c‐erbB‐2 anti‐sense phosphorothioate oligodeoxynucleotides inhibit growth and serum‐induced cell spreading of p185c‐erbB‐2‐overexpressing ovarian carcinoma cells

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Abstract
Overexpression of the c‐erbB‐2 proto‐oncogene product (p185c‐erbB‐2) occurs frequently ihd 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. p185c‐erbB‐2 levels were specifically reduced by a single‐dose application of 5 μM 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 p185c‐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 p 185c‐erbB‐2 in ovarian cancer cells. Thus, anti‐sense strategies have the potential of providing new strategies for the therapy of ovarian cancer.