title: Adeno-associated viral vector-mediated expression of endostatin inhibits tumor growth and metastasis in an orthotropic pancreatic cancer model in hamsters.
abstract: 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 be more effective as an antiangiogenic gene therapy for pancreatic cancer.
authors.affiliation: Departments of Biochemistry and Molecular Biology and Surgery for Organ Function and Biological Regulation, Nippon Medical School, Tokyo, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Noro
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyake
authors.forename: Noriko
authors.initials: N
authors.lastname: Suzuki-Miyake
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Igarashi
authors.forename: Eiji
authors.initials: E
authors.lastname: Uchida
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Misawa
authors.forename: Yoji
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimada
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D006224:Cricetinae; D004195:Disease Models, Animal; D043169:Endostatins / Q000096:biosynthesis* / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics; D008647:Mesocricetus; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000821:virology
chemical_list: D043169:Endostatins