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• W2045694562 abstract "No AccessJournal of UrologyInvestigative urology1 Aug 2006Schedule Dependent Efficacy of Gefitinib and Docetaxel for Bladder Canceris companion ofRandomized Prospective Phase III Trial of Difluoromethylornithine vs Placebo in Preventing Recurrence of Completely Resected Low Risk Superficial Bladder Cancer Wassim Kassouf, Tony Luongo, Gordon Brown, Liana Adam, and Colin P.N. Dinney Wassim KassoufWassim Kassouf More articles by this author , Tony LuongoTony Luongo More articles by this author , Gordon BrownGordon Brown More articles by this author , Liana AdamLiana Adam More articles by this author , and Colin P.N. DinneyColin P.N. Dinney Financial interest and/or other relationship with AstraZeneca, GlaxoSmithKline, National Cancer Institute, Canji/Schering-Plough and Abbott/Vysis. More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2006.03.072AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We determined the sequence specific efficacy of gefitinib and docetaxel treatment for bladder cancer. This combination was selected because it is currently under study in a phase II clinical trial. Materials and Methods: In vitro antiproliferative effects of gefitinib, docetaxel and a combination were determined in the 4 bladder cancer cell lines 253J B-V, UM-UC-3, KU-7 and UM-UC-13 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle analysis was analyzed using flow cytometry and propidium iodide labeling. Epidermal growth factor receptor downstream signaling was assessed by Western blot analysis. In vivo nude mice were injected subcutaneously with 253J B-V cells and treated with placebo, gefitinib, docetaxel, docetaxel followed by gefitinib or gefitinib followed by docetaxel. Tumor kinetics were established. Results: Gefitinib demonstrated antiproliferative effect against 253J B-V cells (50% inhibitory concentration less than 0.5 μM) but no apoptotic effect in vitro, whereas docetaxel demonstrated antiproliferative and apoptotic effects. When gefitinib and docetaxel were combined, gefitinib enhanced the apoptotic and antiproliferative effects of docetaxel only when gefitinib was administered following docetaxel pretreatment. Apoptosis increased from 45% to 66%. In vivo there were significant differences in tumor weight in mice treated with combination therapy vs gefitinib or docetaxel alone. Importantly improved efficacy was observed when docetaxel was followed by gefitinib administration compared with gefitinib followed by docetaxel (mean tumor weight 42 vs 93 mg, p = 0.022). Sequence specific efficacy was not observed in UM-UC-3, UM-UC-13 and KU-7 cells, which are resistant to gefitinib. Conclusions: Docetaxel followed by gefitinib demonstrated sequence specific efficacy against gefitinib sensitive bladder cancer compared with gefitinib followed by docetaxel or either drug alone. Accordingly gefitinib administration concurrently or after chemotherapy might be the sequence of choice and it should be considered for future clinical trials. References 1 : Cancer statistics, 2005. CA Cancer J Clin2005; 55: 10. Google Scholar 2 : A phase II study of gemcitabine and docetaxel therapy in patients with advanced urothelial carcinoma. Cancer2003; 98: 1863. Google Scholar 3 : Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma. J Clin Oncol1998; 16: 1844. Google Scholar 4 : Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol1995; 19: 183. 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Google Scholar 16 : Cytotoxic synergy between flavopiridol (NSC 649890, L86-8275) and various antineoplastic agents: the importance of sequence of administration. Cancer Res1997; 57: 3375. Google Scholar 17 : Involvement of p27KIP1 in G1 arrest mediated by an anti-epidermal growth factor receptor monoclonal antibody. Oncogene1996; 12: 1397. Google Scholar 18 : The effect of gefitinib (Iressa, ZD1839) in combination with oxaliplatin is schedule-dependent in colon cancer cell lines. Cancer Chemother Pharmacol2003; 52: 442. Google Scholar 19 : Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res1999; 5: 257. Google Scholar 20 : Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targets2003; 3: 193. Google Scholar Department of Urology, University of Texas M. D. Anderson Cancer Center, Houston, Texas© 2006 by American Urological AssociationFiguresReferencesRelatedDetailsRelated articlesJournal of Urology9 Nov 2018Randomized Prospective Phase III Trial of Difluoromethylornithine vs Placebo in Preventing Recurrence of Completely Resected Low Risk Superficial Bladder Cancer Volume 176Issue 2August 2006Page: 787-792 Advertisement Copyright & Permissions© 2006 by American Urological AssociationKeywordsdocetaxelbladdergefitinibmicebladder neoplasmsAcknowledgmentsCell lines in the UM-UC series, 253J B-V and KU-7 were provided by the GU SPORE Specimens Core. Gefitinib was provided by AstraZeneca, London, United Kingdom.MetricsAuthor Information Wassim Kassouf More articles by this author Tony Luongo More articles by this author Gordon Brown More articles by this author Liana Adam More articles by this author Colin P.N. Dinney Financial interest and/or other relationship with AstraZeneca, GlaxoSmithKline, National Cancer Institute, Canji/Schering-Plough and Abbott/Vysis. More articles by this author Expand All Advertisement PDF downloadLoading ..." @default.
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