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Research Paper

Gamma-radiation (GR) triggers a unique gene expression profile associated with cell death compared to proton radiation (PR) in mice in vivo

Niklas Finnberg, Chris Wambi, Jeffrey H. Ware, Ann R. Kennedy and Wafik S. El-Deiry

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Proton radiation (PR) therapy offers a number of potential advantages over conventional
(photon) gamma-radiation (GR) therapy for cancer, due to a more localized delivery of
the radiation dose. However, the pathophysiological effects following PR-exposure are
less well characterized than those of GR-exposure and the molecular changes associated
with the acute apoptotic effects in mice in vivo following PR have not been elucidated.
Previous studies have estimated the RBE of protons for various in vivo and in vitro
endpoints at between 1.1 and 1.3. We assumed an RBE of 1.1 for the endpoints to be
evaluated in these studies. Based on this assumption, ICR mice were treated with wholebody
doses of GR (1.1 and 7.0 Gy) and PR (1.0 and 6.4 Gy) that were expected to
represent RBE-weighted doses. The bone marrow, thymus, spleen and GI-tract were
isolated and processed for histology and immunohistochemistry. The apoptotic responses
varied greatly between GR and PR in a tissue- and dose-dependent manner. Surprisingly,
cell death in the splenic white pulp was consistently lower in PR-treated animals
compared to animals treated with GR. This was in spite of an increased presence of
damaged DNA following PR as determined by staining for gamma-H2AX and phospho-
ATM. Interestingly, both PR and GR triggered nuclear accumulation of p53 and no
significant differences were found in the majority of the known pro-apoptotic p53-target
genes in the spleens of treated mice. However, GR uniquely triggered a pro-apoptotic
expression profile including expression of the pro-apoptotic, p53- and interferon
stimulated target gene bcl-g. In contrast to PR, GR may, in a cell type specific manner,
trigger a more diverse non-random stress-response that mediates apoptosis partially
independent of the extent of DNA damage.

Authors

Niklas Finnberg

Laboratory of Molecular Oncology and Cell Cycle Regulation, Departments of Medicine (Hematology/Oncology), Genetics, and Pharmacology, The Institute for Translational Medicine and Therapeutics, The Abramson Comprehensive Cancer Center, University of Penns

Chris Wambi

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Jeffrey H. Ware

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Ann R. Kennedy

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Wafik S. El-Deiry

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If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.