Enhanced antitumor effect of EGF R-targeted p21WAF-1 and GM-CSF gene transfer in the established murine hepatoma by peritumoral injection

Abstract

One of the major obstacles in current cancer gene therapy is the lack of a gene delivery system with high efficiency and targetability. In this paper, a nonviral gene delivery system GE7, which was designed to target EGF receptor (EGF R) overexpressed on the surface of cancer cells through an EGF R-binding oligopeptide (GE7), was used for in vivo gene therapy in a murine subcutaneous hepatoma model. It was demonstrated that the GE7 system could target the reporter gene Β-gal to EGF R-expressing hepatoma cells with high efficiency after in vitro transfection and in vivo peritumoral injection. To improve the therapeutic effect elicited by single gene transfer, human cyclin-dependent kinase inhibitor gene p21WAF-1 and murine cytokine gene GM-CSF were used simultaneously in peritumoral injection of the GE7/DNA polyplex. The results showed that combined gene transfer of p21 WAF-1 and GM-CSF could inhibit the growth of pre-established tumor more effectively and prolong the survival time of hepatoma-bearing mice more significantly than the transfer of a single gene. Apoptosis in the tumor tissues were found when injected with the p21WAF-1 DNA polyplex. Prominent inflammatory infiltration was observed in the tumor tissue transfected with the GM-CSF DNA polyplex. Our data demonstrate that the GE7 system-mediated, EGF R-targeted cotransfer of p21 WAF-1 and GM-CSF genes exhibit more potent antitumor effect by inducing tumor cell apoptosis and inflammatory responses.