TY - JOUR
T1 - SU11248 (Sunitinib) Sensitizes Pancreatic Cancer to the Cytotoxic Effects of Ionizing Radiation
AU - Cuneo, Kyle C.
AU - Geng, Ling
AU - Fu, Allie
AU - Orton, Darren
AU - Hallahan, Dennis E.
AU - Chakravarthy, Anuradha Bapsi
N1 - Funding Information:
Supported by NIH grants RO1-CA112385, RO1-CA70937, RO1-CA88076, RO1-CA89888, P50-CA90949, Vanderbilt-Ingram Cancer Center, CCSG P30-CA6848. K.C. Cuneo is supported by the Vanderbilt University Medical Scholars Program.
PY - 2008/7/1
Y1 - 2008/7/1
N2 - Purpose: SU11248 (sunitinib) is a small-molecule tyrosine kinase inhibitor which targets VEGFR and PDGFR isoforms. In the present study, the effects of SU11248 and ionizing radiation on pancreatic cancer were studied. Methods and Materials: For in vitro studies human pancreatic adenocarcinoma cells lines were treated with 1 μM SU11248 1 h before irradiation. Western blot analysis was used to determine the effect of SU11248 on radiation-induced signal transduction. To determine if SU11248 sensitized pancreatic cancer to the cytotoxic effects of ionizing radiation, a clonogenic survival assay was performed using 0-6 Gy. For in vivo assays, CAPAN-1 cells were injected into the hind limb of nude mice for tumor volume and proliferation studies. Results: SU11248 attenuated radiation-induced phosphorylation of Akt and ERK at 0, 5, 15, and 30 min. Furthermore, SU11248 significantly reduced clonogenic survival after treatment with radiation (p < 0.05). In vivo studies revealed that SU11248 and radiation delayed tumor growth by 6 and 10 days, respectively, whereas combined treatment delayed tumor growth by 30 days. Combined treatment with SU11248 and radiation further attenuated Brdu incorporation by 75% (p = 0.001) compared to control. Conclusions: SU11248 (sunitinib) sensitized pancreatic cancer to the cytotoxic effects of radiation. This compound is promising for future clinical trials with chemoradiation in pancreatic cancer.
AB - Purpose: SU11248 (sunitinib) is a small-molecule tyrosine kinase inhibitor which targets VEGFR and PDGFR isoforms. In the present study, the effects of SU11248 and ionizing radiation on pancreatic cancer were studied. Methods and Materials: For in vitro studies human pancreatic adenocarcinoma cells lines were treated with 1 μM SU11248 1 h before irradiation. Western blot analysis was used to determine the effect of SU11248 on radiation-induced signal transduction. To determine if SU11248 sensitized pancreatic cancer to the cytotoxic effects of ionizing radiation, a clonogenic survival assay was performed using 0-6 Gy. For in vivo assays, CAPAN-1 cells were injected into the hind limb of nude mice for tumor volume and proliferation studies. Results: SU11248 attenuated radiation-induced phosphorylation of Akt and ERK at 0, 5, 15, and 30 min. Furthermore, SU11248 significantly reduced clonogenic survival after treatment with radiation (p < 0.05). In vivo studies revealed that SU11248 and radiation delayed tumor growth by 6 and 10 days, respectively, whereas combined treatment delayed tumor growth by 30 days. Combined treatment with SU11248 and radiation further attenuated Brdu incorporation by 75% (p = 0.001) compared to control. Conclusions: SU11248 (sunitinib) sensitized pancreatic cancer to the cytotoxic effects of radiation. This compound is promising for future clinical trials with chemoradiation in pancreatic cancer.
KW - PDGFR
KW - Pancreatic cancer
KW - Radiosensitizer
KW - SU11248
KW - Sunitinib
KW - VEGFR
UR - http://www.scopus.com/inward/record.url?scp=44349119079&partnerID=8YFLogxK
U2 - 10.1016/j.ijrobp.2008.02.062
DO - 10.1016/j.ijrobp.2008.02.062
M3 - Article
C2 - 18514780
AN - SCOPUS:44349119079
SN - 0360-3016
VL - 71
SP - 873
EP - 879
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 3
ER -