Journal
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
Volume 71, Issue 3, Pages 873-879Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ijrobp.2008.02.062
Keywords
pancreatic cancer; sunitinib; SU11248; radiosensitizer; VEGFR; PDGFR
Funding
- NCI NIH HHS [P50 CA 90949, R01 CA 112385, R01 CA 70937, R01 CA 88076, R01 CA 89888, P30 CA 6848] Funding Source: Medline
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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 mu M 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. (C) 2008 Elsevier Inc.
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