ABSTRACT
It has been demonstrated that interleukin 18 (IL-18) exerts antitumor activity. In this study, we investigated whether oncolytic adenovirus-mediated gene transfer of IL-18 could induce strong antitumor activity. A tumor-selective replicating adenovirus expressing IL-18 (ZD55-IL-18) was constructed by insertion of an IL-18 expression cassette into the ZD55 vector, which is based on deletion of the adenoviral E1B 55-kDa gene. ZD55-IL-18 could express substantially more IL-18 than Ad-IL-18 because of replication of the vector. It has been shown that ZD55-IL-18 exerted a strong cytopathic effect and significant apoptosis in renal cell carcinoma. ZD55-IL-18 significantly decreased VEGF and CD34 expression in the tumor cells. Treatment of established tumors with ZD55-IL-18 showed much stronger antitumor activity than that induced by ZD55-EGFP or Ad-IL-18. These data indicated that oncolytic adenovirus expressing IL-18 could exert potential antitumor activity via inhibition of angiogenesis and offer a novel approach to cancer therapy.
Subject(s)
Carcinoma, Renal Cell/therapy , Genetic Therapy/methods , Interleukin-18/genetics , Kidney Neoplasms/therapy , Adenoviridae/genetics , Adenoviridae/physiology , Animals , Carcinoma, Renal Cell/blood supply , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/virology , Cell Line, Tumor , Genetic Vectors/genetics , Humans , In Situ Nick-End Labeling , Interleukin-18/biosynthesis , Kidney Neoplasms/blood supply , Kidney Neoplasms/genetics , Kidney Neoplasms/virology , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/therapy , Oncolytic Virotherapy , Tumor Cells, Cultured , Virus Replication , Xenograft Model Antitumor AssaysABSTRACT
RNA interference (RNAi) has been proved to be a powerful tool for gene knockdown purpose and holds a great promise for the treatment of cancer. Our previous study demonstrated that the reduction of hTERT expression by means of chemically synthesized siRNAs and shRNAs expressed from plasmid resulted in proliferation inhibition in human renal carcinoma cells. In this study, we constructed a novel oncolytic adenovirus-based shRNA expression system, ZD55-hTERT, and to explore ZD55-hTERT-mediated RNAi for hTERT gene silencing. Our results showed that ZD55-hTERT could induce silencing of hTERT gene effectively, allow for efficient tumor-specific viral replication and induce the apoptosis of tumor cells effectively in vitro and in nude mice. We conclude that combining shRNA gene therapy and oncolytic virotherapy can enhance antitumor efficacy as a result of synergism between CRAd oncolysis and shRNA antitumor responses.
