Specifically targeted killing of carcinoembryonic antigen (CEA)-expressingcells by a retroviral vector displaying single-chain variable fragmented antibody to CEA and carrying the gene for inducible nitric oxide synthase

The generation of retroviral vectors that infect specific cell types throug h recognition of cell surface antigens is a promising and effective approac h to targeted gene therapy of cancer. Carcinoembryonic antigen (CEA), a hig hly characterized, cell surface glycoprotein overexpressed by various tumor cells, provides a specific tool for tumor tissue-specific targeting by ret roviral vectors. The conventional suicidal gene delivery systems need addit ional drugs other than their gene products. The inducible nitric oxide synt hase (iNOS) gene product yields nitric oxide (NO), which directly induces a utocytotoxicity and cytolysis of bystander cells. In the present study, we have developed a novel bifunctional Moloney murine leukemia virus-based rec ombinant retroviral vector that displays a chimeric envelope protein contai ning a single-chain variable fragmented (scFv) antibody to CEA and carries the iNOS gene in the genome. The resultant bifunctional retroviral vector s howed a specific delivery of the iNOS gene to human CEA-expressing carcinom a cells, resulting in the direct and efficient killing of CEA-expressing ca rcinoma cells by induction of apoptosis. This is the first report of succes sful killing of CEA-expressing cells by specific targeting of the iNOS gene . This approach may offer a one-step procedure for effective gene therapy o f CEA-expressing tumors.