Transduction of soluble Flt-1 gene to peritoneal mesothelial cells can effectively suppress peritoneal metastasis of gastric cancer
Transduction of soluble Flt-1 gene to peritoneal mesothelial cells can effectively suppress peritoneal metastasis of gastric cancer
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DOI：
10.1158/0008-5472.can-04-0304
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发表时间：
2004-05-15
期刊：
影响因子：
11.2
通讯作者：
Nagawa, H
中科院分区：
文献类型：
--
作者：
Sako, A;Kitayama, J;Nagawa, H
胃癌腹膜转移患者的预后并未得到改善。尽管有许多有前景的研究，但由于缺乏合适的载体系统来选择性地将基因转导到肿瘤细胞，基因治疗的临床应用受到了限制。本研究的目的是阐明针对腹膜间皮细胞(PMC)的基因治疗是否能抑制胃癌的腹膜转移。体外实验表明，表达LacZ的腺病毒比人胃癌细胞系MKN1和MKN45更有效地感染人大网膜组织来源的PMCs。将表达LacZ的腺病毒注射到裸鼠的腹膜腔内，至少4周后在腹膜中检测到LacZ的表达。此外，当表达可溶性Flt-1的腺病毒(Ad-sFlt-1)腹腔注射时。体内给药8周后，灌洗液中可检测到高水平的sFlt-1蛋白。当MKN45细胞被iP。腺病毒载体接种3d后，Ad-sFlt-1可显著减少腹膜表面直径大于1 mm的转移结节数目，显著延长裸鼠存活时间，且无明显毒副作用。因此，单一的ip显著抑制了腹膜播散。注射Ad-sFlt-1。靶向PMC的抗血管生成基因治疗不需要肿瘤特异性基因转移，可能是一种新的、实用的抗胃癌腹膜转移策略。
The prognosis of gastric cancer with peritoneal metastasis has not improved. Despite many promising studies, gene therapy has limited clinical application because of the lack of suitable vector systems to enable selective gene transduction to tumor cells. The aim of this study was to clarify whether gene therapy targeted to peritoneal mesothelial cells (PMCs) can inhibit peritoneal dissemination of gastric cancer. In vitro experiments showed that adenovirus expressing LacZ infected human omental tissue-derived PMCs more efficiently than human gastric cancer cell lines MKN1 and MKN45. When adenovirus expressing LacZ was injected into the peritoneal cavity of nude mice, the expression was detected in the peritoneum for at least 4 weeks. Furthermore, when adenovirus expressing soluble Flt-1 (Ad-sFLT-1) was i.p. administered in vivo, a high level of sFlt-1 protein could be detected in peritoneal lavage for 8 weeks. When MKN45 cells were i.p. inoculated 3 days after adeno-viral vector injection, Ad-sFLT-1 markedly reduced the number of metastatic nodules larger than I mm in diameter on the peritoneal surface, and significantly prolonged the survival of nude mice without any significant side effects. Thus, peritoneal dissemination was significantly suppressed by a single i.p. injection of Ad-sFlt-1. Anti-angiogenic gene therapy targeted to PMCs could be a novel and practical strategy against peritoneal dissemination of gastric cancer, because it does not require tumor-specific gene transfer.