Combination cancer gene therapy in endostatin and suicide gene for metastatic murine mammary cancers

内皮抑素和自杀基因联合治疗转移性小鼠乳腺癌

• 批准号: 15591368
• 负责人: SHIBATA Masa-aki
• 金额: $ 2.37万
• 依托单位: Osaka Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591368/
• 关键词: Angiogenesis; Endostatin; Angiostatin; Mammary carcinoma; Cancer gene therapy; Electrogene transfer; Mouse; Human umbilical vascular endothelial cell; Mammry carcinoma; Elrctrogene transfer

Experimental mammary cancer therapy in mice was conducted with electrogene transfer of a non-viral plasmid vector containing angiostatic genes. In vitro study : HUVECs transfected with endostatin (pEndo), angiostatin (pAngio) and both fusion genes (pEndo:pAngio) were inhibited the tubular formation on Matrigels. In vivo study : Experiment 1. Mammary tumors induced by inoculation of BALB/c mice with BJMC3879 cells were subsequently treated by direct injection of pEndo,pAngio,pEndo:pAngio or control vector once a week for 7 weeks. Significantly reduced tumor volumes were observed for the pEndo or pEndo:pAngio groups in experimental week 1 and thereafter throughout the study. In the pAngio group, reduced tumor volume was only observed in week 7. Experiment 2. Using the same mammary cancer model, combination therapy in pEndo with suicide gene (HSVtk/GCV) was conducted. Tumor volumes were significantly suppressed in the pEndo,pHSVtk/GGCV and the combination groups. In the combination group, the tumor volumes were further suppressed as compared with respective alone treatment groups. In therapeutic groups, metastases to lungs or lymph nodes were also significantly decreased. However, summative or synergistic effects were not observed in the combination group on metastases. Microvessel density within tumor tissues was significantly decreased in the pEndo or the combination groups. Decreased DNA synthesis and elevated apoptosis were also found in all therapeutic groups. in addition, numbers of lymphatic vessels with migrating cancer cells in their lumens were significantly inhibited in pEndo or the combination groups. We therefore conclude that endostatin gene with in vivo electrogene transfer can result in suppression of mammary tumor growth and metastases. In addition, endostatin in combination therapy with HSVtk/GCV further suppressed tumor growth but summative effects were not observed on reduction of metastases.

在小鼠中使用含有血管抑制基因的非病毒质粒载体的乳腺癌治疗进行了实验性乳腺癌治疗。体外研究：用内骨（Pendo），Angiostatin（Pangio）和两个融合基因（Pendo：Pangio）转染的HUVEC被抑制了Matrigels上的管状形成。体内研究：实验1。通过接种BALB/c小鼠，用BJMC3879细胞接种BALB/C小鼠，随后通过直接注射Pendo，Pangio，Pangio，Pendo：Pangio：Pangio或Control Vector每周一次治疗7周。在实验第1周，然后在整个研究中，Pendo或Pendo组的肿瘤体积显着减少。在Pangio组中，仅在第7周观察到肿瘤体积减少。实验2。使用相同的乳腺癌模型，在Pendo中与自杀基因（HSVTK/GCV）进行了联合治疗。 Pendo，PHSVTK/GGCV和组合组中肿瘤体积受到显着抑制。在组合组中，与单独的治疗组相比，肿瘤量进一步抑制。在治疗组中，对肺或淋巴结的转移也显着降低。但是，在转移组的联合组中未观察到汇总或协同作用。 Pendo或组合组的肿瘤组织中的微壳密度显着降低。在所有治疗组中也发现了DNA合成降低和凋亡升高。另外，在彭多或联合组中，淋巴管中具有癌细胞迁移的癌细胞的数量受到显着抑制。因此，我们得出的结论是，具有体内静脉内转移的内接基因可以导致乳腺肿瘤生长和转移酶的抑制。此外，与HSVTK/GCV联合疗法中的内接抑制素进一步抑制了肿瘤的生长，但未观察到对转移减少的总结作用。