Targeting the EGF receptor in ovarian cancer with the tyrosine kinase inhibitor ZD 1839 ("Iressa").
The modulating effects of the orally active epidermal growth factor receptor-specific tyrosine kinase inhibitor ZD 1839 ("Iressa") on cell growth and signalling were evaluated in four ovarian cancer cell lines (PE01, PE04, SKOV-3, OVCAR-5) that express the epidermal growth factor receptor, and in A2780, which is epidermal growth factor receptor-negative. Transforming growth factor-alpha stimulated growth was completely inhibited by concentrations of ZD 1839 > or =0.3 microM in the epidermal growth factor receptor-expressing cell lines, as were transforming growth factor-alpha stimulated phosphorylation of the epidermal growth factor receptor and downstream components of the MAP kinase and PI-3 kinase signalling cascades. Growth inhibition in the absence of added transforming growth factor-alpha was also observed which could be consistent with suppression of action of autocrine epidermal growth factor receptor-activating ligands by ZD 1839. In support of this, transforming growth factor-alpha, EGF and amphiregulin mRNAs were detected by RT-PCR in the epidermal growth factor receptor-expressing cell lines. ZD 1839 inhibited growth of the PE04 ovarian cancer xenograft at 200 mg kg(-1)day(-1). These data lend further support to the view that targeting the epidermal growth factor receptor in ovarian cancer could have therapeutic benefit.
Sewell
J M
JM
Imperial Cancer Research Fund Medical Oncology Unit, Western General Hospital, Edinburgh EH4 2XU, Scotland, UK.
Macleod
K G
KG
Ritchie
A
A
Smyth
J F
JF
Langdon
S P
SP
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D011799:Quinazolines; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib