Targeting Of Chemotherapy To Tie-2-Receptor Positive Angiogenic Endothelial Cells Of Tumor Vasculature

Abstract Abstract #902 Background: There are at least three types of cells in tumor tissue which express the Tie2 receptor (Tie2R): dividing vascular endothelial cells (TVECs), Tie2R-expressing monocytes (TEMs) and Tie2R-expressing mesenchymal progenitor cells (TMPCs).
 
 We tested if the targeting of chemotherapy to these classes of Tie2R positive cells could suppress tumor cell growth.
 Material and Methods: We constructed replication incompetent adenoviral vectors carrying the cytosine deaminase (CD) suicide gene driven by the mouse Tie2R transcriptional promoter and enhancer sequences. In these viruses, we inserted an RGD-4C peptide into the HI loop of the fiber knob domain of the vector to increase its transduction efficiency in TVECs. At the same time, we added two mutations (S408E and P409A) in the AB loop of the fiber, which ablated the CAR-binding ability of the vector. The resulting vector was named AdTie2RCD(MRGD).
 Results: In vitro viral infection assays involving the human umbilical vein endothelial cells (HUVECs) showed that the RGD-modified vectors have a higher transduction efficiency as compared with their adenoviral vector counterparts which have a wild type fiber protein. Mice carrying the rat Her-2-Neu positive N202 mouse breast cancer cells and the mouse B16 melanoma cells were treated with intravenous injections of Hetastarch and the AdTie2RCD(MRGD) vector followed by intraperitoneal injections of 5-Fluorocytosine (5-FC). The Hetastarch was given before the intraveinous infusion of the adenoviral vector in order to reduce the uptake of the adenoviral vector by the reticuloendothelial cell system. The Tie2R targeted chemotherapy sensitization vectors induced greater degrees of suppression of tumor cell growth than did the control group, achieved the similar treatment effect to its CMV promoter counterpart, but with less side effect.
 
 Histological analysis showed that these vectors specifically targeted the TVECs, TEMs and TMPCs through which they may have exerted cytotoxic effects in the presence of 5-FC on the tumor cells.
 Discussion: Our results showed that N202 breast cancer cell line is more responsive to the Tie2R-targeting therapy compared to B16 mouse melanoma cell line and the Tie2R-directed anti-angiogenic therapy deserves further study, in combination with other types of therapy to pave the way for future clinic trails. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 902.