Antisense DNA toward type I protein kinase A produces sustained inhibition of tumor growth.
Expression of the RI alpha subunit of type I cyclic AMP-dependent protein kinase (PKA) is increased in human cancer cell lines, in primary tumors, in cells after transformation, and in cells upon stimulation of growth. The sequence-specific inhibition of RI alpha gene expression by RI alpha antisense oligodeoxynucleotide results in the differentiation of leukemia cells and growth arrest of cancer cells of epithelial origin. A single-injection RI alpha antisense treatment in vivo also results in a reduction in RI alpha expression and inhibition of tumor growth. One injection was sufficient to inhibit tumor growth in mice for 2 weeks. The antisense DNA achieves this long-lasting effect by altering the balance between the production of PKA type I and a competitive molecule, PKA type II. Tumor cells behaved like untransformed cells by making less protein kinase type I. The RI alpha antisense, which produces a biochemical imprint for growth control, requires infrequent dosing to restrain neoplastic growth in vivo.
Cho-Chung
Y S
YS
Cellular Biochemistry Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1750, USA.
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation; D002455:Cell Division; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000235:genetics*; D016373:DNA, Antisense / Q000494:pharmacology*; D004847:Epithelial Cells; D006801:Humans; D007938:Leukemia / Q000473:pathology; D009374:Neoplasms, Experimental / Q000517:prevention & control*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016373:DNA, Antisense; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases