961. Angiopoietin-1 Enhances the Effect of Paclitaxel on Breast Cancer Cell Killing in a Mouse Model

Top of pageAbstract Angiogenesis has an important role in tumor growth and metastasis. Various factors, such as VEGFs and angiopoietins, have been implicated in the regulation of vessel formation. Angiopoietins regulate angiogenesis by activating or blocking the activation of Tie2, a surface receptor tyrosine kinase generally restricted to endothelial cells. Angiopoietin-1 (Ang1) promotes endothelial cell survival, helps to maintain vascular integrity and is thus involved in vessel maturation. Conversely, Ang2 acts as an antagonist of the Ang1/ Tie2 interaction. Solid tumors require blood vessels for growth, although tumor neovascularization is structurally and functionally abnormal with leaky and tortuous vessels. These abnormalities contribute to impaired blood supply and interstitial hypertension, which interferes with the delivery of therapeutics to the tumor. Since Ang1 stabilizes blood vessels and inhibits vascular permeability, we hypothesized that normalization of tumor vasculature by Ang1 could improve drug delivery and thereby enhance cancer cell killing. The impact of Ang1 delivered by a non-replicating adenoviral vector (AdAng1) on the anti-tumor effect of paclitaxel was studied in a 4T1 murine breast cancer model. The expression and secretion of Ang1 from 4T1 cells infected by AdAng1 in vitro was first confirmed by immunostaining and immunoblotting. AdAng1 did not affect the growth of 4T1 cells in vitro, as the growth rates of 4T1 cells infected with AdAng1 or control AdCon virus were similar. Paclitaxel did inhibit the growth of 4T1 cells in vitro, but the growth inhibition was similar in control virus and AdAng1 treated cultures. For the in vivo model, 4T1 cells were first treated with either AdAng1, AdCon or PBS, and then injected into the flank of syngeneic BALB/c mice. Paclitaxel was administered by i.p. injection twice a week, starting at day 7. The combination of AdAng1 administration together with Paclitaxel reduced tumor growth compared to Paclitaxel alone, AdAng1 alone or control virus plus Paclitaxel. In summary, this study indicates that Ang1 can enhance the effect of chemotherapy in a breast cancer model. These effects are likely to be related to Ang1-mediated vessel normalization and thereby improved drug delivery to the tumor cells.