Adeno-associated viral vector-mediated expression of endostatin inhibits tumor growth and metastasis in an orthotropic pancreatic cancer model in hamsters
Adeno-associated viral vector-mediated expression of endostatin inhibits tumor growth and metastasis in an orthotropic pancreatic cancer model in hamsters
复制标题
DOI：
10.1158/0008-5472.can-03-1296
复制
发表时间：
2004-10-15
期刊：
影响因子：
11.2
通讯作者：
Shimada, T
中科院分区：
文献类型：
--
作者：
Noro, T;Miyake, K;Shimada, T
我们研究了在基因治疗中使用腺相关病毒（AAV）介导的内皮抑素全身递送的可行性。胰腺癌的转移。我们将胰腺癌细胞系PGHAM-1接种于叙利亚金仓鼠胰腺，建立原位转移性胰腺癌动物模型。移植的细胞迅速增殖并转移到肝脏。将表达内皮抑素的AAV载体（5 x 10（10）粒）肌内注射到左股四头肌或静脉注射到门静脉。通过比较肿瘤发展的各种参数，对这些媒介给药途径进行评价。肌内注射载体可适度提高血清内皮抑素水平。在治疗的动物中，转移的数量和出血性腹水的发生率都有所下降。相反，门内注射载体后，血清内皮抑素浓度显著升高。抗肿瘤作用对胰腺原发肿瘤大小、微血管密度、肝转移灶大小、数量、出血性腹水发生率等指标均有显著影响。这些结果表明，全身给药内皮抑素是胰腺癌和肝转移的潜在有效治疗方法。载体给药方式影响aav介导内皮抑素表达的效果。门静脉内注射AAV载体作为胰腺癌的抗血管生成基因治疗似乎更有效。
We examined the feasibility of using adeno-associated virus (AAV)-mediated systemic delivery of endostatin in gene therapy to treat. metastasis of pancreatic cancer. We established an animal model of orthotopic metastatic pancreatic cancer in which the pancreatic cancer cell line PGHAM-1 was inoculated into the pancreas of Syrian golden hamsters. Transplanted cells proliferated rapidly and metastasized to the liver. An AAV vector expressing endostatin (5 x 10(10) particles) was injected intramuscularly into the left quadriceps or intravenously into the portal vein. These routes of vector administration were evaluated by comparing various parameters of tumor development. Intramuscular injection of the vector modestly increased the serum endostatin level. The numbers of metastases and the incidence of hemorrhagic ascites were decreased in the treated animals. In contrast, the serum concentration of endostatin was significantly increased after intraportal injection of the vector. The antitumor effects on all parameters (including the size and microvessel density of primary pancreatic tumors, the sizes and number of liver metastases, and the incidence of hemorrhagic ascites) were significant. These results suggest that systemic delivery of endostatin represents a potentially effective treatment for pancreatic cancer and liver metastases. The route of vector administration influences the efficacy of AAV-mediated endostatin expression. Intraportal injection of the AAV vector appears to tie more effective as an antiangiogenic gene therapy for pancreatic cancer.