Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Mol Cancer Ther. 2010 Mar;9(3):761-71. doi: 10.1158/1535-7163.MCT-09-0800. Epub 2010 Mar 2.
Ionizing radiation is an important component of multimodal therapy for alveolar rhabdomyosarcoma (ARMS). We sought to evaluate the ability of IFN-beta to enhance the activity of ionizing radiation. Rh-30 and Rh-41 ARMS cells were treated with IFN-beta and ionizing radiation to assess synergistic effects in vitro and as orthotopic xenografts in CB17 severe combined immunodeficient mice. In addition to effects on tumor cell proliferation and xenograft growth, changes in the tumor microenvironment including interstitial fluid pressure, perfusion, oxygenation, and cellular histology were assessed. A nonlinear regression model and isobologram analysis indicated that IFN-beta and ionizing radiation affected antitumor synergy in vitro in the Rh-30 cell line; the activity was additive in the Rh-41 cell line. In vivo continuous delivery of IFN-beta affected normalization of the dysfunctional tumor vasculature of both Rh-30 and Rh-41 ARMS xenografts, decreasing tumor interstitial fluid pressure, increasing tumor perfusion (as assessed by contrast-enhanced ultrasonography), and increasing oxygenation. Tumors treated with both IFN-beta and radiation were smaller than control tumors and those treated with radiation or IFN-beta alone. Additionally, treatment with high-dose IFN-beta followed by radiation significantly reduced tumor size compared with radiation treatment followed by IFN-beta. The combination of IFN-beta and ionizing radiation showed synergy against ARMS by sensitizing tumor cells to the cytotoxic effects of ionizing radiation and by altering tumor vasculature, thereby improving oxygenation. Therefore, IFN-beta and ionizing radiation may be an effective combination for treatment of ARMS.
电离辐射是治疗肺泡横纹肌肉瘤（ARMS）的多模态治疗的重要组成部分。我们试图评估 IFN-β增强电离辐射活性的能力。用 IFN-β和电离辐射处理 Rh-30 和 Rh-41 ARMS 细胞，以评估体外协同作用和 CB17 严重联合免疫缺陷小鼠的原位异种移植。除了对肿瘤细胞增殖和异种移植生长的影响外，还评估了肿瘤微环境的变化，包括间质液压力、灌注、氧合和细胞组织学。非线性回归模型和等辐射分析表明，IFN-β和电离辐射影响 Rh-30 细胞系中体外抗肿瘤协同作用；在 Rh-41 细胞系中活性为相加。体内连续给予 IFN-β影响两种 Rh-30 和 Rh-41 ARMS 异种移植中功能失调的肿瘤血管正常化，降低肿瘤间质液压力，增加肿瘤灌注（通过对比增强超声评估），并增加氧合。与对照肿瘤和单独接受放射治疗或 IFN-β 治疗的肿瘤相比，接受 IFN-β 和放射治疗的肿瘤更小。此外，与放射治疗后给予 IFN-β 相比，高剂量 IFN-β 后给予放射治疗可显著减小肿瘤体积。IFN-β 和电离辐射的联合使用通过使肿瘤细胞对电离辐射的细胞毒性作用敏感，并通过改变肿瘤血管，从而改善氧合，对 ARMS 具有协同作用。因此，IFN-β 和电离辐射可能是治疗 ARMS 的有效组合。
