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In vitro and in vivo aspects of intrinsic radiosensitivity
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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 [en]
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: urn:nbn:se:su:diva-96727ISBN: 978-91-7447-821-1 (print)OAI: oai:DiVA.org:su-96727DiVA: diva2:667337
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
List of papers
1. Cytogenetic damage in cells exposed to ionizing radiation under conditions of a changing dose rate
Open this publication in new window or tab >>Cytogenetic damage in cells exposed to ionizing radiation under conditions of a changing dose rate
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2010 (English)In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 173, no 3, 283-9 p.Article in journal (Refereed) Published
Abstract [en]

The current international paradigm on the biological effects of radiation is based mainly on the effects of dose with some consideration for the dose rate. No allowance has been made for the potential influence of a changing dose rate (second derivative of dose), and the biological effects of exposing cells to changing dose rates have never been analyzed. This paper provides evidence that radiation effects in cells may depend on temporal changes in the dose rate. In these experiments, cells were moved toward or away from an X-ray source. The speed of movement, the time of irradiation, and the temperature during exposure were controlled. Here we report the results of the first experiments with TK6 cells that were exposed at a constant dose rate, at an increasing dose rate, or at a decreasing dose rate. The average dose rate and the total dose were same for all samples. Micronuclei were scored as the end point. The results show that the level of cytogenetic damage was higher in cells exposed to a decreasing dose rate compared to both an increasing and a constant dose rate. This finding may suggest that the second derivative of dose may influence radiation risk estimates, and the results should trigger further studies on this issue.

National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-38299 (URN)10.1667/RR2012.1 (DOI)000275688000003 ()20199213 (PubMedID)
Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2017-12-12Bibliographically approved
2. A NEW DEVICE TO EXPOSE CELLS TO CHANGING DOSE RATES OF IONISING RADIATION
Open this publication in new window or tab >>A NEW DEVICE TO EXPOSE CELLS TO CHANGING DOSE RATES OF IONISING RADIATION
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2012 (English)In: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 148, no 3, 366-371 p.Article in journal (Refereed) Published
Abstract [en]

In many exposure scenarios to ionising radiation, the dose rate is not constant. Despite this, most in vitro studies aimed at investigating the effects of ionising radiation are carried out exposing samples at constant dose rates. Consequently, very little data exist on the biological effects of exposures to changing dose rates. This may be due to technical limitations of standard irradiation facilities, but also to the fact that the importance of research in this area has not been appreciated. We have recently shown that cells exposed to a decreasing dose rate suffer higher levels of cytogenetic damage than do cells exposed to an increasing or a constant dose rate. To further study the effects of changing dose rates, a new device was constructed that permits the exposure of cell samples in tubes, flasks or Petri dishes to changing dose rates of X-rays. This report presents the technical data, performance and dosimetry of this novel device.

National Category
Genetics
Identifiers
urn:nbn:se:su:diva-76336 (URN)10.1093/rpd/ncr092 (DOI)000299953600013 ()
Note
6Available from: 2012-05-14 Created: 2012-05-10 Last updated: 2017-12-07Bibliographically approved
3. Micronucleus frequencies and clonogenic cell survival in TK6 cells exposed to changing dose rates under controlled temperature conditions
Open this publication in new window or tab >>Micronucleus frequencies and clonogenic cell survival in TK6 cells exposed to changing dose rates under controlled temperature conditions
2014 (English)In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 90, no 3, 241-247 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: In most exposure scenarios the dose rate of exposure is not constant. Despite this, very little information exists on the possible biological effects of exposing cells to radiation under the conditions of a changing dose rate. The current study highlights interesting effects following exposure under these conditions.

Materials and methods: We constructed a new exposure facility that allows exposing cells inside an incubator and used it to irradiate human lymphoblastoid TK6 cells both after a moderate (0.48 Gy) and a high (1.1 Gy) dose, where the change in dose rate was, respectively, ≈ 17-fold change (2.2 - 37 mGy/min) and ≈ 39-fold (2.7 - 106 mGy/min). Clonogenic survival and micronuclei (MN) induction were the chosen endpoints.

Results: The obtained results confirm the outcome of our first study that TK6 cells exposed to a decreasing dose rate express more MN than cells exposed to an increasing or constant dose rate. The effect was not seen after the moderate dose of 0.48 Gy or detectable at the level of clonogenic cell survival.

Conclusions: We speculate that the high level of MN is probably related to a delayed elimination of damaged cells by interphase death, as opposed to mechanisms relating to DNA damage and repair.

Keyword
Changing dose rates, TK6, Micronuclei, Clonogenic survival, X-rays, Skiftande dosrat, röntgenstrålning, mikrokärnor, TK6
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-96433 (URN)10.3109/09553002.2014.873831 (DOI)000332797500005 ()
Funder
Swedish Radiation Safety Authority
Available from: 2013-11-21 Created: 2013-11-21 Last updated: 2017-12-06Bibliographically approved
4.
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5. Reduced oxidative stress response as a risk factor for normal tissue damage after radiotherapy: a study on mandibular osteoradionecrosis
Open this publication in new window or tab >>Reduced oxidative stress response as a risk factor for normal tissue damage after radiotherapy: a study on mandibular osteoradionecrosis
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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
Radiotherapy, normal tissue effects, head and neck cancer, osteoradionecrosis, 8-oxo-dG, SNP, oxidative stress, multivariate analysis, modelling, 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:nbn:se:su:diva-96442 (URN)
Funder
Swedish Radiation Safety Authority
Available from: 2013-11-21 Created: 2013-11-21 Last updated: 2013-12-11

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