Gefitinib ('Iressa', ZD1839) inhibits the growth response of bladder tumour cell lines to epidermal growth factor and induces TIMP2.
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.
Nutt
J E
JE
Northern Institute for Cancer Research, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. J.E.Nutt@ncl.ac.uk
Lazarowicz
H P
HP
Mellon
J K
JK
Lunec
J
J
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*
D000970:Antineoplastic Agents; D011480:Protease Inhibitors; D011799:Quinazolines; D019716:Tissue Inhibitor of Metalloproteinase-2; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000077156:Gefitinib