Gene therapy for metastatic colon cancer in the liver by using CEA promoter

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As a first step, we established a liver metastasis model of human cancer cell line in nude mice. 1 x 10E6 of cancer cells were intrasplenically inoculated in nude mice. As we could not establish a liver metastasis model of colon cancer cell line, pancreatic cancer cell line was used as a substitute for the model.Subsequently, we constructed replication-deficient recombinant N116Y adenoviruses driven by the cytomegalovirus (CMV) promoter (Ad CMV-N116Y) and the carcinoembryonic antigen (CEA) promoter (Ad CEA-N116Y). A dominant negative H-ras mutant, N116Y, was derived from the v-H-ras oncogene by substituting asparagine with tyrosine at codon 116, which is in the GTP-binding domain. As a control vector, we constructed a beta-galactosidase (LacZ) expressing adenovirus vector driven by the CEA promoter (Ad CEA-LacZ).We examined the effect of Ad CEA-N116Y on the metastatic growth of cancer colonies in liver. Ad CEA-N116Y effectively reduced the number of metastatic colonies without any complication by injecting intrasplenically 5 days after tumor cell inoculation. The result of Ad CEA-LacZ injected mice showed that only cancer cells in liver were positively stained while the liver cells were negative. Thus, N116Y can selectively suppress the metastatic growth of human tumor cell by using the CEA promoter-driven adenovirus vector indicating that N116Y gene therapy may be potentially useful for the treatment of cancer patients with liver metastasis.