SU11248 (sunitinib) sensitizes pancreatic cancer to the cytotoxic effects of ionizing radiation.
OBJECTIVE
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
For in vitro studies human pancreatic adenocarcinoma cells lines were treated with 1 microM 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.
Vanderbilt University School of Medicine, Nashville, TN 37232-5671, USA.
Kyle C
KC
Cuneo
Ling
L
Geng
Allie
A
Fu
Darren
D
Orton
Dennis E
DE
Hallahan
Anuradha Bapsi
AB
Chakravarthy
D000230:Adenocarcinoma / Q000503:physiopathology* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D010190:Pancreatic Neoplasms / Q000503:physiopathology* / Q000532:radiotherapy; D011758:Pyrroles / Q000008:administration & dosage*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D000077210:Sunitinib
D007211:Indoles; D011758:Pyrroles; D011838:Radiation-Sensitizing Agents; D000077210:Sunitinib