Blood outgrowth endothelial cell-based systemic delivery of antiangiogenic gene therapy for solid tumors.
Endothelial cells and endothelial cell precursors encoding a therapeutic gene have induced antitumor responses in preclinical models. Culture of peripheral blood provides a rich supply of autologous, highly proliferative endothelial cells, also referred to as blood outgrowth endothelial cells (BOECs). The aim of this study was to evaluate a novel antiangiogenic strategy using BOECs expressing fms-like tyrosine kinase-1 (sFlt1) and/or angiostatin-endostatin (AE) fusion protein. Conditioned medium from BOECs expressing sFlt1 or AE suppressed in vitro growth of pulmonary vein endothelial cells by 70% compared with conditioned medium from non-transduced BOEC controls. Reverse transcriptase-PCR analysis indicated that systemically administered BOECs proliferated in tumor tissue relative to other organs in C3(1)SV40 TAG transgenic (C3TAG) mice with spontaneous mammary tumors. Tumor volume was reduced by half in C3TAG mice and in mice bearing established lung or pancreatic tumors in response to the treatment with sFlt1-BOECs, AE-BOECs or their combination. Studies of tumor vascular density confirmed that angiogenic inhibition contributed to slowed tumor growth. In an orthotopic model of glioma, the median survival of mice treated with sFlt1-BOECs was double that of mice receiving no BOEC treatment (P=0.0130). These results indicate that further research is warranted to develop BOECs for clinical application.
Bodempudi
V
V
Division of Hematology, Oncology and Transplantation, Vascular Biology Center and Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
Ohlfest
J R
JR
Terai
K
K
Zamora
E A
EA
Vogel
R I
RI
Gupta
K
K
Hebbel
R P
RP
Dudek
A Z
AZ
D020533:Angiogenesis Inhibitors / Q000235:genetics*; D043168:Angiostatins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001773:Blood Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D043169:Endostatins / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000098:blood supply / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000628:therapy*; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy; D010641:Phenotype
D020533:Angiogenesis Inhibitors; D043169:Endostatins; D043168:Angiostatins