1. ¹Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
2. ²Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
3. ³Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
4. ⁴Gene Therapy Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA

Correspondence: Dr Selvarangan Ponnazhagan, PhD, Department of Pathology, LHRB 513, 701, 19th Street South, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA. E-mail: sponnazh@path.uab.edu

Received 13 February 2004; Published online 8 October 2004.

Abstract

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.