Photon Versus Proton Whole-Body Irradiation Combined with Olaparib in C57BL/6 Mice: An Exploratory Study of Oxidative Stress, Inflammatory, and DNA Damage Response Biomarkers

Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor with established radiosensitizing properties, is a candidate for combination with radiotherapy, yet its multi-organ oxidative toxicity when combined with photon versus proton irradiation has not been characterized. In the ToxIP3 project, C57BL/6 male mice were allocated to six groups (n = 10 per group) receiving whole-body irradiation at 7.5 Gy by photons (TrueBeam™) or protons (190.6 MeV, Institut Curie, Orsay), with or without concurrent oral olaparib (50 mg/kg/day). Seventy-four biomarkers spanning protein carbonylation, lipid peroxidation, antioxidant enzyme activities, glutathione redox status, PARP activity, total protein, TGF-β1, and 13 plasma cytokines were quantified across nine compartments. The principal comparison (protons + olaparib vs. photons + olaparib) used two-sided Wilcoxon–Mann–Whitney tests with Benjamini–Hochberg false discovery rate (FDR) correction; time-shifted comparisons used rank-based ANCOVA adjusted for the day of sacrifice. Combination arms showed markedly increased lethality (median survival 9 days for photons + olaparib and 8 days for protons + olaparib in all 60 randomized animals); 54 mice were available for biomarker analysis. Of 74 biomarkers, 18 differed between combination arms after FDR correction; seven hepatic protein-normalized measurements were considered non-interpretable, leaving 11. Protons + olaparib was associated with higher intestinal GPx and GSH/GSSG, higher erythrocyte GSH, GSSG and SOD, higher cerebral SOD (+75.1%, q = 0.010), and a higher hepatic GSH/GSSG ratio (+108.2%, q < 0.001), whereas skin showed a lower GSH/GSSG ratio (−77.6%) and higher protein carbonylation (+142.9%). These exploratory findings, obtained in a near-lethal whole-body irradiation model, show modality-associated differences in redox biomarkers but do not establish differences in normal-tissue toxicity.