Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
PLoS One. 2013;8(1):e53900. doi: 10.1371/journal.pone.0053900. Epub 2013 Jan 11.
KML001 is sodium metaarsenite, and has shown cytotoxic activity in human tumor cell lines. The anti-cancer mechanism of KML001 involves cancer cell destruction due to DNA damage at the telomeres of cancer cell chromosomes. In this study, we assessed the vascular disrupting properties of KML001 and investigated whether KML001 as VDA is able to increase anti-tumor activity in irinotecan combined treatment. We used a murine model of the CT26 colon carcinoma cell line. CT26 isograft mice treated intraperitoneally with 10 mg/kg KML001 displayed extensive central necrosis of tumor by 24 h. The vascular disrupting effects of KML001 were assessed by dynamic contrast enhanced magnetic resonance imaging. Gadopentetic acid-diethylene triaminepentaacetic acid contrast enhancement was markedly decreased in KML001-treated mice one day after treatment, whereas persistently high signal enhancement was observed in mice injected with saline. Rate constant K(ep) value representing capillary permeability was significantly decreased (p<0.05) in mice treated with KML001. Cytoskeletal changes of human umbilical vein endothelial cells (HUVECs) treated with 10 uM KML001 were assessed by immune blotting and confocal imaging. KML001 degraded tubulin protein in HUVECs, which may be related to vascular disrupting properties of KML001. Finally, in the mouse CT26 isograft model, KML001 combined with irinotecan significantly delayed tumor growth as compared to control and irinotecan alone. These results suggest that KML001 is a novel vascular disrupting agent, which exhibits significant vascular shut-down activity and enhances anti-tumor activity in combination with chemotherapy. These data further suggest an avenue for effective combination therapy in treating solid tumors.
KML001 是偏亚砷酸钠，已在人类肿瘤细胞系中显示出细胞毒性活性。KML001 的抗癌机制涉及由于癌细胞染色体端粒处的 DNA 损伤导致癌细胞破坏。在这项研究中，我们评估了 KML001 的血管破坏特性，并研究了 KML001 作为 VDA 是否能够增加伊立替康联合治疗的抗肿瘤活性。我们使用 CT26 结肠癌细胞系的小鼠模型。用 10mg/kg KML001 腹腔内治疗 CT26 同种异体移植小鼠，24 小时内肿瘤出现广泛的中央坏死。通过动态对比增强磁共振成像评估 KML001 的血管破坏作用。KML001 治疗小鼠在治疗后一天，钆喷替酸二乙三胺五乙酸对比增强明显降低，而用生理盐水注射的小鼠则持续观察到高信号增强。代表毛细血管通透性的速率常数 K(ep)值在 KML001 治疗的小鼠中显著降低（p<0.05）。用 10μM KML001 处理的人脐静脉内皮细胞（HUVEC）的细胞骨架变化通过免疫印迹和共聚焦成像进行评估。KML001 降解 HUVEC 中的微管蛋白蛋白，这可能与 KML001 的血管破坏特性有关。最后，在 CT26 同种异体移植小鼠模型中，与对照组和单独使用伊立替康相比，KML001 联合伊立替康显著延迟肿瘤生长。这些结果表明 KML001 是一种新型的血管破坏剂，具有显著的血管关闭活性，并与化疗联合增强抗肿瘤活性。这些数据进一步为治疗实体瘤的有效联合治疗提供了途径。
