Anti-angiogenic Gene Therapy for Retinoblastoma

Abstract

Abstract: : Purpose: Angiogenesis plays a critical role in neoplastic processes and is essential for tumor progression and metastatic spread of solid tumors including retinoblastoma. Vascular endothelial growth factor (VEGF) is the most potent growth factor promoting angiogenesis. In this regard, several studies have shown that either adenovirus or liposome-mediated delivery of soluble FLT-1 (sFLT-1) inhibits the action of VEGF leading to suppression of tumor growth in various cancer models. As well, we have shown therapeutic effect of soluble FLT-1 therapy in ovarian cancer model. We sought to explore the therapeutic potential of sFLT-1 gene therapy in retinoblastoma and hypothesized that adenovirus-mediated sFLT-1 gene therapy inhibits the growth of retinoblastoma tumors. Methods: An E1A/B deleted, infectivity enhanced recombinant adenovirus AdRGDGFPsFLT-1 encoding cDNA for sFLT-1 and green fluorescence protein (GFP) was constructed and validated previously. An adenovirus AdRGDGFP encoding GFP alone was used as control. The therapeutic potential of adenovirus-mediated sFLT-1 to inhibit the growth of retinoblastoma was evaluated by subcutaneous tumor model. The retinoblastoma cells WERI-RB-1 were injected subcutaneously (1x10⁸ cells/nodule) into CB/17 SCID mice and allowed to form tumors. When the tumors have grown to a size of 50-75mm², they are treated intratumorally with two doses of either AdRGDGFPsFLT-1 or control virus AdRGDGFP 0.5x10¹⁰ particles/nodule or PBS on days 42 and 52 post inoculation of cells, and the tumor size was monitored. Results: The intratumoral treatment of AdRGDGFPsFLT-1 significantly decreased the tumor size in mice. Whereas the tumors treated with either AdRGDGFP or PBS continued to grow. The inhibition of angiogenesis in tumors treated with AdRGDGFPsFLT-1 evaluated by immunohistochemistry is higher compared to controls. Conclusions: Our results suggest that adenovirus mediated sFLT-1 gene therapy can effectively inhibit retinoblastoma tumor growth. We conclude that the adenovirus-mediated sFLT-1 gene therapy represents a promising strategy to control retinoblastoma tumor growth.

Keywords: gene transfer/gene therapy • retinoblastoma • tumors