Efficacy of Sunitinib and Radiotherapy in Genetically Engineered Mouse Model of Soft-Tissue Sarcoma
- Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States)
- Department of Surgery, Division of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States)
- Harvard-Partners Center for Genetics and Genomics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (United States)
- Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA (United States)
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States)
- Center for Cancer Research, Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Boston, MA (United States)
Purpose: Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS). Methods and Materials: Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy x 2), or both (SU+RT). Changes in the tumor vasculature before and after treatment were assessed in vivo using fluorescence-mediated tomography. The control and treated tumors were harvested and extensively analyzed. Results: The mean fluorescence in the tumors was not decreased by RT but decreased 38-44% in tumors treated with SU or SU+RT. The control tumors grew to a mean of 1378 mm{sup 3} after 12 days. SU alone or RT alone delayed tumor growth by 56% and 41%, respectively, but maximal growth inhibition (71%) was observed with the combination therapy. SU target effects were confirmed by loss of target receptor phosphorylation and alterations in SU-related gene expression. Cancer cell proliferation was decreased and apoptosis increased in the SU and RT groups, with a synergistic effect on apoptosis observed in the SU+RT group. RT had a minimal effect on the tumor microvessel density and endothelial cell-specific apoptosis, but SU alone or SU+RT decreased the microvessel density by >66% and induced significant endothelial cell apoptosis. Conclusion: SU inhibited STS growth by effects on both cancer cells and tumor vasculature. SU also augmented the efficacy of RT, suggesting that this combination strategy could improve local control of STS.
- OSTI ID:
- 21281977
- Journal Information:
- International Journal of Radiation Oncology, Biology and Physics, Vol. 74, Issue 4; Other Information: DOI: 10.1016/j.ijrobp.2009.02.052; PII: S0360-3016(09)00350-2; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0360-3016
- Country of Publication:
- United States
- Language:
- English
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