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Proapoptotic and Antitumor Activities of Adenovirus-mediated p202 Gene Transfer¹

Departments of Molecular and Cellular Oncology [Y. D., Y. W., B. S., L. W., W. X., K. Y. K., R. S., Z. L., M-C. H., D-H. Y.], Breast Medical Oncology [G. N. H.], and Surgical Oncology [M-C. H., D-H. Y.]. The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Purpose and Experimental Design: p202, a mouse IFN-inducible protein, is a member of the 200-amino acid repeat family. Enforced p202 expression in stable cancer cell lines resulted in growth inhibition in vitro and tumor suppression in vivo. However, to study the immediate effect of p202 and test the potential efficacy of p202 treatment, an efficient gene delivery system for p202 is required. For these purposes, an adenoviral vector expressing the p202 gene (Ad-p202) was generated. We examined the effects of Ad-p202 infection on human breast cancer cells. Furthermore, we tested the efficacy of Ad-p202 treatment on breast and pancreatic cancer xenograft models.

Results: We found that Ad-p202 infection induces growth inhibition and sensitizes the otherwise resistant cells to tumor necrosis factor -induced apoptosis. In addition, we demonstrated for the first time that Ad-p202 infection induces apoptosis and that activation of caspases is required for the full apoptotic effect. More importantly, we showed the efficacy of Ad-p202 treatment on breast cancer xenograft models, and this antitumor effect correlated well with enhanced apoptosis in Ad-p202-treated tumors.

Conclusions: We conclude that Ad-p202 is a potent growth-inhibitory, proapoptotic, and tumor-suppressing agent. Ad-p202 may be further developed into an efficient therapeutic agent for human cancer gene therapy.

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