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Low-dose hypersensitivity of initial and persistent DSB foci in epidermis throughout fractionated radiotherapy treatments
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
Department of Oncology, Göteborg University, Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Oncology, Göteborg University, Sahlgrenska University Hospital, Gothenburg, Sweden.
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(English)Manuscript (Other academic)
Keyword [en]
DNA damage response, Low-dose hypersensitivity, Double strand breaks, γH2AX, 53BP1, foci, fractionated radiotherapy, normal tissues, epidermis
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:uu:diva-101076OAI: oai:DiVA.org:uu-101076DiVA: diva2:211768
Available from: 2009-04-17 Created: 2009-04-17 Last updated: 2010-01-14
In thesis
1. DNA Damage Response of Normal Epidermis in the Clinical Setting of Fractionated Radiotherapy: Evidence of a preserved low-dose hypersensitivity response
Open this publication in new window or tab >>DNA Damage Response of Normal Epidermis in the Clinical Setting of Fractionated Radiotherapy: Evidence of a preserved low-dose hypersensitivity response
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Investigations of DNA damage response (DDR) mechanisms in normal tissues have implications for both cancer prevention and treatments. The accumulating knowledge about protein function and molecular markers makes it possible to directly trace and interpret cellular DDR in a tissue context.

Using immunohistochemical techniques and digital image analysis, we have examined several principal DDR events in epidermis from patients undergoing fractionated radiotherapy. Acquiring biopsies from different regions of the skin provides the possibility to determine in vivo dose response at clinically relevant dose levels throughout the treatment.

A crucial event in cellular DDR is the repair of DNA double strand breaks (DSBs). These serious lesions can be directly visualised in cells by detecting foci forming markers such as γH2AX and 53BP1. Our results reveal that DSB-signalling foci can be detected and quantified in paraffin-embedded tissues. More importantly, epidermal DSB foci dose response reveals hypersensitivity, detected as elevated foci levels per dose unit, for doses below ~0.3Gy. The low-dose hypersensitive dose response is observed throughout the treatment course and also in between fractions: at 30 minutes, 3 hours and 24 hours following delivered fractions. The dose response at 24 hours further reveals that foci levels do not return to background levels between fractions. Furthermore, a low-dose hypersensitive dose response is also observed for these persistent foci.

Investigations of end points further downstream in the DDR pathways confirmed that the low-dose hypersensitivity was preserved for: the checkpoint regulating p21 kinase inhibitor; mitosis suppression; apoptosis induction and basal keratinocyte reduction.

Our results reveal preserved low-dose hypersensitivity both early and late in the DDR pathways. A possible link between the dose-response relationships is therefore suggested. The preserved low-dose hypersensitivity is a cause for re-evaluation of the risks associated with low-dose exposure and has implications for cancer treatments, diagnostics and radiation protection.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 457
Series
Keyword
DNA damage response, low-dose hypersensitivity, dose response, normal tissue, epidermis, keratinocyte, fractionated radiotherapy, DNA double strand break, DSB, foci, γH2AX, 53BP1, checkpoint, p21, apoptosis, mitosis
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-101075 (URN)978-91-554-7523-9 (ISBN)
Public defence
2009-06-03, Universitetshuset sal IX, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-05-13 Created: 2009-04-17 Last updated: 2009-05-13Bibliographically approved

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