Characterization of ras oncogene functions in human cancer using ribozyme-mediated specific gene modulation

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The ras oncogene, especially activated K-ras gene, is thought to play an important role in progression of human cancer. For specific gene modulation, we designed an anti-K-ras ribozyme (anti-K-ras Rz) against activated K-ras mRNA (codon 12, GGT to GTT) and generated a recombinant adenovirus to express the ribozyme (rAd/anti-K-ras Rz). The virus, rAd/anti-K-ras Rz, significantly suppressed activated K-ras gene expression, and inhibited growth of human pancreatic carcinoma cells associated with apoptosis and decreased bcl-2 expression. Also, in a mice model system, rAd/anti-K-ras Rz reversed the malignant phenotype in human pancreatic tumors with K-ras gene mutation. The results indicated that the rAd/anti-K-ras Rz specifically down-regulated the K-ras/bcl-2 pathway, and induced apoptotic changes in pancreatic cancer. Anti-K-ras Rz inhibited not only in vitro cell growth of human colon cancer, but also in vivo tumor growth in mice. Anti-K-ras Rz suppressed VEGF gene expression, and enhanced TSP1 gene expression. The results suggested that the ribozyme-mediated inactivation of the activated K-ras mRNA induced growth suppression, apoptosis and alteration of angiogenic factor expression.