Tumor Oxygenation by Myo-Inositol Trispyrophosphate Enhances Radiation Response.

Abstract

Tumor hypoxia is a major limiting factor for successful radiation therapy outcomes, with hypoxic cells being up to 3-fold more radiation resistant than normoxic cells; tumor hypoxia creates a tumor microenvironment that is hostile to immune response. Thus, pharmaceutical-induced tumor oxygenation before radiation therapy represents an interesting method to enhance the efficacy of radiation therapy. Myo-inositol trispyrophosphate (ITPP) triggers a decrease in the affinity of oxygen to hemoglobin, which leads to an increased release of oxygen upon tissue demand, including in hypoxic tumors. The combined treatment modality of high-dose bolus ITPP with a single high-dose fraction of ionizing radiation (IR) was investigated for its mechanics and efficacy in multiple preclinical animal tumor models in immunocompromised and immunocompetent mice. The dynamics of tumor oxygenation were determined by serial hypoxia-oriented bioimaging. Initial and residual DNA damage and the integrity of the tumor vasculature were quantified on the immunohistochemical level in response to the different treatment combinations. ITPP application did not affect tumor growth as a single treatment modality, but it rapidly induced tumor oxygenation, as demonstrated by invivo imaging, and significantly reduced tumor growth when combined with IR. An immunohistochemical analysis of γH2AX foci demonstrated increased initial and residual IR-induced DNA damage as the primary mechanism for radiosensitization within initially hypoxic but ITPP-oxygenated tumor regions. Scheduling experiments revealed that ITPP increases the efficacy of ionizing radiation only when applied before radiation therapy. Irradiation alone damaged the tumor vasculature and increased tumor hypoxia, which were both prevented by combined treatment with ITPP. Interestingly, the combined treatment modality also promoted increased immune cell infiltration. ITPP-mediated tumor oxygenation and vascular protection triggers immediate and delayed processes to enhance the efficacy of ionizing radiation for successful radiation therapy.