A fiber-modified, secretory leukoprotease inhibitor promoter-based conditionally replicating adenovirus for treatment of ovarian cancer

Daniel T Rein, Martina Breidenbach, Tyler O Kirby, Tie Han, Gene P Siegal, Gerd J Bauerschmitz, Minghui Wang, Dirk M Nettelbeck, Yuko Tsuruta, Masato Yamamoto, Peter Dall, Akseli Hemminki, David T Curiel
Clinical Cancer Research 2005 February 1, 11 (3): 1327-35

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 Ad5/3Delta24, 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.

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