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A Fiber-Modified, Secretory Leukoprotease Inhibitor Promoter-Based Conditionally Replicating Adenovirus for Treatment of Ovarian Cancer

¹ Division of Human Gene Therapy, Departments of Medicine, Surgery, and Pathology and Gene Therapy Center, ² Departments of Pathology, Cell Biology, and Surgery and Gene Therapy Center, and ³ Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, Alabama; ⁴ Department of Obstetrics and Gynecology, University of Düsseldorf Medical Center, Düsseldorf, Germany; ⁵ Department of Obstetrics and Gynecology, Rhine-Westphalian Technical University, Aachen, Germany; ⁶ Department of Dermatology, University of Erlangen-Nürnberg, Erlangen, Germany; and ⁷ Rational Drug Design Program, University of Helsinki and Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland

Requests for reprints: David T. Curiel, Division of Human Gene Therapy, Gene Therapy Center, 901 19th Street South, BMR2-508, University of Alabama at Birmingham, Birmingham, AL 35294-2172. Phone: 205-934-8627; Fax: 205-975-2961; E-mail: david.curiel{at}ccc.uab.edu.

Purpose: The use of conditionally replicating adenoviruses (CRAD) is dependent on molecular differences between tumor cells and nontumor cells. Transcriptional targeting of CRAD replication via tumor-specific promoters is an effective way to control replication regulation. Genetic fiber pseudotyping is an approach for circumventing low expression of the primary adenovirus serotype 5 (Ad5) receptor by using the distinct adenovirus serotype 3 (Ad3) receptor for entry into and subsequent killing of ovarian cancer cells.

Experimental Design: In this study, we constructed a fiber-modified CRAD containing the secretory leukoprotease inhibitor (SLPI) promoter to control viral replication via the E1A gene (Ad5/3SLPI). To evaluate the liver toxicity of chimeric 5/3 fiber-modified CRADs, we compared Ad5/3SLPI with Ad5/3Cox-2L, a CRAD with E1A under control of the Cox-2 promoter, and Ad5/324, a CRAD that replicates in cancer cells inactive in the retinoblastoma/p16 pathway by use of an in vivo hepatotoxicity model and by a model system that uses slices of human liver.

Results: We show efficient viral replication and oncolysis of Ad5/3SLPI in both multiple ovarian cancer cell lines and primary tumor cell spheroids as well as therapeutic efficacy in an orthotopic mouse model of peritoneal carcinomatosis. Ad5/3SLPI showed significantly decreased liver toxicity compared with other 5/3 fiber-modified control vectors examined.

Conclusions: In summary, Ad5/3SLPI is a promising vector candidate for treating metastatic ovarian cancer and showed robust virus replication, oncolysis, and in vivo therapeutic efficacy. Ad5/3SLPI showed comparatively low liver toxicity and therefore holds potential for patient use in the clinic.

Key Words: ovarian cancer • SLPI • adenovirus • liver toxicity • promoter

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