Abstract
During the delivery of advanced radiotherapy treatment techniques modulated beams are utilised to increase dose conformity across the target volume. Recent investigations have highlighted differential cellular responses to modulated radiation fields particularly in areas outside the primary treatment field that cannot be accounted for by scattered dose alone. In the present study, we determined the DNA damage response within the normal human fibroblast AG0-1522B and the prostate cancer cell line DU-145 utilising the DNA damage assay. Cells plated in slide flasks were exposed to 1 Gy uniform or modulated radiation fields. Modulated fields were delivered by shielding 25%, 50% or 75% of the flask during irradiation. The average number of 53BP1 or γH2AX foci was measured in 2 mm intervals across the slide area. Following 30 minutes after modulated radiation field exposure an increase in the average number of foci out-of-field was observed when compared to non-irradiated controls. In-field, a non-uniform response was observed with a significant decrease in the average number of foci compared to uniformly irradiated cells. Following 24 hrs after exposure there is evidence for two populations of responding cells to bystander signals in-and out-of-field. There was no significant difference in DNA damage response between 25%, 50% or 75% modulated fields. The response was dependent on cellular secreted intercellular signalling as physical inhibition of intercellular communication abrogated the observed response. Elevated residual DNA damage observed within out-of-field regions decreased following addition of an inducible nitric oxide synthase inhibitor (Aminoguanidine). These data show, for the first time, differential DNA damage responses in-and out-of-field following modulated radiation field delivery. This study provides further evidence for a role of intercellular communication in mediating cellular radiobiological response to modulated radiation fields and may inform the refinement of existing radiobiological models for the optimization of advanced radiotherapy treatment plans.
Highlights
The delivery of clinical radiotherapy is based upon the assumption that radiobiological response within the target volume is proportional to the dose delivered [1]
A rapid induction of 53BP1 (2A–B) and cH2AX (2C– D) foci is observed with the maximum average number of foci observed 30 minutes after exposure at all doses
With the development of advanced radiotherapy modalities such as intensity modulated radiation therapy (IMRT) it is of increasing importance to gain understanding in the effects of spatially modulated radiation exposures
Summary
The delivery of clinical radiotherapy is based upon the assumption that radiobiological response within the target volume is proportional to the dose delivered [1]. During the delivery of advanced radiotherapy techniques such as intensity modulated radiation therapy (IMRT), modulated beams are utilised to increase conformity of dose delivered to the targeted tumour volume. Several reports have highlighted significant differences in cell survival [2,3,4,5,6,7] and DNA damage response [6] following modulated field exposure. Decreased survival was observed out-of-field after exposure to a modulated radiation field with evidence of increased levels of survival in-field (i.e. within the primary treatment field). This response could be prevented by physically inhibiting communication between the cell populations. By determining the mean nuclear cH2AX-associated fluorescence intensity Syme et al [6] provided evidence for an enhancement of DNA damage within the penumbra and blocked regions in normal fibroblast cells compared to an open-beam irradiation, highlighting a role for differences in beam quality within areas out-of-field
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