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Reduced oxidative stress response as a risk factor for normal tissue damage after radiotherapy: a study on mandibular osteoradionecrosis
Department of Clinical Science, Intervention and Technology, Division of ENT Diseases, Karolinska Institute, Stockholm.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. (Andrzej Wojcik)
Department of Molecular Medicine and Surgery, Reconstructive Plastic Surgery, Karolinska Institute and Karolinska University Hospital, Stockholm.
Data Mining Group, Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background

The use of radiotherapy (RT) to treat cancer involves exposure of normal tissues. Factors that promote the development of normal tissue damage are poorly understood. An increased individual sensitivity to ionizing radiation is a likely candidate, but general phenotypes for late adverse effects of RT are difficult to define. We have found osteoradionecrosis (ORN) in the mandible as a well-defined model phenotype for an in-depth study of clinical and biological risk factors for developing late adverse effects to RT.

Methods

A cohort of patients with stage 2/3 ORN following RT for head and neck cancer (HCN) was studied and compared to a closely matched control group. Blood samples from the patients were collected and irradiated in vitro and the capacity to handle radiation-induced oxidative stress was investigated by measuring the level of 8-oxo-dG in serum 60 min post exposure. The patients were also genotyped for eight SNPs in genes involved in the oxidative stress response and previously studied in the context of individual radiosensitivity. Results from these endpoints were analyzed in conjunction with clinical data using multivariate analysis and an ORN risk model was constructed.

 

Findings

A significant difference in 8-oxo-dG levels was found between the patient cohorts, indicating a heterogeneous response to oxidative stress induced by the in vitro γ-radiation. The SNP rs1695 in GSTP1 was found to be significantly more frequent in the ORN+ compared to ORN- group. Multivariate analysis of the clinical and biological factors revealed concomitant brachytherapy plus the two biomarkers to be the most significant.

 

Interpretation: The current study indicates that patient-related factors are a major source of individual variation in normal tissue response to RT. Two of the studied genetic biomarkers are strong factors in the described risk model of ORN.

Keyword [en]
Radiotherapy, normal tissue effects, head and neck cancer, osteoradionecrosis, 8-oxo-dG, SNP, oxidative stress, multivariate analysis, modelling
Keyword [sv]
Strålterapi, normalvävnadseffekter, huvud/halscancer, osteoradionekros, 8-oxo-dG, SNP, oxidativ stress, multivariat analys, modellering
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biosciences
Identifiers
URN: urn:nbn:se:su:diva-96442OAI: oai:DiVA.org:su-96442DiVA: diva2:665921
Funder
Swedish Radiation Safety Authority
Available from: 2013-11-21 Created: 2013-11-21 Last updated: 2013-12-11
In thesis
1. In vitro and in vivo aspects of intrinsic radiosensitivity
Open this publication in new window or tab >>In vitro and in vivo aspects of intrinsic radiosensitivity
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on how physical and biological factors influence the outcome of exposures to γ/X-rays. That the dose rate changes during real life exposure scenarios is well-known, but radiobiological data from exposures performed at increasing or decreasing dose rates is lacking. In paper I, it was found that an exposure where the dose rate decreases exponentially induces significantly higher levels of micronuclei in TK6 cells than exposures at an increasing or constant dose rate. Paper II describes the construction and validation of novel exposure equipment used to further study this “decreasing dose rate effect”, which is described in paper III. In paper I we also observed a radioprotective effect when cells were exposed on ice. This “temperature effect” (TE) has been known for decades but it is still not fully understood how hypothermia acts in a radioprotective manner. This was investigated in paper IV, where a multiparametric approach was used to investigate the underlying mechanisms. In paper V the aim was to investigate the role of biomarkers and clinical parameters as possible risk factors for late adverse effects to radiotherapy (RT). This was studied in a rare cohort of head-and-neck cancer patients that developed mandibular osteoradionecrosis (ORN) as a severe late adverse effect of RT. Biomarker measurements and clinical factors were then subjected to multivariate analysis in order to identify ORN risk factors. The results suggest that the patient’s oxidative stress response is an important factor in ORN pathogenesis, and support the current view that patient-related factors constitute the largest source of variation seen in the frequency of late adverse effects to RT.

In summary, this thesis provides new and important insights into the roles of biological and physical factors in determining the consequences of γ/X-ray exposures.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, the Wenner-Gren Institute, 2014. 58 p.
Keyword
Radiation biology, changing dose rates, cytogenetics, hypothermia, X-rays, radiotherapy, osteoradionecrosis, biomarkers, oxidative stress, individual radiosensitivity
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biosciences
Identifiers
urn:nbn:se:su:diva-96727 (URN)978-91-7447-821-1 (ISBN)
Public defence
2014-01-10, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Radiation Safety Authority
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Submitted. Paper 5: Manuscript.

Available from: 2013-12-19 Created: 2013-11-26 Last updated: 2013-12-12Bibliographically approved

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