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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, METHODS, RESULTS. Meshes: Animals, Apoptosis, Benzimidazoles, Blotting, Western, Carcinoma, Transitional Cell, Cell Cycle, Cell Proliferation, Cells, Cultured, Humans, Immunoenzyme Techniques, In Vitro Techniques, Male, Mice, Mice, Inbred BALB C, Mutation, Phosphorylation, Protein-Tyrosine Kinases, Pyrimidines, Pyrroles, Quinolones, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 3, Urinary Bladder Neoplasms, Urothelium, Xenograft Model Antitumor Assays.
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Do small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo? Context: Activating mutations of FGFR3 are frequently identified in superficial urothelial carcinoma (UC) and increased expression of FGFR1 and FGFR3 are common in both superficial and invasive UC. The effects of inhibition of receptor activity by three small molecule inhibitors (PD173074, TKI-258 and SU5402) were investigated in a panel of bladder tumour cell lines with known FGFR expression levels and FGFR3 mutation status. All inhibitors prevented activation of FGFR3, and inhibited downstream MAPK pathway signalling. Response was related to FGFR3 and/or FGFR1 expression levels. Cell lines with the highest levels of FGFR expression showed the greatest response and little or no effect was measured in normal human urothelial cells or in UC cell lines with activating RAS gene mutations. In sensitive cell lines, the drugs induced cell cycle arrest and/or apoptosis. IC(50) values for PD173074 and TKI-258 were in the nanomolar concentration range compared with micromolar concentrations for SU5402. PD173074 showed the greatest effects in vitro and in vivo significantly delayed the growth of subcutaneous bladder tumour xenografts.
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These results indicate that inhibition of FGFR1 and wild-type or mutant FGFR3 may represent a useful therapeutic approach in patients with both non-muscle invasive and muscle invasive UC. Final Decision: yes