Preclinical p202 Gene Therapy Studies

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Our first attempt to test the therapeutic value of p202 as an antitumor agent in breast cancer was conducted ex vivo. We showed that transfection of p202/PEI

(polyethylenimine) complex into MCF-7 cells greatly inhibited tumor growth as compared with PEI alone in estrogen-supplemented nude mice (74). Based on this encouraging result, we then developed a systemic delivery system that would allow delivery of p202 gene through intravenous (iv) injection to the primary and metastasized tumor sites. To this end, we undertook two approaches and compared the efficacy of systemic p202 gene therapy treatment using either a p202-expressing recombinant adenovirus (Ad-p202) or CMV-p202/SN2 liposome complex in an orthotopic MDA-MB-468 breast cancer xenograft model. CMV-p202 is a p202 expression vector driven by a cytomegalovirus (CMV) promoter. SN2 liposome formulation has been tested and shown to be an efficient gene delivery system in systemic gene therapy models (47). The tumor growth was significantly reduced in both Ad-p202 and CMV-p202/SN2 treatment groups (79), (Wen and Hung, unpublished data). These results strongly suggest the feasibility of a systemic p202-based gene therapy treatment for breast cancer.

In addition, upon examining the tumor treated with Ad-p202 or CMV-p202/SN2 by immunohistochemical assays, we found that the p202 protein levels correlates well with the extent of apoptosis in tumors in both models as determined by TUNEL (TdT [terminal deoxynucleotidyl transferase]-mediated dUTP nick end labeling) assay that stains the ends of DNA fragments. This observation is in agreement with our in vitro data that show Ad-p202 infection induces apoptosis (79). Thus, the p202-induced apoptosis contributes to the overall antitumor activities in vivo. Furthermore, we observed the levels of an angiogenic factor, vascular endothelial growth factor (VEGF), were significantly reduced in breast tumors treated with either CMV-p202/SN2 or Ad-p202 as compared with that of the control treatments. This observation is also consistent to our previous finding that angiogenesis was reduced in p202-treated pancreatic tumors (76). Together, our data strongly suggest p202 is a potent therapeutic agent suitable for breast cancer therapy.

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