Gene therapy for hepatocellular carcinoma using two recombinant adenovirusvectors with alpha-fetoprotein promoter and Cre/lox P system

Tissue-specific promoter has been used for cancer-specific suicide gene the rapy, but its transcriptional activity is relatively low. For more efficien t gene therapy of hepatocellular carcinoma, a simultaneous infection method of two recombinant adenoviruses was developed, in which one carried Cre ge ne under the control of a-fetoprotein promoter and the other a potent expre ssion unit activated by Cre. When the vectors with lacZ reporter gene were introduced systematically into mouse models of disseminated tumors, specifi c and enhanced gene expression was observed exclusively in hepatocellular c arcinomas both in the liver and in the lung. Next, using herpes simplex vir us thymidine kinase, the anti-tumor effect was examined. Although in cultur ed cells, 60-300-fold expression of enzymatic activity and enhanced gancicl ovir sensitivity was obtained compared with that of the single recombinant adenovirus directly driven by a-fetoprotein promoter, there was no signific ant anti-tumor effect for subcutaneous tumor on athymic mice. The lack of a nti-tumor effect in mice could be explained by insufficient simultaneous tr ansduction of the two vectors in the tumors, since it was found that a high multiplicity of infection was required to activate this system. Some strat egies to overcome this dose limitation are needed, at least in the case of hepatocellular carcinoma. (C) 2001 Elsevier Science B.V. All rights reserve d.