Gene therapy utilizing the Cre/loxP system selectively suppresses tumor growth of disseminated carcinoembryonic antigen-producing cancer cells

Recent clinical trials of cancer gene therapy have shown encouraging result s for controlling localized tumors. However, to control metastatic or disse minated tumor cells, further modification of vectors is required to enhance specificity and infectivity against targets. We investigated whether utili zation of the Cre recombinase(Cre)/loxP system contributes to enhanced anti tumor effects together with minimal adverse reactions in specific gene ther apy against disseminated carcinoembryonic antigen (CEA)-producing cancer ce lls in the peritoneal cavity of mice. CEA-producing cancer would be a good therapeutic target because it is found in lung, stomach and colon sites, wh ich account for most cancers. We constructed a pair of recombinant adenovir al vectors (Ads), one of which expresses the Cre gene under the control of the CEA promoter (Ad.CEA-Cre); the other expresses the herpes simplex virus thymidine kinase (HSV-TK) gene (Ad.lox-TK), or the beta -galactosidase gen e (beta -gal) by Cre (Ad.lox-beta -gal). Intraperitoneal coinjection of Ad. CEA-Cre and Ad.lox-beta -gal into mice with peritonitis carcinomatosa by CE A-producing tumor cells showed selective expression of the beta -gal gene i n tumor foci. Coinfection of Ad.CEA-Cre and Ad.lox-TK followed by ganciclov ir (GCV) administration significantly suppressed the total tumor weight in the peritoneal cavity of the mice to 13% of that of the untreated mice and 22% of that of the mice treated with Ad.CEA-TK/GCV, an Ad that expressed th e HSV-TK gene driven by the CEA promoter alone. Moreover, treatment with Ad .CEA-Cre and Ad.lox-TK/GCV completely suppressed tumors in 4 of 10 (40%) mi ce without significant weight loss, although 2 of 10 mice treated with Ad.C AG-TK/GCV, an adenovirus vector that strongly but nonspecifically expressed the TK gene, died due to severe side effects including diarrhea, weight lo ss and liver dysfunction. These findings suggest that cell type-specific ge ne therapy using the Cre/loxP system is effective against disseminated canc er cells without significant side effects. (C) 2001 Wiley-Liss, Inc.