Reversal of HER-2 over-expression renders human ovarian cancer cells highly resistant to taxol

Currently, the treatment options for advanced ovarian cancer are limited. T hus, the majority of the patients are treated with drugs with considerable side effects but in many cases without clinical benefit. The relationship b etween activation of an oncogene like the HER-2 receptor and drug sensitivi ty, is of considerable interest as this molecular marker may allow to bette r predict response to chemotherapy. The aim of this study was to evaluate w hether over-expression of the HER-2 receptor would modulate drug responsive ness to doxorubicin, cisplatin and taxol in ovarian cancer cells. An anti-H ER-2-targeted ribozyme approach was used to abrogate HER-2 expression in hu man SK-OV-3 ovarian cancer cells. SK-OV-3 cells expressing very low residua l levels of HER-2 protein, were then assessed for their sensitivity to doxo rubicin, cisplatin and taxol and compared to control cells. HER-2 expressio n had no effect on the cytotoxicity of doxorubicin (IC50 = 10 nM) or cispla tin (IC50 = 5 mu M) in proliferation assays. In contrast. the sensitivity t o taxol was increased approximate to 70-fold in SK-OV-3 ovarian cancer cell s expressing high levels of HER-2 (IC50 = 10(-5) nM) compared to HER-2 depl eted cells (IC50 = 7 x 10(-4) nM). If these findings can be confirmed in pa tients, it could be possible that HER-2 expression may serve as a marker Fo r response to taxol treatment in ovarian cancer patients. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.