847. Combined Oncolytic Adenovirus with Double Suicide Gene in Killing Lung Cancer

Abstract

Oncolytic adenoviruses is the use of genetically engineered adenoviruses that specifically target and destroy tumor cells via their cytolytic replication cycle and also may provide a highly efficient means of delivering therapeutic genes to tumor,which combines the advantages of gene therapy and viral therapy. Adenovirus vector Ad5- hTERT -E1Arep (A telomerase gene-derived promoter was used to control the expression of the E1A gene ) was constructed and cytosine deaminase(CD)/herpes simplex type 1 thymidine kinase(HSV-1 TK) fusion gene were inserted into Ad5- hTERT -E1Arep to form Ad5- hTERT -E1Arep -CD/TK. The (5- FC+GCV) produg enhanced the tumor cell-specific cytopathic effects of the Ad5- hTERT -E1Arep -CD/TK against A549 human lung cancer cell.Neither the Ad5- hTERT -E1Arep-CD/TK nor suicide gene system showed significant toxicity to normal human fibroblast or epithelial cells. Furthermore,we demonstrated that the survival of A549 human lung cancer xenografted mice treated with Ad5- hTERT -E1Arep -CD/TK alone was prolonged.Therapeutic outcome was dramatically improved with systemic administration of double prodrug (5-FC+GCV) therapy. These data demonstrate that combination of oncolytic adenoviruses with the (CD+TK)/(5- FC+GCV) suicide gene system resulted in a striking improvement in treatment efficacy.