SU11248 (sunitinib) sensitizes pancreatic cancer to the cytotoxic effects of ionizing radiation.

Cuneo KC, Geng L, Fu A, Orton D, Hallahan DE, Chakravarthy AB
Int J Radiat Oncol Biol Phys. 2008 71 (3): 873-9

PMID: 18514780 · DOI:10.1016/j.ijrobp.2008.02.062

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 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.

MeSH Terms (12)

Adenocarcinoma Cell Line, Tumor Cell Survival Dose-Response Relationship, Drug Dose-Response Relationship, Radiation Humans Indoles Pancreatic Neoplasms Pyrroles Radiation-Sensitizing Agents Radiation Tolerance Sunitinib

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