The γH2AX DSB marker may not be a suitable biodosimeter to measure the biological MRT valley dose

Jessica A. Ventura, Jacqueline F. Donoghue, Cameron J. Nowell, Leonie M. Cann, Liam R.J. Day, Lloyd M.L. Smyth, Helen B. Forrester, Peter A.W. Rogers, Jeffrey C. Crosbie

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose: γH2AX biodosimetry has been proposed as an alternative dosimetry method for microbeam radiation therapy (MRT) because conventional dosimeters, such as ionization chambers, lack the spatial resolution required to accurately measure the MRT valley dose. Here we investigated whether γH2AX biodosimetry should be used to measure the biological valley dose of MRT-irradiated mammalian cells. Materials and methods: We irradiated human skin fibroblasts and mouse skin flaps with synchrotron MRT and broad beam (BB) radiation. BB doses of 1–5 Gy were used to generate a calibration curve in order to estimate the biological MRT valley dose using the γH2AX assay. Results: Our key finding was that MRT induced a non-linear dose response compared to BB, where doses 2–3 times greater showed the same level of DNA DSB damage in the valley in cell and tissue studies. This indicates that γH2AX may not be an appropriate biodosimeter to estimate the biological valley doses of MRT-irradiated samples. We also established foci yields of 5.9 ± (Formula presented.) and 27.4 ± (Formula presented.) foci/cell/Gy in mouse skin tissue and human fibroblasts respectively, induced by BB. Using Monte Carlo simulations, a linear dose response was seen in cell and tissue studies and produced predicted peak-to-valley dose ratios (PVDRs) of ∼30 and ∼107 for human fibroblasts and mouse skin tissue respectively. Conclusions: Our report highlights novel MRT radiobiology, attempts to explain why γH2AX may not be an appropriate biodosimeter and suggests further studies aimed at revealing the biological and cellular communication mechanisms that drive the normal tissue sparing effect, which is characteristic of MRT.

Original languageEnglish
Pages (from-to)642-656
Number of pages15
JournalInternational Journal of Radiation Biology
Volume97
Issue number5
DOIs
Publication statusPublished - Mar 2021

Keywords

  • Biodosimetry
  • DNA damage
  • dose response curve
  • microbeam radiation therapy
  • synchrotron radiation
  • γH2AX

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