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Abstract

Hypoxia is a well-known resistance factor in the treatment of solid tumors and correlates with increased tumor malignancy and poor treatment prognosis, especially in conventional radiation therapy with photons. In contrast, high-linear energy transfer (LET) particle irradiation shows promising results in overcoming hypoxia-induced radiation resistance. This study analyzes the effects of low-, intermediate- and high-LET irradiation on the radiation response in two sublines of the Dunning R3327 prostate tumor carcinoma model, HI and H, which differ in their heterogeneity and hypoxic fraction. Based on previous experiments with photons and carbon ions, I performed dose-response studies for the endpoint local tumor control within a follow-up time of 300 days using protons and helium ions exhibiting an intermediate LET. From these dose-response studies, the relative biological effectiveness (RBE) and the oxygen enhancement ratio (OER) was determined. Irradiations were performed in single fractions either under oxic (oxygen breathing) or hypoxic conditions induced by clamping the tumor supplying vessels. In a separate histological study, the reversibility of the effects induced by vessel clamping on the tumor micro milieu was demonstrated. Under hypoxic conditions, I found a shift of the dose response curves to higher doses indicating the increased radiation resistance under hypoxic conditions. The measured proton and helium ion RBE values were higher than one, demonstrating a higher effectiveness compared to conventionally used photons. Since the measured OER values of protons and helium ions were lower than that of photons, this also indicated that the biological efficacy was less dependent on the presence of molecular oxygen. Despite the significant LET-differences, I did not measure any significant differences in RBE or OER values between proton and helium ions. Based on these and other previously published dose-response studies, the radiation response at the histological level was investigated in the HI- and H-tumor up to 21 d after irradiation. Either curative doses (100% measured local tumor control) of photons, protons (HI-tumor only) and carbon ions or subcurative doses (0% local tumor control) of photons and carbon ions (HI-tumor only) were used for this study. The spatiotemporally altered radiation response of oxic and hypoxic cells was analyzed using multicolor immunofluorescence staining. The results showed that the effects of photons and protons on the investigated markers of the tumor micro milieu, the cells and the immune cell response did not differ significantly. Only curative doses of carbon ions induced increased tumor perfusion and longer-lasting DNA damage. This highlighted the higher effectiveness and potentially different mechanisms of action induced by high-LET carbon ion irradiation compared to low- and intermediate-LET irradiation