title: Gefitinib ('Iressa', ZD1839) inhibits the growth response of bladder tumour cell lines to epidermal growth factor and induces TIMP2.
abstract: The effect of EGF stimulation and its inhibition with gefitinib ('Iressa', ZD1839), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been investigated in two EGFR-positive human bladder tumour cell lines, RT112 and RT4. The growth of RT112 cells in a medium containing 10% foetal bovine serum was inhibited by 50% with 10 microM gefitinib, whereas this dose completely inhibited RT4 cell growth. Cells were more sensitive to growth inhibition in the serum-free medium. Increased growth of cells in the serum-free medium was observed with 10 or 50 ng x ml(-1) EGF and the proliferative effect of EGF stimulation in both cell lines was inhibited in the presence of 1 microM, but not 0.1 microM gefitinib. Zymography of the conditioned medium from RT112 cells treated with EGF and gefitinib showed a decrease in matrix metalloproteinase 2 (MMP2) concentrations. Western blot analysis showed that tissue inhibitor of metalloproteinase 1(TIMP1) increased in the conditioned medium from RT112 cells treated with EGF, and this was partially inhibited with both 1 and 5 microM gefitinib. Conversely, TIMP2 decreased with EGF stimulation and this was reversed with gefitinib. Tissue inhibitor of metalloproteinase 1 had no effect on the growth of either cell line. These studies show alterations in the balance of MMPs and their inhibitors in EGF-stimulated bladder tumour cells, which are reversed by gefitinib, suggesting gefitinib should be investigated for its effect on human bladder tumours.
authors.affiliation: Northern Institute for Cancer Research, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. J.E.Nutt@ncl.ac.uk
authors.forename: J E
authors.initials: JE
authors.lastname: Nutt
authors.forename: H P
authors.initials: HP
authors.lastname: Lazarowicz
authors.forename: J K
authors.initials: JK
authors.lastname: Mellon
authors.forename: J
authors.initials: J
authors.lastname: Lunec
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects* / Q000502:physiology*; D000077156:Gefitinib; D006801:Humans; D011480:Protease Inhibitors / Q000032:analysis*; D011799:Quinazolines / Q000494:pharmacology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D011799:Quinazolines; D019716:Tissue Inhibitor of Metalloproteinase-2; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000077156:Gefitinib