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.


CONCLUSIONS
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.
Department of Radiation Oncology, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Ahmed
A
El Kaffas
Department of Radiation Oncology, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Azza
A
Al-Mahrouki
Department of Radiation Oncology, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
William T
WT
Tran
Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
Anoja
A
Giles
Department of Radiation Oncology, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada; Imaging Research and Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. Electronic address: gregory.czarnota@sunnybrook.ca.
Gregory J
GJ
Czarnota
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D011758:Pyrroles / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D000077210:Sunitinib; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib