PURPOSE Src family kinases (SFK) have been identified as molecular targets. SU6656 is a small-molecle indolinone that specifically inhibits this family of kinases. METHODS AND MATERIALS Human umbilical vein endothelial cells were used to study the effects of SFK inhibition. Western blot analysis was performed to determine the effect of SFK inhibition on the PI3K/Akt pathway and caspase cleavage. Apoptosis was studied by propidium iodide staining of nuclei. Angiogenesis was examined using capillary tubule formation in Matrigel. Tumor response was further studied in vivo using Lewis lung carcinoma cells implanted into the dorsal skin fold of mice in the window model and in the hind limb in the tumor volume model. RESULTS Clonogenic survival of endothelial cells was decreased after the combined therapy of SU6656 and radiation compared with radiotherapy alone. Furthermore, SFK inhibition by SU6656 attenuated radiation-induced Akt phosphorylation and increased radiation-induced apoptosis and vascular endothelium destruction. In vivo, SU6656 administered before irradiation significantly enhanced radiation-induced destruction of blood vessels within the tumor windows and enhanced tumor growth delay when administered during fractionated irradiation. CONCLUSIONS This study demonstrates the potential use of SFK inhibition to enhance the effects of ionizing radiation during radiotherapy.

中文翻译：

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SRC家族激酶抑制剂SU6656增强了辐射的抗血管生成作用。

目的Src家族激酶（SFK）已被确定为分子靶标。SU6656是一种小分子吲哚酮，可特异性抑制该激酶家族。方法和材料使用人脐静脉内皮细胞研究SFK抑制作用。进行蛋白质印迹分析以确定SFK抑制对PI3K / Akt途径和胱天蛋白酶裂解的影响。通过细胞核碘化丙啶染色研究细胞凋亡。使用Matrigel中的毛细管形成检查血管生成。在窗口模型和肿瘤体积模型的后肢中，使用植入小鼠背部皮肤褶皱的Lewis肺癌细胞进一步研究了体内肿瘤反应。结果与单独放疗相比，SU6656和放疗联合治疗后内皮细胞的克隆生存率降低。此外，SU6656对SFK的抑制作用减弱了辐射诱导的Akt磷酸化，并增加了辐射诱导的凋亡和血管内皮破坏。在体内，在分次照射期间给药时，在照射前给药的SU6656显着增强了辐射诱导的肿瘤窗口内血管的破坏，并增强了肿瘤的生长延迟。结论这项研究证明了SFK抑制在增强放射治疗过程中电离辐射作用方面的潜在用途。在体内，在分次照射期间给药时，在照射前给药的SU6656显着增强了辐射诱导的肿瘤窗口内血管的破坏，并增强了肿瘤的生长延迟。结论这项研究证明了SFK抑制在增强放射治疗过程中电离辐射作用方面的潜在用途。在体内，在分次照射期间给药时，在照射前给药的SU6656显着增强了辐射诱导的肿瘤窗口内血管的破坏，并增强了肿瘤的生长延迟。结论这项研究证明了SFK抑制在增强放射治疗过程中电离辐射作用方面的潜在用途。