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

Abstract

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.