Effective and safe gene therapy for colorectal carcinoma using the cytosine deaminase gene directed by the carcinoembryonic antigen promoter

We have recently isolated carcinoembryonic antigen (CEA) promoter regions c onsisting of 419 bp and 204 bp from CEA-producing human colorectal carcinom a (CRC). We constructed CEA419/CD and CEA204/CD retroviruses carrying the b acterial cytosine deaminase (CD) gene directed by the CEA promoter regions, pCD2 retroviruses carrying the CD gene directed by the retrovirus long ter minal repeat promoter were also used. CEA419/CD or CEA204/CD retrovirus-inf ected CRC cells were found to be susceptible to 5-fluorocytosine (5-FC), wh ile non-CRC cells infected with the same retroviruses were not. CD-transduc ed CRC xenografts in nude mice were sensitive to 5 FC treatment, resulting in arrest of tumor growth. When mice with intraperitoneally disseminated CR Cs were given intraperitoneal injections of CEA419/CD retrovirus-producing cells followed by 5-FC treatment, significantly prolong survival rates were observed compared with animals injected with pCD2 retrovirus-producing cel ls followed by 5-FC treatment. importantly, bone marrow suppression was not observed in animals injected with CEA419/CD retrovirus-producing cells and 5-FC, while profound bone marrow suppression was observed in those injecte d with pCD2 retrovirus-producing cells and 5-FC. These results indicate tha t effective and safe in vivo gene therapy for advanced CRC may be feasible by transferring the CD gene controlled by the CEA promoter followed by 5-FC treatment.