Ribozyme against mutant K-ras mRNA suppresses tumor growth of pancreatic cancer.
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 right curved arrow 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 mm(3), 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.
Kijima
Hiroshi
H
Department of Pathology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan. hkijima@is.icc.u-tokai.ac.jp
Yamazaki
Hitoshi
H
Nakamura
Masato
M
Scanlon
Kevin J
KJ
Osamura
R Yoshiyuki
RY
Ueyama
Yoshito
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D003062:Codon; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009154:Mutation; D009368:Neoplasm Transplantation; D009690:Nucleic Acid Conformation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000628:therapy; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D016337:RNA, Catalytic / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D013997:Time Factors
D003062:Codon; D016337:RNA, Catalytic; D012333:RNA, Messenger