Inhibition of orthotopic human bladder tumor growth by lentiviral gene transfer of endostatin
Inhibition of orthotopic human bladder tumor growth by lentiviral gene transfer of endostatin
复制标题
DOI：
10.1158/1078-0432.ccr-03-0099
复制
发表时间：
2004-03-01
影响因子：
11.5
通讯作者：
Bochner, BH
中科院分区：
文献类型：
--
作者：
Kikuchi, E;Menendez, S;Bochner, BH
目的：内皮细胞增殖抑制剂，如内皮抑制素，导致肿瘤相关血管生成的抑制，并可根据治疗的肿瘤类型实现生长抑制作用。本研究的目的是调查是否局部过度表达内皮抑素可以减少肿瘤生长的膀胱cancer. Experimental Design在vivo.Experimental设计：我们检查的能力，慢病毒介导的基因转移在体外和治疗效果的慢病毒为基础的载体表达内皮抑素对肿瘤生长使用原位人膀胱肿瘤模型。我们发现，含有绿色荧光蛋白的自失活慢病毒载体，单独或与内皮抑制素组合，能够有效和稳定的基因转移到各种人膀胱肿瘤细胞系。Western blot和竞争性酶免疫分析证实慢病毒转导的KU-7人膀胱癌细胞产生和分泌内皮抑素。在鼠模型中进行未转导的、绿色荧光蛋白对照慢病毒转导的和内皮抑制素转导的KU-7细胞的膀胱内滴注以建立原位肿瘤。在慢病毒转导的原位膀胱肿瘤中实现了内皮抑素的持续长期表达，并且其与血管形成减少和肿瘤生长抑制相关。慢病毒载体介导的内皮抑素的过表达并没有影响碱性成纤维细胞生长因子和血管内皮生长因子的内在生产。结论：这些研究结果表明，慢病毒介导的基因转移可能是一种有效的策略，表达血管抑制肽，以实现抑制人膀胱癌的增殖和肿瘤进展。
Purpose: Inhibitors of endothelial cell proliferation, such as endostatin, result in suppression of tumor-associated angiogenesis and can achieve growth-inhibitory effects depending on the type of tumor treated. The purpose of this study was to investigate whether local overexpression of endostatin could serve to diminish tumor growth of bladder cancer in vivo.Experimental Design: We examined the capability of lentiviral-mediated gene transfer in vitro and therapeutic effects of lentivirus-based vectors expressing endostatin on tumor growth using an orthotopic human bladder tumor model.Results: We found that self-inactivating lentivirus vectors containing green fluorescent protein, alone or in combination with endostatin, were capable of efficient and stable gene transfer to a variety of human bladder tumor cell lines. The production and secretion of endostatin from lentivirus-transduced KU-7 human bladder cancer cells was confirmed by Western blot and competitive enzyme immunoassay. Intravesical instillation of untransduced, green fluorescent protein control lentivirus-transduced, and endostatin-transduced KU-7 cells was performed in murine models to establish orthotopic tumors. Sustained long-term expression of endostatin was achieved in lentivirus-transduced orthotopic bladder tumors, and it was associated with decreased vascularization and inhibition of tumor growth. Lentivirus vector-mediated overexpression of endostatin did not affect the intrinsic production of basic fibroblast growth factor and vascular endothelial growth factor.Conclusions: These findings suggest that lentivirus-mediated gene transfer might represent an effective strategy for expression of angioinhibitory peptides to achieve inhibition of human bladder cancer proliferation and tumor progression.