Gene therapy with E2F-1 up-regulates the protein kinase PKR and inhibits growth of leiomyosarcoma in vivo

摘要: Overexpression of the transcription factor E2F-1 induces apoptosis in a variety carcinoma cells and inactivates murine double minute protein 2, associated with poor prognosis soft tissue sarcomas. We have shown previously that double-stranded RNA-activated kinase PKR plays an important role mediating this apoptotic response to E2F-1. sought evaluate potential gene therapy sarcomas study involvement overexpression mesenchymal cells. A replication-deficient adenovirus carrying (Ad5E2F) was used induce p53 mutated leiomyosarcoma cell line, SKLMS-1. Western blot analysis confirmed up-regulation antiapoptotic Bcl-2 48 hours following infection Ad5E2F. Apoptosis Ad5E2F-treated by fluorescence-activated sorting poly(ADP-ribose) polymerase cleavage DNA fragmentation assays. Vector-dependent correlated amount Ad5E2F-induced apoptosis. In vivo treatment SKLMS-1 tumor-bearing BALB/c mice intratumoral injections Ad5E2F at dose 2 x 10(10) viral particles resulted significant inhibition tumor growth compared control-treated animals (P < 0.016). Complete disappearance all tumors seen two seven animals. Immunohistochemical specimens showed tumors. These findings show adenovirus-mediated results suppression leiomyosarcomas vivo. Taken together, these data suggest modulation might be promising strategy for are highly resistant conventional therapies.