title: Reversal of HER-2 over-expression renders human ovarian cancer cells highly resistant to taxol.
abstract: Currently, the treatment options for advanced ovarian cancer are limited. Thus, the majority of the patients are treated with drugs with considerable side effects but in many cases without clinical benefit. The relationship between activation of an oncogene like the HER-2 receptor and drug sensitivity, is of considerable interest as this molecular marker may allow to better predict response to chemotherapy. The aim of this study was to evaluate whether over-expression of the HER-2 receptor would modulate drug responsiveness to doxorubicin, cisplatin and taxol in ovarian cancer cells. An anti-HER-2-targeted ribozyme approach was used to abrogate HER-2 expression in human SK-OV-3 ovarian cancer cells. SK-OV-3 cells expressing very low residual levels of HER-2 protein, were then assessed for their sensitivity to doxorubicin, cisplatin and taxol and compared to control cells. HER-2 expression had no effect on the cytotoxicity of doxorubicin (IC50=10 nM) or cisplatin (IC50=5 microM) in proliferation assays. In contrast, the sensitivity to taxol was increased approximately 70-fold in SK-OV-3 ovarian cancer cells expressing high levels of HER-2 (IC50=10(-5) nM) compared to HER-2 depleted cells (IC50=7x10(-4) nM). If these findings can be confirmed in patients, it could be possible that HER-2 expression may serve as a marker for response to taxol treatment in ovarian cancer patients.
authors.affiliation: Department of Pharmacology and Toxicology, Philipps University, Forschungseinrichtungen, Karl-von-Frisch-Str. 1, 35033 Medizinische, Marburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Aigner
authors.forename: S S
authors.initials: SS
authors.lastname: Hsieh
authors.forename: C
authors.initials: C
authors.lastname: Malerczyk
authors.forename: F
authors.initials: F
authors.lastname: Czubayko
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D000970:Antineoplastic Agents / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D010957:Plasmids; D016337:RNA, Catalytic / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002945:Cisplatin; D004317:Doxorubicin; D017239:Paclitaxel; D016337:RNA, Catalytic; D018719:Erb-b2 Receptor Tyrosine Kinases