Survivin and Granzyme B-induced apoptosis, a novel anticancer therapy.
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.
Center for Childhood Cancer, Columbus Children's Research Institute, Room WA5021, 700 Children's Drive, Columbus, OH 43205, USA.
Hugo
H
Caldas
Florinda O
FO
Jaynes
Michael W
MW
Boyer
Sue
S
Hammond
Rachel A
RA
Altura
D000818:Animals; D017209:Apoptosis; D019677:Artificial Gene Fusion; D002277:Carcinoma / Q000188:drug therapy / Q000556:secondary / Q000628:therapy*; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D005260:Female; D015316:Genetic Therapy; D053804:Granzymes; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D017239:Paclitaxel / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D012697:Serine Endopeptidases / Q000235:genetics*; D000077022:Survivin; D014162:Transfection
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; D017239:Paclitaxel