Clinical research of gene therapy against digestive tract cancers by using ras suppressor mutant.

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Our previous studies demonstrated that introduction of a dominant negative H-ras mutant, N116Y,inhibits the growth of various types of cancer cells in vitro. In this study, we testedthe efficacy of N116Y in blocking the growth of human pancreatic and esophageal cancer cells using viral vectors.We transfected an retrovirus-expression vector of N116Y,pZIP-NI16Y,into eight human pancreatic cancer cell lines with K-ras mutations. The growth of the pancreatic cancer cell lines was strongly inhibited, and the N116Y-expressing clones became less spread and lost their anchorage-independent growth ability. Furthermore, they were non-tumorigenic in vivo. Infection with Nl16Y adenovirus (AdCMV-N116Y) inhibitedthe in vitro growth of all esophageal cancer cell lines studied. In the AdCMV-N116Y virus-infected cells, progression into S phase was clearly blocked, and did not show the activation of Erk2 after EGF stimulation. Most importantly, direct injection of AdCMV-N116Y into the esophageal tumors in nude mice suppressed their growth significantly.These observations suggest that N116Y suppresses growth of human pancreatic and esophageal cancer cells in vitro and in vivo through the inhibition of Erk2 activation, and that N116Y is a potential candidate gene for gene therapy against human pancreatic and esophageal cancers.