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Inhibition of Growth of Human Tumor Cell Lines in Nude Mice by an Antisense Oligonucleotide Inhibitor of Protein Kinase C-α Expression
12 auth. N. Dean, R. Mckay, L. Miraglia, R. Howard, S. Cooper, J. Giddings, ...
A 20-mer phosphorothioate oligodeoxynucleotide (ISIS 3521) designed to hybridize sequences in the 3′-untranslated region of human protein kinase C-α (PKC-α) mRNA has been shown to inhibit the expression of PKC-α in multiple human cell lines. In huma…
A 20-mer phosphorothioate oligodeoxynucleotide (ISIS 3521) designed to hybridize sequences in the 3′-untranslated region of human protein kinase C-α (PKC-α) mRNA has been shown to inhibit the expression of PKC-α in multiple human cell lines. In human bladder carcinoma (T-24) cells, inhibition of PKC-α was both concentration dependent and oligo-nucleotide sequence specific. ISIS 3521 had a IC50 of 50–100 nm for PKC-α mRNA reduction and was without effect on the expression of other members of the PKC family of genes (PKC-η and ξ). Toxicity studies in mice revealed that the oligodeoxynucleotide was well tolerated at repeat doses of 100 mg/kg i.v. for up to 14 days, with no acute toxicity apparent. The oligodeoxynucleotide was found to also inhibit the growth of three different human tumor cell lines, the T-24 bladder, human lung carcinoma (A549), and Colo 205 colon carcinoma grown in nude mice. The inhibition was dose dependent with ID50 values for the growth inhibition between 0.06 and 0.6 mg/kg daily when given i.v., depending on the cell line examined. Three control phosphorothioate oligodeoxynucleotides not targeting human PKC-α were without effect on the growth of the tumors at doses as high as 6 mg/kg. Recovery of ISIS 3521 from tumor tissue and resolution by capillary gel electrophoresis revealed that 24 h after the final dose of oligodeoxynucleotide, intact, full-length 20-mer material was present as well as some apparent exonuclease degradation products ( e.g. , n-1 and n-2 mers). These studies demonstrate the in vivo antitumor effects of an antisense oligodeoxynucleotide targeting PKC-α and suggest that this compound may be of value as a chemotherapeutic agent in the treatment of human cancers.
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7
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7 | 1996 |
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