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  • 1
    Language: English
    In: Investigational New Drugs, 2013, Vol.31(2), pp.265-272
    Description: Pharmacologic options for patients with castration-resistant prostate cancer are limited. It has been suggested that targeting intracellular molecules, which have been altered during neoplastic development, may slow tumor growth. Therefore, the growth-blocking potential of the histone deacetylase-inhibitor LBH589 and the multiple tyrosine kinase-inhibitor TKI258, applied alone or in combination, was investigated in a panel of prostate cancer cell lines. PC-3, DU-145 or LNCaP cells were treated with various concentrations of LBH589 and/or TKI258. Tumor cell growth, cell cycle regulating proteins, HDAC3- and HDAC4-expression and histone H3 and H4 acetylation were then evaluated by MTT assay and Western blotting. LBH589 dose-dependently blocked prostate cancer cell growth. In contrast, TKI258 did not down-regulate tumor cell growth up to a 1,000 nM dosage. LBH589 elevated histone H3 and H4 acetylation. The cell cycle regulators cyclin B, cyclin D1, cdk1 and cdk4 were down-regulated in PC-3, whereas the suppressor proteins p21 and p27 were up-regulated in LNCaP by LBH589. TKI258 up-regulated p27 in PC-3 or p21 in LNCaP and additionally elevated cyclin B, cyclin D1, cdk1 and cdk4 in both cell lines. Presumably, the increase in cyclin and cdk caused by TKI258 counteracts the benefit of p21 or p27 up-regulation, resulting in TKI258 non-responsiveness. The LBH589/TKI258-combination was not superior to the LBH589 single-drug use in terms of growth reduction. Obviously, TKI258 did not enhance the sensitivity of prostate cancer cells towards an HDAC based regimen. Therefore, the LBH589/TKI258-combination probably does not provide an optimum strategy in fighting advanced prostate cancer.
    Keywords: Prostate cancer ; LBH589 ; TKI258 ; Molecular therapy ; Tumor growth
    ISSN: 0167-6997
    E-ISSN: 1573-0646
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  • 2
    Language: English
    In: World Journal of Urology, 2015, Vol.33(11), pp.1753-1761
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s00345-015-1502-y Byline: Vladimir Novotny (1), Michael Froehner (1), Matthias May (2), Chris Protzel (3), Katrin Hergenrother (3), Michael Rink (4), Felix K. Chun (4), Margit Fisch (4), Florian Roghmann (5), Rein-Juri Palisaar (5), Joachim Noldus (5), Michael Gierth (6), Hans-Martin Fritsche (6), Maximilian Burger (6), Danijel Sikic (7), Bastian Keck (7), Bernd Wullich (7), Philipp Nuhn (8), Alexander Buchner (8), Christian G. Stief (8), Stefan Vallo (9), Georg Bartsch (9), Axel Haferkamp (9), Patrick J. Bastian (10), Oliver W. Hakenberg (3), Stefan Propping (1), Atiqullah Aziz (4) Keywords: Bladder cancer; Radical cystectomy; Recurrence; Outcome Abstract: Purpose To externally validate the Christodouleas risk model incorporating pathological tumor stage, lymph node (LN) count and soft tissue surgical margin (STSM) and stratifying patients who develop locoregional recurrence (LR) after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). In addition, we aimed to generate a new model including established clinicopathological features that were absent in the Christodouleas risk model. Methods Prospectively assessed multicenter data from 565 patients undergoing RC for UCB in 2011 qualified for final analysis. For the purpose of external validation, risk group stratification according to Christodouleas was performed. Competing-risk models were calculated to compare the cumulative incidences of LR after RC. Results After a median follow-up of 25 months (interquartile range 19--29), the LR-rate was 11.5 %. The Christodouleas model showed a predictive accuracy of 83.2 % in our cohort. In multivariable competing-risk analysis, tumor stage a[yen]pT3 (HR 4.32, p 〈 0.001), positive STSM (HR 2.93, p = 0.005), lymphovascular invasion (HR 3.41, p 〈 0.001), the number of removed LNs 〈10 (HR 2.62, p 〈 0.001) and the administration of adjuvant chemotherapy (HR 0.40, p = 0.008) independently predicted the LR-rate. The resulting risk groups revealed significant differences in LR-rates after 24 months with 4.8 % for low-risk patients, 14.7 % for intermediate-risk patients and 38.9 % for high-risk patients (p 〈 0.001 for all), with a predictive accuracy of 85.6 %, respectively. Conclusions The Christodouleas risk model has been successfully externally validated in the present prospective series. However, this analysis finds that overall model performance may be improved by incorporating lymphovascular invasion. After external validation of the newly proposed risk model, it may be used to identify patients who benefit from an adjuvant therapy and suit for inclusion in clinical trials. Author Affiliation: (1) Department of Urology, University Hospital "Carl Gustav Carus", Dresden, Germany (2) Department of Urology, St. Elisabeth Hospital, Straubing, Germany (3) Department of Urology, University Medical Center Rostock, Rostock, Germany (4) Department of Urology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany (5) Department of Urology, Marienhospital Herne, Ruhr-University Bochum, Herne, Germany (6) Department of Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany (7) Department of Urology, University Hospital Erlangen, Erlangen, Germany (8) Department of Urology, Ludwig-Maximilians-University Munich, Munich, Germany (9) Department of Urology, Goethe-University Frankfurt, Frankfurt am Main, Germany (10) Department of Urology, Paracelsus Medical Center Golzheim, Dusseldorf, Germany Article History: Registration Date: 27/01/2015 Received Date: 02/12/2014 Accepted Date: 25/01/2015 Online Date: 08/02/2015
    Keywords: Bladder cancer ; Radical cystectomy ; Recurrence ; Outcome
    ISSN: 0724-4983
    E-ISSN: 1433-8726
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