Antiangiogenesis gene armed tumor‐targeting adenovirus yields multiple antitumor activities in human HCC xenografts in nude mice

Abstract

Gene therapy represents a promising therapeutic strategy for hepatocellular carcinoma (HCC). To improve the ratio of killing efficacy on tumor cells to side-effect on normal cells, we constructed an oncolytic adenovirus vector, AdSu-hE, expressing the human endostatin (hE) gene, in which the chimeric promoter of human epidermal growth factor receptor 2 enhancer and human telomerase reverse transcriptase promoter was used to control the adenoviral E1a gene. Tumor-selective replication of adenovirus AdSu-hE and its concomitant expression of endostatin were measured by 50% tissue culture infective dose method, fluorescent protein expression, Western blot and enzyme linked immunosorbent assay in cancer and normal cell lines. The antitumor efficacy was observed in nude mice bearing human HCCs. The oncolytic adenovirus AdSu-hE replicated restrictedly in telomerase-positive cancer cells and resulted in oncolysis, but did not replicate in normal cell lines. Along with virus replication, AdSu-hE mediated 5-fold increased expression of endostatin in tumor cells compared with that in normal cells. Moreover, AdSu-hE expressed more endostatin in cancer cells than the non-replicative adenovirus vector Ad-hE. In vivo administration of the oncolytic adenovirus AdSu-hE into HCC-bearing nude mice produced a significant tumor reduction by synergistic effects of virus oncolysis and endostatin antiangiogenesis. The oncolytic virus with antiangiogenesis gene driven by the chimeric promoter has an improved killing efficacy on tumor cells, and may be useful for cancer gene therapy.