293. Sustained Expression of Kringle 1 Domain of Human Hepatocyte Growth Factor (HGFK1) Effectively Inhibits Angiogenesis, Growth and Metastasis of Hepatocellular Carcinoma

We have previously shown that recombinant protein of kringle 1 domain of human hepatocyte growth factor (HGFK1) exhibits anti- angiogenesis activity. Here we investigated the in vivo therapeutic effect of long term expression of HGFK1 on hepatocellular carcinoma (HCC) using a recombinant adenoassociated virus carrying the HGFK1 gene (rAAV-HGFK1). We first showed that rAAV-HGFK1 infection significantly inhibited the proliferation, and the microvascular tube formation of mice microvascular endothelial cells (MEC), as well as the proliferation of the rat HCC McA-RH7777 cells but not in the non-tumor C9 cells. The in vivo efficacy of rAAV-HGFK1 was then studied in an established orthotopic Buffalo rat model of HCC. HCC was induced by injection of McA-RH7777 cells into the left lobe of the liver. Ten days after tumor cell inoculation, surgeries were performed to confirm the tumor formation, followed by injections of PBS, rAAV-EGFP (1.2|[times]|1012 v.p.) or rAAV-HGFK1 (1.2|[times]|1012 v.p.) directly into the tumor nodule (0.2|[times]|1012 v.p.), and by portal vein (1.0|[times]|1012 v.p.). We showed that rAAV-HGFK1 treatment significantly prolonged the median survival time of the HCC bearing rats from 30 days (PBS and rAAV-EGFP groups) to 49 days (rAAV-HGFK1 group). Importantly, rAAV-HGFK1 inhibited tumor growth and completely prevented liver, lung and peritoneal metastasis. No toxicity was observed when high dosage of rAAV-HGFK1 was administered in C57 mice. Furthermore, rAAV-HGFK1 appears to work by mechanisms differ from that reported for endostatin. In conclusion, this study demonstrated that rAAV-HGFK1 is potentially a promising treatment for HCC and other cancers.