Cuneo Kyle C, Geng Ling, Fu Allie, Orton Darren, Hallahan Dennis E, Chakravarthy Anuradha Bapsi
Vanderbilt University School of Medicine, Nashville, TN 37232-5671, USA.
Int J Radiat Oncol Biol Phys. 2008 Jul 1;71(3):873-9. doi: 10.1016/j.ijrobp.2008.02.062.
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.
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.
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.
SU11248 (sunitinib) sensitized pancreatic cancer to the cytotoxic effects of radiation. This compound is promising for future clinical trials with chemoradiation in pancreatic cancer.
SU11248（舒尼替尼）是一种靶向VEGFR和PDGFR亚型的小分子酪氨酸激酶抑制剂。在本研究中，研究了SU11248和电离辐射对胰腺癌的影响。
在体外研究中，人胰腺腺癌细胞系在照射前1小时用1μM的SU11248处理。采用蛋白质免疫印迹分析来确定SU11248对辐射诱导信号转导的影响。为了确定SU11248是否使胰腺癌对电离辐射的细胞毒性作用敏感，使用0 - 6 Gy进行克隆形成存活试验。在体内试验中，将CAPAN - 1细胞注射到裸鼠后肢进行肿瘤体积和增殖研究。
在0、5、15和30分钟时，SU11248减弱了辐射诱导的Akt和ERK磷酸化。此外，SU11248显著降低了辐射治疗后的克隆形成存活率（p < 0.05）。体内研究表明，SU11248和辐射分别使肿瘤生长延迟6天和10天，而联合治疗使肿瘤生长延迟30天。与对照组相比，SU11248和辐射联合治疗使溴脱氧尿苷掺入进一步减少75%（p = 0.001）。
SU11248（舒尼替尼）使胰腺癌对辐射的细胞毒性作用敏感。该化合物有望用于未来胰腺癌放化疗的临床试验。
