Inhibition of transforming growth factor α (TGF-α)-mediated growth effects in ovarian cancer cell lines by a tyrosine kinase inhibitor ZM 252868

• Published in: British journal of cancer 1999-03, Vol.79 (7), p.1098-1103
• Main Authors: Simpson, B J B, Bartlett, J M S, Macleod, K G, Rabiasz, G, Miller, E P, Rae, A L, Gordge, P, Leake, R E, Miller, W R, Smyth, J, Langdon, S P
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Division - drug effects; Drug Resistance; Enzyme Inhibitors - pharmacology; Epidemiology; Female; General aspects; Humans; Medical sciences; Molecular Medicine; Oncology; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Pharmacology. Drug treatments; Phosphorylation - drug effects; Proto-Oncogene Proteins - drug effects; Proto-Oncogene Proteins - metabolism; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - drug effects; Receptor, Epidermal Growth Factor - metabolism; Receptor, ErbB-2 - drug effects; Receptor, ErbB-2 - metabolism; Receptor, ErbB-3; Regular; regular-article; Signal Transduction; Transforming Growth Factor alpha - antagonists & inhibitors; Transforming Growth Factor alpha - pharmacology; Tumor Cells, Cultured - drug effects
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6690175

Summary The modulating effects of the epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor ZM 252868 on cell growth and signalling have been evaluated in four ovarian carcinoma cell lines PE01, PE04, SKOV-3 and PE01 CDDP . Transforming growth factor α (TGF-α)-stimulated growth was completely inhibited by concentrations ≥ 0.3 μ M in the PE01 and PE04 cell lines and by ≥ 0.1 μ M in SKOV-3 cells. TGF-α inhibition of PE01 CDDP growth was reversed by concentrations ≥ 0.1 μ M ZM 252868. TGF-α-stimulated tyrosine phosphorylation of both the EGF receptor and c-erbB2 receptor in all four cell lines. The inhibitor ZM 252868, at concentrations ≥ 0.3 μ M , completely inhibited TGF-α-stimulated tyrosine phosphorylation of the EGF receptor and reduced phosphorylation of the c-erbB2 protein. EGF-activated EGF receptor tyrosine kinase activity was completely inhibited by 3 μ M ZM 252868 in PE01, SKOV-3 and PE01 CDDP cells. These data indicate that the EGF receptor-targeted TK inhibitor ZM 252868 can inhibit growth of ovarian carcinoma cells in vitro consistent with inhibition of tyrosine phosphorylation at the EGF receptor.