Efficacy of Sunitinib and Radiotherapy in Genetically Engineered Mouse Model of Soft-Tissue Sarcoma

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• 作者：Sam S. Yoon ; Lars Stangenberg ; Yoon-Jin Lee ; Courtney Rothrock ; Jonathan M. Dreyfuss ; Kwan-Hyuck Baek ; Peter R. Waterman ; G. Petur Nielsen ; Ralph Weissleder ; Umar Mahmood ; Peter J. Park ; Tyler Jacks
• 刊名：International Journal of Radiation Oncology*Biology*Physics
• 出版年：2009
• 出版时间：15 July 2009
• 年：2009
• 卷：74
• 期：4
• 页码：1207-1216
• 全文大小：868 K

文摘

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 × 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 mm³ 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.