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• W2316574798 abstract "You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) I1 Apr 2016PD28-11 NOVEL DRUGS FOR TARGETING HISTONE DEACETYLASE INHIBITOR TO CELLS CONTAINING ANDROGEN RECEPTORS: ANALYSIS OF IN VIVO EFFECTIVENESS AGAINST HUMAN PROSTATE CANCER. Carrie Sun, Rebecca Arnold, David Gaul, Subhasish Tapadar, Berkley Gryder, Adegboyega Oyelere, and John Petros Carrie SunCarrie Sun More articles by this author , Rebecca ArnoldRebecca Arnold More articles by this author , David GaulDavid Gaul More articles by this author , Subhasish TapadarSubhasish Tapadar More articles by this author , Berkley GryderBerkley Gryder More articles by this author , Adegboyega OyelereAdegboyega Oyelere More articles by this author , and John PetrosJohn Petros More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.398AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES There are no highly effective chemotherapeutic agents for castration resistant prostate cancer, however these cancers typically have upregulated and overexpressed androgen receptor (AR). Histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs that are limited in effectiveness due to inefficient delivery to the tumors. We have therefore synthesized a series of novel bifunctional drugs that combine an androgen moiety and an HDACi. The objective of this study was to test the effectiveness of these new drugs in an in vivo model of human prostate cancer and compare to HDACi and antiandrogens alone. METHODS Athymic mice were injected subcutaneously with approximately 1 million LNCaP or LNCaP AR (LNCaP cells transfected with the androgen receptor to be high AR expressers). Mice were monitored until tumor formation was evident. The mice were divided into cohorts with equal average tumor volume and compounds and SAHA control administered using IP while enzalutamide was administered via oral gavage. Tumor volume was measured several times a week. For the androgen sensitive LNCaP cell line, all compounds were compared to the HDACi suberoylanilide hydroxamic acid (SAHA), enzalutamide and the combination of SAHA and enzalutamide. Four separate compounds differing in the linker length separating the AR-binding hydanthoin and HDAC inhibiting hydroxamate moieties, designated 17, 19, 22 and 28, were investigated. RESULTS Of the 4 compounds tested, there was minimal toxicity observed at the doses given. When tested against established LNCaP xenograft tumors at the 10 mg/kg dose, the most effective treatment was SAHA/enzalutamide. Next most effective (and similar in their effect) were enzalutamide alone, and compounds 19, 22 and 28 alone. Less effective but still different than vehicle control were SAHA alone and compound 17 alone. A subsequent study examining compounds 17, 19 and 22 at different doses demonstrated that even at a dose of 20 mg/kg compound 17 remained relatively less effective whereas compounds 19 and 22 remained relatively more effective even at the reduced dose of 5 mg/kg. When these compounds were tested at 10 mg/kg in established xenografts made from LNCaP AR cells that overexpressed the androgen receptor, they all showed similar effectiveness that was statistically significantly different from no treatment controls and indistinguishable from enzalutamide or the combination of SAHA and enzalutamide. CONCLUSIONS Our novel combination drugs are non-toxic to mice and are effective anti-cancer agents. SAHA was less effective in LNCaP model while significant differences in effectiveness were observed based on chemical structure for the antiandrogen-HDACi agents. Differences were less in cells that were engineered to overexpress the androgen receptor, a clinically relevant condition in prostate cancer. These data are the basis for continued evaluation of AR targeted HDACi therapy in prostate cancer. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e658 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Carrie Sun More articles by this author Rebecca Arnold More articles by this author David Gaul More articles by this author Subhasish Tapadar More articles by this author Berkley Gryder More articles by this author Adegboyega Oyelere More articles by this author John Petros More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ..." @default.
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• W2316574798 title "PD28-11 NOVEL DRUGS FOR TARGETING HISTONE DEACETYLASE INHIBITOR TO CELLS CONTAINING ANDROGEN RECEPTORS: ANALYSIS OF IN VIVO EFFECTIVENESS AGAINST HUMAN PROSTATE CANCER." @default.
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