Radiotherapy for Non–Small Cell Lung Cancer Induces DNA Damage Response in Both Irradiated and Out-of-field Normal Tissues

Siva, Shankar; Lobachevsky, Pavel; MacManus, Michael; Kron, Tomas; Möller, Andreas; Lobb, Richard J.; Ventura, Jessica; Best, Nickala; Smith, Jai; Ball, David; Martin, Olga A.

doi:10.1158/1078-0432.ccr-16-0138

Cited by 64 publications

(62 citation statements)

References 48 publications

(51 reference statements)

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“…The most important aim in radiotherapy is the complete eradication of tumor cells, with minimal or no side effects on normal tissues . Unfortunately, tumor control requires high doses of ionizing radiation, which usually lead to some acute and late side effects, especially for tumors located within or adjacent to some radiosensitive organs such as bone marrow, gastrointestinal system, central nervous system, lung, heart, lens, ovary, and testis …”

Section: Introductionmentioning

confidence: 99%

“…2 Unfortunately, tumor control requires high doses of ionizing radiation, which usually lead to some acute and late side effects, especially for tumors located within or adjacent to some radiosensitive organs such as bone marrow, gastrointestinal system, central nervous system, lung, heart, lens, ovary, and testis. 3,4 In addition to clinical applications, ionizing radiations are used for several aims, such as industrial, agriculture, and nuclear power. Each year, millions of people may be exposed to different doses of ionizing radiation in several ways such as clinical applications and accidental exposure.…”

Section: Introductionmentioning

confidence: 99%

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Selenium as an adjuvant for modification of radiation response

Farhood

Mortezaee

Motevaseli

et al. 2019

J of Cellular Biochemistry

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Ionizing radiation plays a central role in several medical and industrial purposes. In spite of the beneficial effects of ionizing radiation, there are some concerns related to accidental exposure that could pose a threat to the lives of exposed people. This issue is also very critical for triage of injured people in a possible terror event or nuclear disaster. The most common side effects of ionizing radiation are experienced in cancer patients who had undergone radiotherapy. For complete eradication of tumors, there is a need for high doses of ionizing radiation. However, these high doses lead to severe toxicities in adjacent organs. Management of normal tissue toxicity may be achieved via modulation of radiation responses in both normal and malignant cells. It has been suggested that treatment of patients with some adjuvant agents may be useful for amelioration of radiation toxicity or sensitization of tumor cells. However, there are always some concerns for possible severe toxicities and protection of tumor cells, which in turn affect radiotherapy outcomes. Selenium is a trace element in the body that has shown potent antioxidant and radioprotective effects for many years. Selenium can potently stimulate antioxidant defense of cells, especially via upregulation of glutathione (GSH) level and glutathione peroxidase activity. Some studies in recent years have shown that selenium is able to mitigate radiation toxicity when administered after exposure. These studies suggest that selenium may be a useful radiomitigator for an accidental radiation event. Molecular and cellular studies have revealed that selenium protects different normal cells against radiation, while it may sensitize tumor cells. These differential effects of selenium have also been revealed in some clinical studies. In the present study, we aimed to review the radiomitigative and radioprotective effects of selenium on normal cells/tissues, as well as its radiosensitive effect on cancer cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Selenium as an adjuvant for modification of radiation response

Farhood

Mortezaee

Motevaseli

et al. 2019

J of Cellular Biochemistry

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“…The methodologies for DNA extraction and OCDL analysis, immunohistochemistry, and plasma cytokine measurements are described elsewhere (15,16,19,20,26) and presented in Supplementary Materials and Methods.…”

Section: Harvesting Of Mouse Tissuesmentioning

confidence: 99%

“…Cell-cell communication in vivo is believed to involve components of the immune system that work as an ensemble to transmit the systemic effects of radiation (1). Our group recently reported induction of persistent DSBs in normal tissues outside the irradiated volume in patients receiving radiotherapy for lung cancer; this effect has been associated with changes in plasma cytokines (19,20). Extensive bioinformatics studies have identified unique interactions between proteins participating in the RIBE, DNA damage response (DDR) pathway, and the immune system, unraveling the mechanistic puzzle of radiation-induced systemic effects (21).…”

Section: Introductionmentioning

confidence: 99%

Localized Synchrotron Irradiation of Mouse Skin Induces Persistent Systemic Genotoxic and Immune Responses

et al. 2017

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The importance of nontargeted (systemic) effects of ionizing radiation is attracting increasing attention. Exploiting synchrotron radiation generated by the Imaging and Medical Beamline at the Australian Synchrotron, we studied radiation-induced nontargeted effects in C57BL/6 mice. Mice were locally irradiated with a synchrotron X-ray broad beam and a multiplanar microbeam radiotherapy beam. To assess the influence of the beam configurations and variations in peak dose and irradiated area in the response of normal tissues outside the irradiated field at 1 and 4 days after irradiation, we monitored oxidatively induced clustered DNA lesions (OCDL), DNA double-strand breaks (DSB), apoptosis, and the local and systemic immune responses. All radiation settings induced pronounced persistent systemic effects in mice, which resulted from even short exposures of a small irradiated area. OCDLs were elevated in a wide variety of unirradiated normal tissues. In out-of-field duodenum, there was a trend for elevated apoptotic cell death under most irradiation conditions; however, DSBs were elevated only after exposure to lower doses. These genotoxic events were accompanied by changes in plasma concentrations of macrophage-derived cytokine, eotaxin, IL10, TIMP1, VEGF, TGFβ1, and TGFβ2, along with changes in tissues in frequencies of macrophages, neutrophils, and T lymphocytes. Overall, our findings have implications for the planning of therapeutic and diagnostic radiation treatments to reduce the risk of radiation-related adverse systemic effects. .

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“…Chemotherapy and radiotherapy can lead to tumor cells death, followed by the release of immunogenic antigen, resulting in enhancing antigen presentation and adaptive immune responses (7). Based on this hypothesis along with anecdotal observation, so-called "abscopal effect", the combination of immune checkpoint inhibitors and radiotherapy has become increasing interest to improve the efficacy of radiotherapy.…”

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confidence: 99%

Consolidation of immunotherapy becomes new standard of care in unresectable stage III non-small cell lung cancer

Ahn¹

2018

J. Thorac. Dis.

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Ahn. Durvalumab in locally advanced NSCLC arm and the placebo arm (3.4% vs. 2.6%). Moreover, the discontinuation rate due to pneumonitis between two arms is quite comparable (6.3% for the durvalumab arm vs. 4.3% for the placebo arm). In general, a slight increase of toxicity was observed in the durvalumab arm, however, severe toxicity was similar between groups.Until now, PACIFIC is one of the largest studies addressing the role of immune checkpoint inhibitors as consolidation therapy after chemoradiotherapy in unresectable NSCLC and demonstrated clinically meaningful benefit. Overall survival data are still immature, however, the magnitude of benefit in terms of PFS might be enough to support the consolidation therapy with durvalumab as a new standard care for unresectable NSCLC patients who do not progress on chemoradiotherapy.Several issues still remained to be elucidated. In PACIFIC study, patients received 12 months of durvalumab after chemoradiotherapy, thus the duration of therapy should be further evaluated. Durvalumab was given after chemoradiotherapy, where all the adverse events related to chemoradiation have been resolved. However, it is unknown whether concurrent administration of immune checkpoint inhibitors with chemoradiation compared to sequential approach can improve more clinical outcome or increase toxicity. Given the encouraging results with PACIFIC study, incorporation of immune checkpoint inhibitors can be applied to the earlier stage of NSCLC such as resectable N2 disease or stage I-II disease. To address this issue, several studies are currently undergoing as neoadjuvant setting or adjuvant setting. Considering significant prolongation of PFS with durvalumab after concurrent chemoradiotherapy (CTRT) in locally advanced NSCLC from PACIFIC study, the role of surgery in locally advanced NSCLC, especially N2 disease might be challenging. In line with this issue, the association between the burden of lymph node metastasis and efficacy of immune check point inhibitor should be further evaluated. Finally, further research to identify predictive biomarkers for the selection of patients who will most likely to benefit from immune checkpoint inhibitors should be warranted. AcknowledgementsNone. Footnote Conflicts of Interest:The author has no conflicts of interest to declare.

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Radiotherapy for Non–Small Cell Lung Cancer Induces DNA Damage Response in Both Irradiated and Out-of-field Normal Tissues

Cited by 64 publications

References 48 publications

Selenium as an adjuvant for modification of radiation response

Selenium as an adjuvant for modification of radiation response

Localized Synchrotron Irradiation of Mouse Skin Induces Persistent Systemic Genotoxic and Immune Responses

Consolidation of immunotherapy becomes new standard of care in unresectable stage III non-small cell lung cancer

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