C-ERBB-2 ANTISENSE PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDES INHIBIT GROWTH AND SERUM-INDUCED CELL SPREADING OF P185(C-ERBB-2)-OVEREXPRESSING OVARIAN-CARCINOMA CELLS

Overexpression of the c-erbB-2 proto-oncogene product (p185(c-erbB-2)) occurs frequently in different types of human cancer and is correlated with a significantly decreased survival in ovarian cancer patients. The effect of c-erbB-2 anti-sense phosphorothioate oligodeoxynucleotides (S-ODNs) was examined on the ovarian cancer cell line SK-OV-3. p185(c-erbB-2) levels were specifically reduced by a single-dose application of 5 mu M c-erbB-2 anti-sense S-ODNs. This was accompanied by a 60% inhibition of anchorage-dependent cell growth. More strikingly, c-erbB-2 anti-sense S-ODNs almost completely abrogated serum-induced cell spreading. A control of complementary sense oligodeoxynucleotides did not show significant inhibitory effects on cell growth or on cell spreading. The inhibition of cell spreading was imitated by a monoclonal antibody (9G6) targeting the extracellular domain of p185(c-erbB-2) and by the tyrosine kinase inhibitor erbstatin. The inhibitory activity of these 2 compounds was lost after a few hours, while the inhibition of serum-induced cell spreading by anti-sense S-ODNs was still present after 24 hr. Our results show that c-erbB-2 anti-sense S-ODNs effectively inhibit the mitogenic and spreading activity of p185(c-erbB-2) in ovarian cancer cells. Thus, anti-sense strategies have the potential of providing new strategies for the therapy of ovarian cancer. (C) 1995 Wiley-Liss, Inc.