participants. Further culture independent analysis of mucosal microbiota will provide detail pictures of microbial composition differences and pathogenesis of CRC in Ethiopian settings.


2013 ◽  
Vol 127 (3) ◽  
pp. 285-294 ◽  
Author(s):  
L A Joseph ◽  
J A Routledge ◽  
M P Burns ◽  
R Swindell ◽  
A J Sykes ◽  
...  

AbstractBackground:Few studies have prospectively investigated psychological morbidity in UK head and neck cancer patients. This study aimed to explore changes in psychological symptoms over time, and associations with patients' tumour and treatment characteristics, including toxicity.Methods:Two hundred and twenty patients were recruited to complete the Hospital Anxiety and Depression Scale and the Late Effects on Normal Tissue (Subjective, Objective, Management and Analytic) (‘LENT-SOMA’) questionnaires, both pre- and post-treatment.Results:Anxiety was highest pre-treatment (38 per cent) and depressive symptoms peaked at the end of treatment (44 per cent). Anxiety significantly decreased and depression significantly increased, comparing pre- versus post-treatment responses (p < 0.001). Hospital Anxiety and Depression Scale scores were significantly correlated with toxicity, age and chemotherapy (p < 0.01 for all).Conclusion:This is the first study to analyse the relationship between Hospital Anxiety and Depression Scale scores and toxicity scores in head and neck cancer patients. It lends support for the use of the Hospital Anxiety and Depression Scale and the Late Effects on Normal Tissue (Subjective, Objective, Management and Analytic) questionnaire in routine clinical practice; furthermore, continued surveillance is required at multiple measurement points.


2016 ◽  
Vol 17 (2) ◽  
pp. 119-127 ◽  
Author(s):  
Muriel Brengues ◽  
Ariane Lapierre ◽  
Céline Bourgier ◽  
André Pèlegrin ◽  
Mahmut Özsahin ◽  
...  

Author(s):  
Christopher M Iannuzzi ◽  
David P Atencio ◽  
Sheryl Green ◽  
Richard G Stock ◽  
Barry S Rosenstein

2021 ◽  
Vol 22 (19) ◽  
pp. 10880
Author(s):  
Zain Mehdi ◽  
Michael S. Petronek ◽  
Jeffrey M. Stolwijk ◽  
Kranti A. Mapuskar ◽  
Amanda L. Kalen ◽  
...  

Interest in the use of pharmacological ascorbate as a treatment for cancer has increased considerably since it was introduced by Cameron and Pauling in the 1970s. Recently, pharmacological ascorbate has been used in preclinical and early-phase clinical trials as a selective radiation sensitizer in cancer. The results of these studies are promising. This review summarizes data on pharmacological ascorbate (1) as a safe and efficacious adjuvant to cancer therapy; (2) as a selective radiosensitizer of cancer via a mechanism involving hydrogen peroxide; and (3) as a radioprotector in normal tissues. Additionally, we present new data demonstrating the ability of pharmacological ascorbate to enhance radiation-induced DNA damage in glioblastoma cells, facilitating cancer cell death. We propose that pharmacological ascorbate may be a general radiosensitizer in cancer therapy and simultaneously a radioprotector of normal tissue.


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