IFN-β Restricts Tumor Growth and Sensitizes Alveolar Rhabdomyosarcoma to Ionizing Radiation
Abstract
Ionizing radiation is an important component of multimodal therapy for alveolar rhabdomyosarcoma (ARMS). We sought to evaluate the ability of IFN-β to enhance the activity of ionizing radiation. Rh-30 and Rh-41 ARMS cells were treated with IFN-β 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-β 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-β 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-β and radiation were smaller than control tumors and those treated with radiation or IFN-β alone. Additionally, treatment with high-dose IFN-β followed by radiation significantly reduced tumor size compared with radiation treatment followed by IFN-β. The combination of IFN-β 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-β and ionizing radiation may be an effective combination for treatment of ARMS. Mol Cancer Ther; 9(3); 761–71 Keywords rhabdomyosarcoma radiation IFN-β radiosensitizing agent vascular normalization