Point mutations in the K-ras gene are observed at a high incidence in human pancreatic carcinomas. These alterations can be used as potential targets for specific ribozyme-mediated reversal of the malignant phenotype. We designed an anti-K-ras ribozyme against codon 12 of the mutant K-ras gene transcripts (GGT↷GTT), and generated a recombinant adenovirus to express the ribozyme (rAd/anti-K-ras Rz). We inoculated Capan-1 human pancreatic carcinoma cells in athymic mice, and made Capan-1 tumor xenografts. When the Capan-1 tumors in athymic mice became approximately 100 mm3, rAd/anti-K-ras Rz was directly injected into the tumor xenografts. Fifteen (68%) of 22 tumors injected with rAd/anti-K-ras Rz showed tumor growth suppression or tumor regression; 6 of 15 tumors were completely regressive, and 1 tumor was recurrent after the tumor regression. By using the recombinant adenovirus in a mice model system, it was possible to accomplish efficient reversion of the malignant phenotype in human pancreatic tumors with K-ras gene mutation.

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