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• W2071417433 abstract "No AccessJournal of UrologyInvestigative Urology1 Mar 2015Dutasteride and Enzalutamide Synergistically Suppress Prostate Tumor Cell Proliferation Agus Rizal A.H. Hamid, Gerald W. Verhaegh, Frank P. Smit, Cindy van Rijt-van de Westerlo, Inna Armandari, Andre Brandt, Fred C.G.J. Sweep, John P.M. Sedelaar, and Jack A. Schalken Agus Rizal A.H. HamidAgus Rizal A.H. Hamid Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands Department of Urology, Ciptomangunkusumo Hospital, Faculty of Medicine, University of Indonesia, Indonesia More articles by this author , Gerald W. VerhaeghGerald W. Verhaegh Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands More articles by this author , Frank P. SmitFrank P. Smit NovioGendix, Nijmegen, The Netherlands Financial interest and/or other relationship with Novogendix. More articles by this author , Cindy van Rijt-van de WesterloCindy van Rijt-van de Westerlo Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands More articles by this author , Inna ArmandariInna Armandari Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands More articles by this author , Andre BrandtAndre Brandt Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands More articles by this author , Fred C.G.J. SweepFred C.G.J. Sweep Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands More articles by this author , John P.M. SedelaarJohn P.M. Sedelaar Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands More articles by this author , and Jack A. SchalkenJack A. Schalken Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.09.021AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Dihydrotestosterone is the main active androgen in the prostate and it has a role in prostate cancer progression. After androgen deprivation therapy androgen receptor signaling is still active in tumor cells. Persistent intratumor steroidogenesis and androgen receptor changes are responsible for this continued activity, which influences the efficacy of prostate cancer treatment. We hypothesized that combining a 5α-reductase inhibitor and an antiandrogen would block intratumor androgen synthesis and androgen receptor protein activity. Thus, it would act synergistically to reduce tumor cell proliferation. Materials and Methods: The expression level of 5α-reductase and androgen receptor in endocrine therapy naïve prostate cancer and castration resistant prostate cancer tissues, and cell line models was determined by microarray and quantitative polymerase chain reaction analysis. Intracellular androgen was measured with radioimmunoassay. Tumor cell proliferation was determined using coloric MTT assay. The synergistic effects of combination treatments on tumor cell proliferation were calculated using the Chou-Talalay equation. Results: In all prostate cancer cases 5α-reductase-1 and 3 were up-regulated. Androgen receptor was up-regulated in metastatic prostate cancer and castration resistant prostate cancer cases. The 5α-reductase inhibitor dutasteride effectively decreased dihydrotestosterone production in prostate cancer and castration resistant prostate cancer cell lines. Furthermore, dutasteride combined with the novel antiandrogen enzalutamide synergistically suppressed endocrine therapy naïve prostate cancer and castration resistant prostate cancer cell proliferation. Conclusions: In this study the combination of a 5α-reductase inhibitor and (novel) antiandrogens synergistically inhibited tumor cell proliferation. These findings support clinical studies of combinations of a 5α-reductase inhibitor and (novel) antiandrogens as first line treatment of prostate cancer and castration resistant prostate cancer. References 1 : Androgen biosynthetic pathways in the human prostate. Best Pract Res Clin Endocrinol Metab2008; 22: 207. Google Scholar 2 : Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol Ther2013; 140: 223. 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Google Scholar 21 : Prostate cancer cells differ in testosterone accumulation, dihydrotestosterone conversion, and androgen receptor signaling response to steroid 5alpha-reductase inhibitors. Prostate2013; 73: 1470. Google Scholar 22 : Pharmacologic basis for the enhanced efficacy of dutasteride against prostatic cancers. Clin Cancer Res2006; 12: 4072. Google Scholar 23 : The effects of the dual 5alpha-reductase inhibitor dutasteride on localized prostate cancer—results from a 4-month pre-radical prostatectomy study. Prostate2006; 66: 1674. Google Scholar 24 : Dutasteride treatment over 2 years delays prostate-specific antigen progression in patients with biochemical failure after radical therapy for prostate cancer: results from the randomised, placebo-controlled Avodart After Radical Therapy for Prostate Cancer Study (ARTS). Eur Urol2013; 63: 779. Google Scholar 25 : Phase II study of Dutasteride for recurrent prostate cancer during androgen deprivation therapy. J Urol2009; 181: 621. Link, Google Scholar 26 : Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res2010; 70: 440. Google Scholar 27 : In vivo-in vitro tumour cell lines: characteristics and limitations as models for human cancer. Br J Cancer1980; 4: 118. Google Scholar 28 : 5alpha-reductase type 3 enzyme in benign and malignant prostate. Prostate2014; 74: 235. Google Scholar © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited ByAtala A (2018) Re: Rb1 and Trp53 Cooperate to Suppress Prostate Cancer Lineage Plasticity, Metastasis, and Antiandrogen ResistanceJournal of Urology, VOL. 198, NO. 1, (102-104), Online publication date: 1-Jul-2017.Atala A (2018) Re: PLCε Knockdown Inhibits Prostate Cancer Cell Proliferation via Suppression of Notch Signalling and Nuclear Translocation of the Androgen ReceptorJournal of Urology, VOL. 195, NO. 2, (524-525), Online publication date: 1-Feb-2016.Andersson K (2018) This Month in Investigative UrologyJournal of Urology, VOL. 193, NO. 3, (751-752), Online publication date: 1-Mar-2015. Volume 193Issue 3March 2015Page: 1023-1029Supplementary Materials Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.Keywordsantineoplastic combined chemotherapy protocolsprostatic neoplasmscastration-resistantprostatic neoplasmsMDV 3100dutasterideAcknowledgmentsMaureen Völler, Cornelius F. Jansen, Tilly W. Aalders and Aleksandra M. Dudek provided laboratory support.MetricsAuthor Information Agus Rizal A.H. Hamid Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands Department of Urology, Ciptomangunkusumo Hospital, Faculty of Medicine, University of Indonesia, Indonesia More articles by this author Gerald W. Verhaegh Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands More articles by this author Frank P. Smit NovioGendix, Nijmegen, The Netherlands Financial interest and/or other relationship with Novogendix. More articles by this author Cindy van Rijt-van de Westerlo Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands More articles by this author Inna Armandari Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands More articles by this author Andre Brandt Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands More articles by this author Fred C.G.J. Sweep Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands More articles by this author John P.M. Sedelaar Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands More articles by this author Jack A. Schalken Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands More articles by this author Expand All Advertisement PDF DownloadLoading ..." @default.
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