Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University Zurich, Zurich, Switzerland.
Laboratory of the Swiss-Hepato-Pancreatico-Biliary (HPB) Centre, Department of Visceral Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Int J Radiat Oncol Biol Phys. 2021 Jul 15;110(4):1222-1233. doi: 10.1016/j.ijrobp.2021.02.012. Epub 2021 Feb 12.
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 in vivo 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.
肿瘤缺氧是影响放射治疗效果的主要限制因素，缺氧细胞的放射抵抗性是正常氧合细胞的 3 倍以上；肿瘤缺氧会导致肿瘤微环境对免疫反应产生敌意。因此，在放射治疗前用药物使肿瘤氧合代表了一种增强放射治疗效果的有趣方法。肌醇三磷酸（ITPP）可降低氧与血红蛋白的亲和力，从而导致组织需求（包括缺氧肿瘤）时释放更多的氧气。
在免疫缺陷和免疫功能正常的小鼠的多个临床前动物肿瘤模型中，研究了高剂量 ITPP 与单次大剂量电离辐射（IR）联合治疗的作用机制和疗效。通过连续缺氧导向生物成像来确定肿瘤氧合动力学。根据不同的治疗组合，在免疫组化水平上定量评估初始和残留的 DNA 损伤以及肿瘤血管完整性。
ITPP 作为单一治疗方法不会影响肿瘤生长，但它可迅速诱导肿瘤氧合，如体内成像所示，并与 IR 联合使用时可显著抑制肿瘤生长。γH2AX 焦点的免疫组化分析表明，作为最初缺氧但 ITPP 氧合肿瘤区域放射增敏的主要机制，初始和残留的 IR 诱导的 DNA 损伤增加。时间安排实验表明，只有在放射治疗前应用 ITPP 才能提高电离辐射的疗效。单独照射会损伤肿瘤血管并增加肿瘤缺氧，这两种情况均可通过 ITPP 联合治疗来预防。有趣的是，联合治疗还促进了免疫细胞的浸润增加。
ITPP 介导的肿瘤氧合和血管保护可触发即时和延迟过程，以提高电离辐射治疗成功的疗效。
