Antiangiogenic cancer gene therapy by adeno-associated virus 2-mediated stable expression of the soluble FMS-like tyrosine kinase-1 receptor.
Antiangiogenic gene transfer has the potential to be more efficacious than protein-based therapies or pharmacotherapies for the control of solid tumor growth, invasion and metastasis. For a sustained antiangiogenic effect, a vector capable of long-term expression without vector-associated immunity or toxicity is advantageous. The present study evaluated the potential of a recombinant adeno-associated virus-2 (rAAV) encoding the human soluble FMS-like tyrosine kinase receptor 1 (sFlt-1), which functions by both sequestering vascular endothelial growth factor (VEGF) and forming inactive heterodimers with other membrane-spanning VEGF receptors, in vitro and in vivo. Results indicated significant growth inhibitory activity of the transgenic factor in a human umbilical vein endothelial cell proliferation assay in vitro and protection against the growth of an angiogenesis-dependent human ovarian cancer cell line, SKOV3.ip1, xenograft in vivo with increased disease-free survival. Stable expression of the secretory factor and transgene persistence were confirmed by immunohistochemistry and in situ hybridization analyses, respectively. Increased therapeutic effects on both the growth index of the implanted tumor cells and tumor-free survival also correlated with an increasing dose of the vector used. These studies indicate that rAAV-mediated sFlt-1 gene therapy may be a feasible approach for inhibiting tumor angiogenesis, particularly as an adjuvant/therapy.
Mahendra
Gandham
G
Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Kumar
Sanjay
S
Isayeva
Tatyana
T
Mahasreshti
Parameshwar J
PJ
Curiel
David T
DT
Stockardt
Cecil R
CR
Grizzle
William E
WE
Alapati
Vidya
V
Singh
Raj
R
Siegal
Gene P
GP
Meleth
Sreelatha
S
Ponnazhagan
Selvarangan
S
D020533:Angiogenesis Inhibitors / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation; D000229:Dependovirus / Q000235:genetics*; D018572:Disease-Free Survival; D042783:Endothelial Cells; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D019076:Transgenes; D014183:Transplantation, Heterologous; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis* / Q000235:genetics*
D020533:Angiogenesis Inhibitors; D040281:Vascular Endothelial Growth Factor Receptor-1