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

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 15591368
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Osaka Medical College
• Principal Investigator: SHIBATA Masa-aki Osaka Medical College, Faculty of Medicine, Associate Professor, 医学部, 助教授 (10319543)
• Co-Investigator(Kenkyū-buntansha): MORIMOTO Junji Osaka Medical College, Faulty of Medicine, Assistant Professor, 医学部, 講師 (90145889) ; OTSUKI Yoshinori Osaka Medical College, Faulty of Medicine, Assistant Professor, 医学部, 教授 (50140166)
• Project Period (FY): 2003 – 2004
• Keywords: Angiogenesis / Endostatin / Angiostatin / Mammary carcinoma / Cancer gene therapy / Electrogene transfer / Mouse / Human umbilical vascular endothelial cell

Research Abstract

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.