1019. Enhanced Therapeutic Effects of Recombinant Adenovirus Ad-AFP|[Delta]|19, Selectively Replicating in |[alpha]|-Fetoprotein-Producing Human Liver Cancer Cells

Alfa-feto protein (AFP) protein is expressed in 70-80% of patients with hepatocellular carcinomas but not in normal adult tissues. In this study, we evaluated the liver cancer-specific oncolytic potential of E1B 19kDa-deleted replicating adenoviruses, Ad-hAFP|[Delta]|19 and Ad-rAFP|[Delta]|19, which express E1A gene controlled by human AFP promoter and rat AFP promoter, respectively. Transient transfection study using luciferase indicated the selective activation of the AFP promoter only in human liver cancer cells secreting AFP. Next, we evaluated in vitro efficacy and specificity by comparing viral replication and cytopathic effect in AFP-positive (Huh7, HepG2, and Hep3B), AFP-negative (HeLa, A549, U343, and SK-Hep1) cancer cells and normal (BJ, Chang, IMR90) cells. Our results show that the viral replication and cytopathic effects of Ad-hAFP|[Delta]|19 and Ad-rAFP|[Delta]|19 were substantially lower in AFP-negative cancer and normal cells compared to that of AFP-positive cancer cells. Ad-hAFP|[Delta]|19 and Ad-rAFP|[Delta]|19 also replicated in and cytolyzed the AFP-positive cancer cells in a dose-dependent manner. More importantly, Ad-hAFP|[Delta]|19 and Ad-rAFP|[Delta]|19 significantly inhibited the growth of established human hepatocellular carcinoma tumors. Taken together, these lines of evidence demonstrate that Ad-hAFP|[Delta]|19 and Ad-rAFP|[Delta]|19 hold a significant promise as an oncolytic agent in AFP-positive tumors.