Sunitinib effects on the radiation response of endothelial and breast tumor cells

Background: Endothelial cells are suggested regulators of tumor response to radiation. Anti-vascular targeting agents can enhance tumor response by targeting endothelial cells. Here, we have conducted experiments in vitro to discern the effects of radiation combined with the anti-angiogenic Sunitinib on endothelial (HUVEC) and tumor (MDA-MB-231) cells, and further compared findings to results obtained in vivo. Methods: In vitro and in vivo treatments consisted of single dose radiation therapy of 2, 4, 8 or 16 Gy administered alone or in combination with bFGF or Sunitinib. In vitro, in situ end labeling (ISEL) was used to assess 24-hour apoptotic cell death, and clonogenic assays were used to assess long-term response. In vivo MDA-MB-231 tumors were grown in CB-17 SCID mice. The vascular marker CD31 was used to assess 24-hour acute response while tumor clonogenic assays were used to assess long-term tumor cell viability following treatments. Results: Using in vitro studies, we observed an enhanced endothelial cell response to radiation doses of 8 and 16 Gy when compared to tumor cells. Administering Sunitinib alone significantly increased HUVEC cell death, while having modest additive effects when combined with radiation. Sunitinib also increased tumor cell death when combined with 8 and 16 Gy radiation doses. In comparison, we found that the clonogenic response of in vivo treated tumor cells more closely resembled that of in vitro treated endothelial cells than in vitro treated tumor cells. Conclusion: Our results indicate that the endothelium is an important regulator of tumor response to radiotherapy, and that Sunitinib can enhance tumor radiosensitivity. To the best of our knowledge, this is the first time that Sunitinib is investigated in combination with radiotherapy on the MDA-MB-231 breast cancer cell line. (C) 2013 Elsevier Inc. All rights reserved.