The regulatory sequences of the secretory leukoprotease inhibitor gene as a tissue-specific promoter for gene therapy of ovarian carcinoma.

摘要

Adenoviruses allow efficient infection of dividing and nondividing cells, and their safety for the treatment of cancer has been established in clinical trials. However, one disadvantage is their promiscuous tropism. In this regard, tissue-specific promoters (TSP) could be useful for directing transgene expression to target tissues and for reducing adverse effects in nontarget tissues. It was hypothesized that selective adenovirus-mediated transgene expression in ovarian carcinoma may be achieved through the use of the promoter of the secretory leukoprotease inhibitor (SLPI) gene, which is expressed in ovarian cancer cells. For this purpose, adenoviruses containing the SLPI promoter driving reporter and suicide gene expression were constructed and tested in ovarian cancer cell lines and primary ovarian tumor cells isolated from patients. The SLPI promoter retained its fidelity in an adenoviral vector context and was activated in both cell lines and primary cancer cells. To evaluate the in vivo activation of the SLPI promoter in comparison to a ubiquitously activated promoter, intraperitoneal (i.p.) delivery was performed in tumor-bearing mice, followed by analysis of gene expression in normal organs and tumor. The SLPI promoter was induced to a high degree in ovarian cancer cells while showing significantly reduced activity in normal issues. The therapeutic efficacy of SLPI promoter-controlled gene expression was similar to the ubiquitously activated promoter in vitro and in an orthotopic murine model of peritoneally disseminated ovarian cancer, with higher activity than controls. Thus, it was demonstrated that the SLPI promoter is a potentially useful TSP for ovarian cancer and facilitates further development of targeting strategies for improved gene therapy of ovarian carcinomas.