Oral antisense that targets protein kinase A cooperates with taxol and inhibits tumor growth, angiogenesis, and growth factor production

Protein kinase A type I (PKAI) transduces mitogenic signals from different growth factors and oncogenes and is overexpressed in the majority of human cancers. We and other investigators previously have reported that different PKAI inhibitors, including antisense oligonucleotides, have antitumor acti vity, In this study, we used a novel hybrid DNA/RNA mixed-backbone oligonuc leotide (MBO) targeting the PKAI subunit RI alpha, We demonstrated that aft er oral administration, the MBO antisense RI alpha inhibited the growth of human colon cancer xenografts in nude mice and showed a cooperative antitum or effect with Taxol, which outlasted treatment withdrawal and significantl y prolonged survival of mice compared with untreated controls or to single- agent-treated mice. Immunohistochemical analysis of tumor specimens showed inhibition of target protein RIa and of growth factor expression along with a marked inhibition of angiogenesis and an increase in p27 expression. In conclusion, a novel MBO that targets PKAI, administered p.o., is effective and cooperates with the anticancer drug Taxol on both tumor growth and expr ession of factors involved in the control of cell proliferation, cell cycle , and angiogenesis. Because the MBO described has completed a phase I trial involving i.v. injection in cancer patients, these results provide the bio logical rationale of its activity after oral administration and may be tran slated into a therapeutic strategy in a clinical setting.