Suppression of ovarian cancer by muscle‐mediated expression of soluble VEGFR‐1/Flt‐1 using adeno‐associated virus serotype 1‐derived vector
Suppression of ovarian cancer by muscle‐mediated expression of soluble VEGFR‐1/Flt‐1 using adeno‐associated virus serotype 1‐derived vector
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DOI：
10.1002/ijc.22307
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发表时间：
2007-01
影响因子：
6.4
通讯作者：
Y. Takei;H. Mizukami;Y. Saga;I. Yoshimura;Y. Hasumi;T. Takayama;T. Kohno;T. Matsushita;T. Okada;A. Kume;Mitsuaki Suzuki;K. Ozawa
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作者：
Y. Takei;H. Mizukami;Y. Saga;I. Yoshimura;Y. Hasumi;T. Takayama;T. Kohno;T. Matsushita;T. Okada;A. Kume;Mitsuaki Suzuki;K. Ozawa
血管内皮生长因子（VEGF）在多种肿瘤的血管生成中起重要作用。可溶性形式的Flt-1（sFlt-1）是一种VEGF受体，可能用作VEGF的拮抗剂，并且越来越多的证据表明sFlt-1通过抗血管生成在肿瘤抑制中的适用性。我们先前证明了sflt-1基因原位表达抑制卵巢癌肿瘤生长和腹水的疗效。在这里，我们证明了肌肉介导的sFlt-1表达在荷瘤小鼠中的治疗适用性。最初，肿瘤抑制作用通过皮下和腹膜内将表达SHIN-1的卵巢癌（SHIN-3）细胞植入小鼠体内来证实。为了在临床相关性更高的模型中验证治疗效果，将编码sflt-1的腺相关病毒载体导入小鼠骨骼肌，随后接种肿瘤细胞。结果，持续观察到高血清sFlt-1水平，皮下和腹膜内接种的肿瘤生长均受到显著抑制。未观察到伤口愈合延迟或神经肌肉损伤不良事件，体重未发生变化，实验室数据（如代表肝功能和肾功能的数据）未受到影响。这些结果表明，sFlt-1通过抑制血管生成抑制卵巢癌的生长和腹膜扩散，因此表明基因治疗对卵巢癌的有用性。© 2006 Wiley利斯公司
Vascular endothelial growth factor (VEGF) is known to play a major role in angiogenesis in a variety of tumors. A soluble form of Flt‐1 (sFlt‐1), a VEGF receptor, is potentially useful as an antagonist of VEGF, and accumulating evidences suggest the applicability of sFlt‐1 in tumor suppression by means of anti‐angiogenesis. We previously demonstrated the efficacy of sflt‐1 gene expression in situ to suppress tumor growth and ascites in ovarian cancer. Here, we demonstrate the therapeutic applicability of muscle‐mediated expression of sFlt‐1 in tumor‐bearing mice. Initially, tumor suppressive action was confirmed by inoculating sFlt‐1‐expressing ovarian cancer (SHIN‐3) cells into mice, both subcutaneously and intraperitoneally. To validate the therapeutic efficacy in a more clinically relevant model, adeno‐associated virus vectors encoding sflt‐1 were introduced into mouse skeletal muscles and were subsequently inoculated with tumor cells. As a result, high serum sFlt‐1 levels were constantly observed, and the growth of both subcutaneously‐ and intraperitoneally‐inoculated tumors was significantly suppressed. No delay in wound healing or adverse events of neuromuscular damage were noted, body weight did not change, and laboratory data, such as those representing liver and renal functions, were not affected. These results indicate that sFlt‐1 suppresses growth and peritoneal dissemination of ovarian cancer by the inhibition of angiogenesis, and thus suggest the usefulness of gene therapy for ovarian cancer. © 2006 Wiley‐Liss, Inc.