This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Caldas, H. Articles by Altura, R. A. Search for Related Content PubMed PubMed Citation Articles by Caldas, H. Articles by Altura, R. A.

¹ Center for Childhood Cancer and ² Center of Biopathology, Columbus Children's Research Institute; ³ Department of Pediatrics, College of Medicine and Public Health, The Ohio State University; and ⁴ Department of Laboratory Medicine, Columbus Children's Hospital, Columbus, Ohio

Requests for reprints: Rachel A. Altura, Columbus Children's Research Institute, Room WA5021, 700 Children's Drive, Columbus, OH 43205. Phone: 614-355-2671; Fax: 614-722-5895. E-mail: AlturaR{at}ccri.net

Survivin is an antiapoptotic protein highly expressed in malignant cells that confers resistance to cytotoxic therapy. Granzyme B is a potent cytotoxic protein that is released from mammalian natural killer cells and CTLs following noxious stimuli, including foreign invaders. Here, we took advantage of the properties of these two functionally divergent molecules to create a molecular agent that specifically activates Granzyme B within tumor cells. We designed Survivin and Granzyme B–induced apoptosis (SAGA), which consists of a fusion of the Survivin gene promoter to the coding sequence of active Granzyme B. In cultured human tumor cells transfected with SAGA DNA, Granzyme B is rapidly expressed and results in significant tumor cell death. In vivo, mice harboring human ovarian tumors had statistically significant clinical responses to SAGA treatment that were magnified following combination therapy with SAGA and paclitaxel. At the completion of a 3-week therapeutic trial, 3 of 15 animals were free of disease in the SAGA-treated group, and an additional eight animals had tumors that were nonpalpable and only detected on surgical resection. In contrast, 15 of 15 animals in the control and paclitaxel-only–treated groups had tumors at end of therapy. Treatment with SAGA with or without paclitaxel also prevented disease dissemination in 19 of 20 animals. These results strongly suggest that SAGA has the potential to be a potent agent for the treatment of primary and recurrent human ovarian carcinoma. Moreover, we predict that SAGA will be useful therapeutically in any human cancer that expresses Survivin. [Mol Cancer Ther 2006;5(3):693–703]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: This work was presented in part at the 96th Annual Meeting of the American Association for Cancer Research.

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 10/12/05; revised 12/26/05; accepted 1/18/06.