Telomerase-Specific Replication-Selective Virotherapy for Oral Squamous Cell Carcinoma Cell Lines

Abstract

Replication-selective tumor-specific viruses present a novel approach for treating neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis, and its activity is closely correlated with human telomerase reverse transcriptase (hTERT) expression. We investigated the antitumor effect of the hTERT-specific replication-competent adenovirus on oral squamous cell carcinoma (OSCC) cells. An adenovirus 5 vector [tumor- or telomerase-specific replication-competent adenovirus (OBP-301)] was constructed by Center for Gene and Cell Therapy, Okayama University Hospital, in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site, and we examined the selective replication and antitumor effect in human OSCC cells in vitro and in vivo orthotopic graft model. OBP-301 replicated efficiently and induced more over 50% cell killing in a panel of human OSCC cell lines, but not in normal human fibroblasts, which were lacking telomerase activity. In orthotopic graft model, intratumoral injection of OBP-301 resulted in a significant inhibition of tumor growth and prolongation of survival. Furthermore, mice’s weight recovered as same as before bearing OSCC tumors. Our data clearly indicate that OBP-301 displays an acceptable toxicity profile as well as a therapeutic oncolytic activity for OSCC cells in vitro and in vivo. These results suggested that treatment of OBP-301 is possible to improvement of QOL of oral cancer patients.