A novel and effective hepatocyte growth factor kringle 1 domain and p53 cocktail viral gene therapy for the treatment of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, yet effective therapeutic options for advanced HCC are limited. Kringle 1 domain of HGF (HGFK1) has been demonstrated as a potent anti-tumor molecule and p53 is a well established tumor suppressor. Recently we developed AAV transducing HGFK1 (AAV-HGFK1) as a gene therapy for HCC. Here we investigated the possibility of enhancing the effect of AAV-HGFK1 by combining it with Adv transducing p53 (Adv-p53). In vitro expression experiments suggested a small amount of Adv-p53 could increase the expression of AAV transgenes. AAV-HGFK1 + Adv-p53 cocktail strongly inhibited the proliferation of microvascular endothelial cell (MEC) and two HCC cell lines, Hepa1-6 and McA-RH7777. In two orthotopic mice and rat HCC models the cocktail gene therapy also significantly reduced the tumor burdens and prolonged the survival time by inhibiting tumor angiogenesis and inducing tumor cell death. Significantly, tumor metastasis was completely prevented. AAV-HGFK1 + Adv-p53 viral cocktail may be a promising cancer therapy for the treatment of HCC. © 2008 Elsevier Ireland Ltd. All rights reserved.